Neil Osterweil

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.

Neil Osterweil/MDedge News

After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.

“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.

The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.

Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.

As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.

The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.


Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.

Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.

“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.

The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.

SOURCE: Salles G et al. 15-ICML, Abstract 124.

LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.

Neil Osterweil/MDedge News

After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.

“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.

The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.

Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.

As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.

The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.


Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.

Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.

“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.

The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.

SOURCE: Salles G et al. 15-ICML, Abstract 124.

LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.

Neil Osterweil/MDedge News

After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.

“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.

The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.

Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.

As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.

The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.


Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.

Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.

“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.

The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.

SOURCE: Salles G et al. 15-ICML, Abstract 124.

LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.

Neil Osterweil/MDedge News

Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.

“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.

So what’s behind the conflicting findings?

Neil Osterweil/MDedge News

The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.

The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.

In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
 

ECOG-ACRIN 1412 details

Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.

To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.

The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.

The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.

In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.

The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.

Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.

The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.

After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.

There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.

Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.

R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.

Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.

In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.

“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.

Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.

ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.

SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.

LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.

Neil Osterweil/MDedge News

Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.

“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.

So what’s behind the conflicting findings?

Neil Osterweil/MDedge News

The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.

The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.

In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
 

ECOG-ACRIN 1412 details

Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.

To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.

The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.

The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.

In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.

The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.

Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.

The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.

After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.

There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.

Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.

R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.

Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.

In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.

“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.

Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.

ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.

SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.

LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.

Neil Osterweil/MDedge News

Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.

“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.

So what’s behind the conflicting findings?

Neil Osterweil/MDedge News

The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.

The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.

In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
 

ECOG-ACRIN 1412 details

Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.

To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.

The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.

The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.

In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.

The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.

Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.

The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.

After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.

There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.

Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.

R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.

Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.

In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.

“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.

Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.

ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.

SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

AMSTERDAM – Rituximab maintenance therapy did not significantly prolong disease-free survival among patients with diffuse large B-cell lymphoma in complete remission after induction chemotherapy, investigators in the HOVON-Nordic trial collaboration found.

Among 380 patients with diffuse large B-cell lymphoma (DLBCL) in complete remission following induction chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the median disease-free survival (DFS) after a median follow-up of 79.9 months had not been reached for patients randomized to either rituximab maintenance therapy or observation alone, reported Pieternella J. Lugtenburg, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands.

“In patients with diffuse large B-cell lymphoma in first complete remission after R-CHOP induction therapy, rituximab maintenance therapy does not prolong disease-free survival, and we could not identify a clinical subgroup that benefited,” she said at the annual congress of the European Hematology Association.

The randomized, phase 3 HOVON-Nordic LG trial compared R-CHOP-14 with rituximab delivered on day 1 for four cycles in one arm, and on days 1 and 8 in the comparison arm (R2-CHOP). Patients were assessed for response after four cycles, and those with progressive disease were taken off the study. The remaining patients continued on their assigned regimen for an additional four cycles and second assessment, and those who had complete responses then underwent a second randomization to rituximab maintenance or observation. Patients randomized to maintenance could receive up to 12 8-week cycles.

The second randomization was stratified by age (18-65 vs. 66-80 years), age-adjusted International Prognostic Index score, and R-CHOP regimen (one or two infusions per cycle in the first randomization).

The induction phase found no significant benefit for the additional rituximab infusion for the primary endpoint of progression-free survival, with 3-year PFS rates of 74% for R-CHOP and 71% for R2-CHOP. Respective 5-year PFS rates were 68% and 62%.

There were no differences between the arms by any of the stratification factors, and no difference in overall survival.

Dr. Lugtenburg presented results of the maintenance phase, which included all patients in complete remission at least 4 weeks after the last cycle of R-CHOP-14 who did not have rituximab-related adverse events or active infections.

A total of 195 patients were randomized to observation, and 185 to maintenance. Of this latter group, 149 patients received all 12 cycles, with a median duration of exposure of 22.5 months.

As noted, DFS, the primary endpoint for the maintenance phase, was not significantly different between the arms, with 136 events in the maintenance arm versus 134 in the observation arm. A total of 21 patients assigned to maintenance died, and 22 patients assigned to observation died during follow-up.

The respective 5-year DFS rates were 79% and 74%, a difference that was not statistically significant.

There were no significant differences between the arms in either time to relapse or death, and no difference in overall survival.

In the question-and-answer section following her talk, Marek Trnený, MD, from Charles University in Prague, pointed out that, in the NHL 13 study, which looked at rituximab maintenance for patients with DLBCL or follicular lymphoma in first remission, there was an apparent clinical benefit with rituximab maintenance for men with low International Prognostic Index scores, and asked whether Dr. Lugtenburg and colleagues had seen similar trends.

“We knew about this finding, and we really didn’t see any differences between males and females, not only in terms of efficacy, but also in terms of toxicity, they had actually the same rates of toxicity,” she said.

In NHL 13, women had a significantly higher incidence of grade 3-4 adverse events, compared with men.

The study was sponsored by HOVON, the HematoOncology Foundation for Adults in the Netherlands, with additional support from Roche. Dr. Lugtenburg reported consultancy for and research funding from Roche and others. Dr. Trnený reported advisory board activity, research support, and honoraria from Roche and others.

SOURCE: Lugtenburg PJ et al. EHA 2019, Abstract S1559.

AMSTERDAM – Rituximab maintenance therapy did not significantly prolong disease-free survival among patients with diffuse large B-cell lymphoma in complete remission after induction chemotherapy, investigators in the HOVON-Nordic trial collaboration found.

Among 380 patients with diffuse large B-cell lymphoma (DLBCL) in complete remission following induction chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the median disease-free survival (DFS) after a median follow-up of 79.9 months had not been reached for patients randomized to either rituximab maintenance therapy or observation alone, reported Pieternella J. Lugtenburg, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands.

“In patients with diffuse large B-cell lymphoma in first complete remission after R-CHOP induction therapy, rituximab maintenance therapy does not prolong disease-free survival, and we could not identify a clinical subgroup that benefited,” she said at the annual congress of the European Hematology Association.

The randomized, phase 3 HOVON-Nordic LG trial compared R-CHOP-14 with rituximab delivered on day 1 for four cycles in one arm, and on days 1 and 8 in the comparison arm (R2-CHOP). Patients were assessed for response after four cycles, and those with progressive disease were taken off the study. The remaining patients continued on their assigned regimen for an additional four cycles and second assessment, and those who had complete responses then underwent a second randomization to rituximab maintenance or observation. Patients randomized to maintenance could receive up to 12 8-week cycles.

The second randomization was stratified by age (18-65 vs. 66-80 years), age-adjusted International Prognostic Index score, and R-CHOP regimen (one or two infusions per cycle in the first randomization).

The induction phase found no significant benefit for the additional rituximab infusion for the primary endpoint of progression-free survival, with 3-year PFS rates of 74% for R-CHOP and 71% for R2-CHOP. Respective 5-year PFS rates were 68% and 62%.

There were no differences between the arms by any of the stratification factors, and no difference in overall survival.

Dr. Lugtenburg presented results of the maintenance phase, which included all patients in complete remission at least 4 weeks after the last cycle of R-CHOP-14 who did not have rituximab-related adverse events or active infections.

A total of 195 patients were randomized to observation, and 185 to maintenance. Of this latter group, 149 patients received all 12 cycles, with a median duration of exposure of 22.5 months.

As noted, DFS, the primary endpoint for the maintenance phase, was not significantly different between the arms, with 136 events in the maintenance arm versus 134 in the observation arm. A total of 21 patients assigned to maintenance died, and 22 patients assigned to observation died during follow-up.

The respective 5-year DFS rates were 79% and 74%, a difference that was not statistically significant.

There were no significant differences between the arms in either time to relapse or death, and no difference in overall survival.

In the question-and-answer section following her talk, Marek Trnený, MD, from Charles University in Prague, pointed out that, in the NHL 13 study, which looked at rituximab maintenance for patients with DLBCL or follicular lymphoma in first remission, there was an apparent clinical benefit with rituximab maintenance for men with low International Prognostic Index scores, and asked whether Dr. Lugtenburg and colleagues had seen similar trends.

“We knew about this finding, and we really didn’t see any differences between males and females, not only in terms of efficacy, but also in terms of toxicity, they had actually the same rates of toxicity,” she said.

In NHL 13, women had a significantly higher incidence of grade 3-4 adverse events, compared with men.

The study was sponsored by HOVON, the HematoOncology Foundation for Adults in the Netherlands, with additional support from Roche. Dr. Lugtenburg reported consultancy for and research funding from Roche and others. Dr. Trnený reported advisory board activity, research support, and honoraria from Roche and others.

SOURCE: Lugtenburg PJ et al. EHA 2019, Abstract S1559.

AMSTERDAM – Rituximab maintenance therapy did not significantly prolong disease-free survival among patients with diffuse large B-cell lymphoma in complete remission after induction chemotherapy, investigators in the HOVON-Nordic trial collaboration found.

Among 380 patients with diffuse large B-cell lymphoma (DLBCL) in complete remission following induction chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the median disease-free survival (DFS) after a median follow-up of 79.9 months had not been reached for patients randomized to either rituximab maintenance therapy or observation alone, reported Pieternella J. Lugtenburg, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands.

“In patients with diffuse large B-cell lymphoma in first complete remission after R-CHOP induction therapy, rituximab maintenance therapy does not prolong disease-free survival, and we could not identify a clinical subgroup that benefited,” she said at the annual congress of the European Hematology Association.

The randomized, phase 3 HOVON-Nordic LG trial compared R-CHOP-14 with rituximab delivered on day 1 for four cycles in one arm, and on days 1 and 8 in the comparison arm (R2-CHOP). Patients were assessed for response after four cycles, and those with progressive disease were taken off the study. The remaining patients continued on their assigned regimen for an additional four cycles and second assessment, and those who had complete responses then underwent a second randomization to rituximab maintenance or observation. Patients randomized to maintenance could receive up to 12 8-week cycles.

The second randomization was stratified by age (18-65 vs. 66-80 years), age-adjusted International Prognostic Index score, and R-CHOP regimen (one or two infusions per cycle in the first randomization).

The induction phase found no significant benefit for the additional rituximab infusion for the primary endpoint of progression-free survival, with 3-year PFS rates of 74% for R-CHOP and 71% for R2-CHOP. Respective 5-year PFS rates were 68% and 62%.

There were no differences between the arms by any of the stratification factors, and no difference in overall survival.

Dr. Lugtenburg presented results of the maintenance phase, which included all patients in complete remission at least 4 weeks after the last cycle of R-CHOP-14 who did not have rituximab-related adverse events or active infections.

A total of 195 patients were randomized to observation, and 185 to maintenance. Of this latter group, 149 patients received all 12 cycles, with a median duration of exposure of 22.5 months.

As noted, DFS, the primary endpoint for the maintenance phase, was not significantly different between the arms, with 136 events in the maintenance arm versus 134 in the observation arm. A total of 21 patients assigned to maintenance died, and 22 patients assigned to observation died during follow-up.

The respective 5-year DFS rates were 79% and 74%, a difference that was not statistically significant.

There were no significant differences between the arms in either time to relapse or death, and no difference in overall survival.

In the question-and-answer section following her talk, Marek Trnený, MD, from Charles University in Prague, pointed out that, in the NHL 13 study, which looked at rituximab maintenance for patients with DLBCL or follicular lymphoma in first remission, there was an apparent clinical benefit with rituximab maintenance for men with low International Prognostic Index scores, and asked whether Dr. Lugtenburg and colleagues had seen similar trends.

“We knew about this finding, and we really didn’t see any differences between males and females, not only in terms of efficacy, but also in terms of toxicity, they had actually the same rates of toxicity,” she said.

In NHL 13, women had a significantly higher incidence of grade 3-4 adverse events, compared with men.

The study was sponsored by HOVON, the HematoOncology Foundation for Adults in the Netherlands, with additional support from Roche. Dr. Lugtenburg reported consultancy for and research funding from Roche and others. Dr. Trnený reported advisory board activity, research support, and honoraria from Roche and others.

SOURCE: Lugtenburg PJ et al. EHA 2019, Abstract S1559.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.