User login
Atypical case of cutaneous MCL mimics SPTCL
An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.
This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.
“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.
The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.
Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.
Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.
Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.
Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.
Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.
Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”
Subsequent treatment was unsuccessful, and the patient died from his disease.
“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.
The investigators did not report conflicts of interest.
SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.
An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.
This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.
“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.
The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.
Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.
Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.
Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.
Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.
Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.
Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”
Subsequent treatment was unsuccessful, and the patient died from his disease.
“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.
The investigators did not report conflicts of interest.
SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.
An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.
This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.
“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.
The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.
Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.
Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.
Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.
Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.
Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.
Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”
Subsequent treatment was unsuccessful, and the patient died from his disease.
“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.
The investigators did not report conflicts of interest.
SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.
FROM JOURNAL OF CUTANEOUS PATHOLOGY
ctDNA predicts recurrence in nonmetastatic colorectal cancer
Circulating tumor DNA (ctDNA) could be used to predict disease recurrence in patients with nonmetastatic colorectal cancer (CRC), according to investigators following an observational study.
About three out of four patients with a positive ctDNA test went on to have disease recurrence, reported lead author Yuxuan Wang, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and her colleagues. On average, positive tests preceded clinical and radiologic evidence of recurrence by 3 months.
“[T]he optimal protocol for surveillance of resected colorectal cancer remains uncertain,” the investigators wrote in JAMA Oncology.
“The only recommended blood marker for CRC surveillance is serum [carcinoembryonic antigen (CEA)], an oncofetal protein that is elevated in the serum of patients with a variety of disease conditions, including CRC. Unfortunately, its utility is limited by the lack of sensitivity and specificity.” Although computed tomography and magnetic resonance imaging can improve disease detection, these techniques also have their own shortcomings, the investigators noted, setting the stage for the present study.
The investigators recruited 63 patients with stage I, II, or III CRC who underwent surgical resection in Sweden between 2007 and 2013. Blood samples for ctDNA testing were collected 1 month after surgery, then every 3-6 months. CT was performed every 6-12 months. During this process, 5 patients were excluded, leaving 58 patients in the final dataset, 18 (31%) of whom received adjuvant chemotherapy. Patients were followed until metastasis or a median of 49 months.
Among all patients, 13 tested positive for ctDNA, and 10 of these relapsed (77%), with a median time of 3 months between ctDNA positivity and CT or clinical evidence of recurrence. Three of the 48 patients (6%) who did not relapse had a positive ctDNA result that later dropped to an undetectable level. Of the 45 patients who tested negative for ctDNA, none had recurrence, although 1 was positive for CEA.
Results were also divided into patients who received or did not receive adjuvant chemotherapy. Among the 40 patients who did not receive chemotherapy, 8 had disease recurrence after a positive ctDNA test, although only 5 tested positive for CEA. Among the 18 patients who did receive chemotherapy, 2 tested positive for ctDNA and later relapsed, although only 1 tested positive for CEA. These figures translated to a ctDNA sensitivity for recurrence of 100%, compared with 60% for CEA testing.
“Serial ctDNA levels during follow-up can precede disease recurrence prior to routine radiographic imaging,” the investigators concluded. “Because ctDNA measurements can be obtained from blood samples collected during routine follow-up, they may be easily incorporated into routine follow-up to complement a CEA test, radiographic imaging, and other conventional modalities to help stratify patients on the basis of the risk of disease recurrence. Such a personalized surveillance strategy may allow for earlier detection of relapse and minimize unnecessary testing.”
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, the John Templeton Foundation, and others. The investigators reported financial relationships with PapGene, Sysmex, Eisai, and others.
SOURCE: Wang et al. JAMA Onc. 2019 May 9. doi: 10.1001/jamaoncol.2019.0512.
Based on recent findings of a study conducted by Wang et al. and an increasing amount of research, circulating tumor DNA (ctDNA) testing “will likely revolutionize” postoperative management for patients with early-stage colorectal cancer (CRC), according to Van Morris, MD; Arvind Dasari, MD; and Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The ability to optimize adjuvant chemotherapy recommendations for patients with resected CRC has been historically limited by the use of clinicopathologic characteristics, which imperfectly prognosticate the risk for recurrence,” the doctors wrote in a JAMA Oncology editorial accompanying the article by Wang et al.
In the study by Dr. Wang and associates, “clinical recurrence was strongly linked with ctDNA detection at the time of recurrence,” the doctors wrote, adding that “the absence of ctDNA was highly associated with excellent oncologic outcomes.” These associations translated to predictive advantages, as “[ctDNA] status outperformed traditional risk factors, including the pathological stage, in stratifying patients’ risk for recurrence.”
“With the implications of ctDNA status for recurrence risk, the question remains regarding how this exciting technology can be used to improve the standard practices for CRC,” the authors of the editorial wrote, noting that the National Comprehensive Cancer Network currently recommends monitoring with imaging studies, carcinoembryonic antigen (CEA) tests, and endoscopies. “ctDNA positivity may eventually serve as a biomarker for high-risk patients for whom a more aggressive systemic treatment against residual micrometastatic disease may be advantageous,” they wrote.
They also highlighted how, in the Wang et al. study, chemotherapy was associated with conversion from ctDNA positivity to negativity in one patient, a phenomenon that has been observed in other trials. “Interpretation of these data is limited by a small sample size of patients,” the doctors wrote, “but these findings nonetheless begin to provide important insight into the ability of chemotherapy to clear minimal residual disease, as tracked by serial changes in ctDNA status over time, which is associated with favorable prognostic implications for patients with early-stage CRC. Future trials in CRC and other solid cancers should assess ctDNA clearance more robustly as a surrogate marker for disease-free survival in patients undergoing definitive therapies for their solid tumors.”
“At present, payers in the United States have not yet approved the routine use of ctDNA technologies in patients with early-stage CRC after resection,” the doctors wrote. “However, compelling data on ctDNA as a robust prognostic marker should be a reason to reassess coverage.”
“[With payer support and improved techniques], then this exciting ctDNA technology will likely revolutionize the routine postoperative management of early-stage CRC by providing a reliable, objective tool for oncologists,” they concluded.
Dr. Morris, Dr. Dasari, and Dr. Kopetz are affiliated with the University of Texas MD Anderson Cancer Center in Houston. Dr. Morris reported financial relationships with GuardantHealth and Array Biopharma. Dr. Kopetz reported relationships with Symphogen, Amgen, Merck, and Holy Stone.
Based on recent findings of a study conducted by Wang et al. and an increasing amount of research, circulating tumor DNA (ctDNA) testing “will likely revolutionize” postoperative management for patients with early-stage colorectal cancer (CRC), according to Van Morris, MD; Arvind Dasari, MD; and Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The ability to optimize adjuvant chemotherapy recommendations for patients with resected CRC has been historically limited by the use of clinicopathologic characteristics, which imperfectly prognosticate the risk for recurrence,” the doctors wrote in a JAMA Oncology editorial accompanying the article by Wang et al.
In the study by Dr. Wang and associates, “clinical recurrence was strongly linked with ctDNA detection at the time of recurrence,” the doctors wrote, adding that “the absence of ctDNA was highly associated with excellent oncologic outcomes.” These associations translated to predictive advantages, as “[ctDNA] status outperformed traditional risk factors, including the pathological stage, in stratifying patients’ risk for recurrence.”
“With the implications of ctDNA status for recurrence risk, the question remains regarding how this exciting technology can be used to improve the standard practices for CRC,” the authors of the editorial wrote, noting that the National Comprehensive Cancer Network currently recommends monitoring with imaging studies, carcinoembryonic antigen (CEA) tests, and endoscopies. “ctDNA positivity may eventually serve as a biomarker for high-risk patients for whom a more aggressive systemic treatment against residual micrometastatic disease may be advantageous,” they wrote.
They also highlighted how, in the Wang et al. study, chemotherapy was associated with conversion from ctDNA positivity to negativity in one patient, a phenomenon that has been observed in other trials. “Interpretation of these data is limited by a small sample size of patients,” the doctors wrote, “but these findings nonetheless begin to provide important insight into the ability of chemotherapy to clear minimal residual disease, as tracked by serial changes in ctDNA status over time, which is associated with favorable prognostic implications for patients with early-stage CRC. Future trials in CRC and other solid cancers should assess ctDNA clearance more robustly as a surrogate marker for disease-free survival in patients undergoing definitive therapies for their solid tumors.”
“At present, payers in the United States have not yet approved the routine use of ctDNA technologies in patients with early-stage CRC after resection,” the doctors wrote. “However, compelling data on ctDNA as a robust prognostic marker should be a reason to reassess coverage.”
“[With payer support and improved techniques], then this exciting ctDNA technology will likely revolutionize the routine postoperative management of early-stage CRC by providing a reliable, objective tool for oncologists,” they concluded.
Dr. Morris, Dr. Dasari, and Dr. Kopetz are affiliated with the University of Texas MD Anderson Cancer Center in Houston. Dr. Morris reported financial relationships with GuardantHealth and Array Biopharma. Dr. Kopetz reported relationships with Symphogen, Amgen, Merck, and Holy Stone.
Based on recent findings of a study conducted by Wang et al. and an increasing amount of research, circulating tumor DNA (ctDNA) testing “will likely revolutionize” postoperative management for patients with early-stage colorectal cancer (CRC), according to Van Morris, MD; Arvind Dasari, MD; and Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The ability to optimize adjuvant chemotherapy recommendations for patients with resected CRC has been historically limited by the use of clinicopathologic characteristics, which imperfectly prognosticate the risk for recurrence,” the doctors wrote in a JAMA Oncology editorial accompanying the article by Wang et al.
In the study by Dr. Wang and associates, “clinical recurrence was strongly linked with ctDNA detection at the time of recurrence,” the doctors wrote, adding that “the absence of ctDNA was highly associated with excellent oncologic outcomes.” These associations translated to predictive advantages, as “[ctDNA] status outperformed traditional risk factors, including the pathological stage, in stratifying patients’ risk for recurrence.”
“With the implications of ctDNA status for recurrence risk, the question remains regarding how this exciting technology can be used to improve the standard practices for CRC,” the authors of the editorial wrote, noting that the National Comprehensive Cancer Network currently recommends monitoring with imaging studies, carcinoembryonic antigen (CEA) tests, and endoscopies. “ctDNA positivity may eventually serve as a biomarker for high-risk patients for whom a more aggressive systemic treatment against residual micrometastatic disease may be advantageous,” they wrote.
They also highlighted how, in the Wang et al. study, chemotherapy was associated with conversion from ctDNA positivity to negativity in one patient, a phenomenon that has been observed in other trials. “Interpretation of these data is limited by a small sample size of patients,” the doctors wrote, “but these findings nonetheless begin to provide important insight into the ability of chemotherapy to clear minimal residual disease, as tracked by serial changes in ctDNA status over time, which is associated with favorable prognostic implications for patients with early-stage CRC. Future trials in CRC and other solid cancers should assess ctDNA clearance more robustly as a surrogate marker for disease-free survival in patients undergoing definitive therapies for their solid tumors.”
“At present, payers in the United States have not yet approved the routine use of ctDNA technologies in patients with early-stage CRC after resection,” the doctors wrote. “However, compelling data on ctDNA as a robust prognostic marker should be a reason to reassess coverage.”
“[With payer support and improved techniques], then this exciting ctDNA technology will likely revolutionize the routine postoperative management of early-stage CRC by providing a reliable, objective tool for oncologists,” they concluded.
Dr. Morris, Dr. Dasari, and Dr. Kopetz are affiliated with the University of Texas MD Anderson Cancer Center in Houston. Dr. Morris reported financial relationships with GuardantHealth and Array Biopharma. Dr. Kopetz reported relationships with Symphogen, Amgen, Merck, and Holy Stone.
Circulating tumor DNA (ctDNA) could be used to predict disease recurrence in patients with nonmetastatic colorectal cancer (CRC), according to investigators following an observational study.
About three out of four patients with a positive ctDNA test went on to have disease recurrence, reported lead author Yuxuan Wang, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and her colleagues. On average, positive tests preceded clinical and radiologic evidence of recurrence by 3 months.
“[T]he optimal protocol for surveillance of resected colorectal cancer remains uncertain,” the investigators wrote in JAMA Oncology.
“The only recommended blood marker for CRC surveillance is serum [carcinoembryonic antigen (CEA)], an oncofetal protein that is elevated in the serum of patients with a variety of disease conditions, including CRC. Unfortunately, its utility is limited by the lack of sensitivity and specificity.” Although computed tomography and magnetic resonance imaging can improve disease detection, these techniques also have their own shortcomings, the investigators noted, setting the stage for the present study.
The investigators recruited 63 patients with stage I, II, or III CRC who underwent surgical resection in Sweden between 2007 and 2013. Blood samples for ctDNA testing were collected 1 month after surgery, then every 3-6 months. CT was performed every 6-12 months. During this process, 5 patients were excluded, leaving 58 patients in the final dataset, 18 (31%) of whom received adjuvant chemotherapy. Patients were followed until metastasis or a median of 49 months.
Among all patients, 13 tested positive for ctDNA, and 10 of these relapsed (77%), with a median time of 3 months between ctDNA positivity and CT or clinical evidence of recurrence. Three of the 48 patients (6%) who did not relapse had a positive ctDNA result that later dropped to an undetectable level. Of the 45 patients who tested negative for ctDNA, none had recurrence, although 1 was positive for CEA.
Results were also divided into patients who received or did not receive adjuvant chemotherapy. Among the 40 patients who did not receive chemotherapy, 8 had disease recurrence after a positive ctDNA test, although only 5 tested positive for CEA. Among the 18 patients who did receive chemotherapy, 2 tested positive for ctDNA and later relapsed, although only 1 tested positive for CEA. These figures translated to a ctDNA sensitivity for recurrence of 100%, compared with 60% for CEA testing.
“Serial ctDNA levels during follow-up can precede disease recurrence prior to routine radiographic imaging,” the investigators concluded. “Because ctDNA measurements can be obtained from blood samples collected during routine follow-up, they may be easily incorporated into routine follow-up to complement a CEA test, radiographic imaging, and other conventional modalities to help stratify patients on the basis of the risk of disease recurrence. Such a personalized surveillance strategy may allow for earlier detection of relapse and minimize unnecessary testing.”
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, the John Templeton Foundation, and others. The investigators reported financial relationships with PapGene, Sysmex, Eisai, and others.
SOURCE: Wang et al. JAMA Onc. 2019 May 9. doi: 10.1001/jamaoncol.2019.0512.
Circulating tumor DNA (ctDNA) could be used to predict disease recurrence in patients with nonmetastatic colorectal cancer (CRC), according to investigators following an observational study.
About three out of four patients with a positive ctDNA test went on to have disease recurrence, reported lead author Yuxuan Wang, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and her colleagues. On average, positive tests preceded clinical and radiologic evidence of recurrence by 3 months.
“[T]he optimal protocol for surveillance of resected colorectal cancer remains uncertain,” the investigators wrote in JAMA Oncology.
“The only recommended blood marker for CRC surveillance is serum [carcinoembryonic antigen (CEA)], an oncofetal protein that is elevated in the serum of patients with a variety of disease conditions, including CRC. Unfortunately, its utility is limited by the lack of sensitivity and specificity.” Although computed tomography and magnetic resonance imaging can improve disease detection, these techniques also have their own shortcomings, the investigators noted, setting the stage for the present study.
The investigators recruited 63 patients with stage I, II, or III CRC who underwent surgical resection in Sweden between 2007 and 2013. Blood samples for ctDNA testing were collected 1 month after surgery, then every 3-6 months. CT was performed every 6-12 months. During this process, 5 patients were excluded, leaving 58 patients in the final dataset, 18 (31%) of whom received adjuvant chemotherapy. Patients were followed until metastasis or a median of 49 months.
Among all patients, 13 tested positive for ctDNA, and 10 of these relapsed (77%), with a median time of 3 months between ctDNA positivity and CT or clinical evidence of recurrence. Three of the 48 patients (6%) who did not relapse had a positive ctDNA result that later dropped to an undetectable level. Of the 45 patients who tested negative for ctDNA, none had recurrence, although 1 was positive for CEA.
Results were also divided into patients who received or did not receive adjuvant chemotherapy. Among the 40 patients who did not receive chemotherapy, 8 had disease recurrence after a positive ctDNA test, although only 5 tested positive for CEA. Among the 18 patients who did receive chemotherapy, 2 tested positive for ctDNA and later relapsed, although only 1 tested positive for CEA. These figures translated to a ctDNA sensitivity for recurrence of 100%, compared with 60% for CEA testing.
“Serial ctDNA levels during follow-up can precede disease recurrence prior to routine radiographic imaging,” the investigators concluded. “Because ctDNA measurements can be obtained from blood samples collected during routine follow-up, they may be easily incorporated into routine follow-up to complement a CEA test, radiographic imaging, and other conventional modalities to help stratify patients on the basis of the risk of disease recurrence. Such a personalized surveillance strategy may allow for earlier detection of relapse and minimize unnecessary testing.”
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, the John Templeton Foundation, and others. The investigators reported financial relationships with PapGene, Sysmex, Eisai, and others.
SOURCE: Wang et al. JAMA Onc. 2019 May 9. doi: 10.1001/jamaoncol.2019.0512.
FROM JAMA ONCOLOGY
ARCHES: Enzalutamide improves mHSPC survival regardless of baseline PSA
For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.
Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.
ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.
Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.
Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.
For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.
Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.
ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.
Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.
Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.
For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.
Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.
ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.
Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.
Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.
FROM AUA 2019
Key clinical point: For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy offers longer radiographic progression-free survival (rPFS) compared with placebo and androgen deprivation therapy, regardless of baseline prostate-specific antigen level (PSA).
Major finding: A greater percentage of patients treated with enzalutamide and androgen deprivation therapy had a prostate-specific antigen reduction from baseline of at least 90%, compared with those who received placebo and androgen deprivation therapy (72.8% vs. 30.0%).
Study details: ARCHES was a double-blind, placebo-controlled, phase 3 study involving 1,150 men with metastatic hormone-sensitive prostate cancer.
Disclosures: The study was funded by Astellas Pharma and Medivation. The investigators reported no conflicts of interest.
Source: Stenzl et al. AUA 2019. Abstract LBA-10.
Systemic therapies are impacting melanoma’s prognostic factors
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
FROM JAMA DERMATOLOGY
CAR T-cell therapy bb2121 performs well in phase 1 trial of refractory multiple myeloma
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Idelalisib shows long-term safety, efficacy for relapsed CLL
For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.
Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.
During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.
This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.
Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.
During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.
After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.
With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.
However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.
“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.
Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.
SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.
For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.
Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.
During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.
This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.
Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.
During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.
After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.
With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.
However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.
“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.
Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.
SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.
For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.
Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.
During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.
This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.
Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.
During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.
After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.
With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.
However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.
“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.
Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.
SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Circulating tumor cells predict NSCLC survival, but clinical role uncertain
GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.
This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.
“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”
The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.
The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.
“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”
Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.
“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.
SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.
GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.
This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.
“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”
The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.
The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.
“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”
Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.
“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.
SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.
GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.
This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.
“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”
The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.
The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.
“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”
Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.
“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.
SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.
REPORTING FROM ELCC 2019
BWH classification system better predicts outcomes in HNCSCC
For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.
Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.
“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.
Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.
The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.
The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.
“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”
The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”
The investigators reported no conflicts of interest.
SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.
For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.
Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.
“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.
Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.
The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.
The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.
“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”
The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”
The investigators reported no conflicts of interest.
SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.
For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.
Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.
“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.
Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.
The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.
The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.
“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”
The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”
The investigators reported no conflicts of interest.
SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.
FROM JAMA DERMATOLOGY
TTP death linked to elevated troponin and neurological signs
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
GLASGOW – , according to retrospective analysis of 475 patients from the United Kingdom TTP registry.
In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.
Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.
“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”
To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.
The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.
Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).
The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.
In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).
Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 109/L.
Median platelet count upon presentation was 15 x 109/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 109/L.
Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.
Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.
The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.
Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.
Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).
“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”
The investigators reported having no conflicts of interest.
REPORTING FROM BSH 2019
Key clinical point: Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP).
Major finding: ADAMTS13 IgG antibody level, elevated troponin, and neurological abnormalities were all linked to an increased mortality risk.
Study details: A retrospective analysis of 475 patients with clinically suspected thrombotic thrombocytopenic purpura (TTP) from the U.K. registry (2009-2018).
Disclosures: The investigators reported having no conflicts of interest.
High-dose MTX-based chemo is well tolerated in older PCNSL patients
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
REPORTING FROM BSH 2019