The recently published Centers for Medicare & Medicaid Services (CMS) rules on accountable-care organizations (ACOs) are an improvement over the draft rules from this spring, but whether they spur wider formation of the new care model remains to be seen, a leading hospitalist says.

"They did some smart things," says Ron Greeno, MD, MHM, chief medical officer of Brentwood, Tenn.-based Cogent HMG and chair of SHM's Public Policy Committee. "I don't know yet that I have a great feel for how many people are going to apply—certainly more than before."

Released in March, the draft rules prompted more than 1,000 formal comments, spurring changes in several areas, including a significant reduction in the number of quality measures that CMS would monitor (33 from 65), and the elimination of assigning patients to ACOs retrospectively.

The revisions have been made to the Pioneer ACO Model, which offers higher payments to providers and organizations that already have experience with shared savings contracts, and a related program, the Medicare Shared Savings Program, which requires no previous experience.

Overall, the changes "increase incentives and eliminate downside risk," Dr. Greeno says, adding that he would like even more incentives to encourage more providers and organizations to participate. A recent white paper from healthcare research group Leavitt Partners of Salt Lake City identified 165 ACOs nationwide. Dr. Greeno believes that with more opportunity for providers and health systems to share in potential savings, that number can grow quickly.

In a comment letter posted to its website, SHM suggested "that limiting the incentive will also limit the results. ACOs that continually innovate to achieve progressive savings should have ongoing incentives to do so.”

"It's like [CMS] wants this to work, but they're almost scared people will make money doing this," he adds. "If you think this is important, make it worthwhile ... let organizations find the level of risk they're comfortable taking. And reward them accordingly if they're successful."

The recently published Centers for Medicare & Medicaid Services (CMS) rules on accountable-care organizations (ACOs) are an improvement over the draft rules from this spring, but whether they spur wider formation of the new care model remains to be seen, a leading hospitalist says.

"They did some smart things," says Ron Greeno, MD, MHM, chief medical officer of Brentwood, Tenn.-based Cogent HMG and chair of SHM's Public Policy Committee. "I don't know yet that I have a great feel for how many people are going to apply—certainly more than before."

Released in March, the draft rules prompted more than 1,000 formal comments, spurring changes in several areas, including a significant reduction in the number of quality measures that CMS would monitor (33 from 65), and the elimination of assigning patients to ACOs retrospectively.

The revisions have been made to the Pioneer ACO Model, which offers higher payments to providers and organizations that already have experience with shared savings contracts, and a related program, the Medicare Shared Savings Program, which requires no previous experience.

Overall, the changes "increase incentives and eliminate downside risk," Dr. Greeno says, adding that he would like even more incentives to encourage more providers and organizations to participate. A recent white paper from healthcare research group Leavitt Partners of Salt Lake City identified 165 ACOs nationwide. Dr. Greeno believes that with more opportunity for providers and health systems to share in potential savings, that number can grow quickly.

In a comment letter posted to its website, SHM suggested "that limiting the incentive will also limit the results. ACOs that continually innovate to achieve progressive savings should have ongoing incentives to do so.”

"It's like [CMS] wants this to work, but they're almost scared people will make money doing this," he adds. "If you think this is important, make it worthwhile ... let organizations find the level of risk they're comfortable taking. And reward them accordingly if they're successful."

The recently published Centers for Medicare & Medicaid Services (CMS) rules on accountable-care organizations (ACOs) are an improvement over the draft rules from this spring, but whether they spur wider formation of the new care model remains to be seen, a leading hospitalist says.

"They did some smart things," says Ron Greeno, MD, MHM, chief medical officer of Brentwood, Tenn.-based Cogent HMG and chair of SHM's Public Policy Committee. "I don't know yet that I have a great feel for how many people are going to apply—certainly more than before."

Released in March, the draft rules prompted more than 1,000 formal comments, spurring changes in several areas, including a significant reduction in the number of quality measures that CMS would monitor (33 from 65), and the elimination of assigning patients to ACOs retrospectively.

The revisions have been made to the Pioneer ACO Model, which offers higher payments to providers and organizations that already have experience with shared savings contracts, and a related program, the Medicare Shared Savings Program, which requires no previous experience.

Overall, the changes "increase incentives and eliminate downside risk," Dr. Greeno says, adding that he would like even more incentives to encourage more providers and organizations to participate. A recent white paper from healthcare research group Leavitt Partners of Salt Lake City identified 165 ACOs nationwide. Dr. Greeno believes that with more opportunity for providers and health systems to share in potential savings, that number can grow quickly.

In a comment letter posted to its website, SHM suggested "that limiting the incentive will also limit the results. ACOs that continually innovate to achieve progressive savings should have ongoing incentives to do so.”

"It's like [CMS] wants this to work, but they're almost scared people will make money doing this," he adds. "If you think this is important, make it worthwhile ... let organizations find the level of risk they're comfortable taking. And reward them accordingly if they're successful."

Hospitalists are at the center of many proposed interventions to improve antimicrobial prescribing practices, half of which are estimated to be unnecessary or inappropriate, with serious cost and safety consequences, says Scott Flanders, MD, FACP, SFHM, professor of medicine and director of the hospitalist program at the University of Michigan Health System in Ann Arbor.

Dr. Flanders, past president of SHM, is on the faculty of a new Institute for Healthcare Improvement (IHI) initiative kicked off in Boston in late October to test the feasibility of those interventions in hospitals of varying models.

The CDC's national campaign Get Smart for Healthcare recommends formal antimicrobial stewardship programs in hospitals to ensure that patients routinely receive the right antibiotic in the right dose at the right time for the right duration. The CDC website cites a number of studies showing the positive effects of such stewardship on antimicrobial use, antimicrobial resistance, the incidence of Clostridium difficile infections, cost, and other endpoints.

The CDC has engaged IHI to define and pilot-test the feasibility of expert-recommended interventions and approaches at eight hospitals through June 2012. The testing could lead to modifications in approaches, perhaps a second round of testing, and an IHI collaborative, says Diane Jacobsen, IHI project manager.

Eventually, Dr. Flanders adds, SHM might offer its own toolkit of resources for hospitals and hospitalists, and mentored implementation along the lines of its other major quality initiatives.

"The biggest thing for hospitalists is awareness of the problem, and then a commitment to appropriate, evidence-based selection and de-escalation of antibiotics," Jacobsen adds.

Hospitalists are at the center of many proposed interventions to improve antimicrobial prescribing practices, half of which are estimated to be unnecessary or inappropriate, with serious cost and safety consequences, says Scott Flanders, MD, FACP, SFHM, professor of medicine and director of the hospitalist program at the University of Michigan Health System in Ann Arbor.

Dr. Flanders, past president of SHM, is on the faculty of a new Institute for Healthcare Improvement (IHI) initiative kicked off in Boston in late October to test the feasibility of those interventions in hospitals of varying models.

The CDC's national campaign Get Smart for Healthcare recommends formal antimicrobial stewardship programs in hospitals to ensure that patients routinely receive the right antibiotic in the right dose at the right time for the right duration. The CDC website cites a number of studies showing the positive effects of such stewardship on antimicrobial use, antimicrobial resistance, the incidence of Clostridium difficile infections, cost, and other endpoints.

The CDC has engaged IHI to define and pilot-test the feasibility of expert-recommended interventions and approaches at eight hospitals through June 2012. The testing could lead to modifications in approaches, perhaps a second round of testing, and an IHI collaborative, says Diane Jacobsen, IHI project manager.

Eventually, Dr. Flanders adds, SHM might offer its own toolkit of resources for hospitals and hospitalists, and mentored implementation along the lines of its other major quality initiatives.

"The biggest thing for hospitalists is awareness of the problem, and then a commitment to appropriate, evidence-based selection and de-escalation of antibiotics," Jacobsen adds.

Hospitalists are at the center of many proposed interventions to improve antimicrobial prescribing practices, half of which are estimated to be unnecessary or inappropriate, with serious cost and safety consequences, says Scott Flanders, MD, FACP, SFHM, professor of medicine and director of the hospitalist program at the University of Michigan Health System in Ann Arbor.

Dr. Flanders, past president of SHM, is on the faculty of a new Institute for Healthcare Improvement (IHI) initiative kicked off in Boston in late October to test the feasibility of those interventions in hospitals of varying models.

The CDC's national campaign Get Smart for Healthcare recommends formal antimicrobial stewardship programs in hospitals to ensure that patients routinely receive the right antibiotic in the right dose at the right time for the right duration. The CDC website cites a number of studies showing the positive effects of such stewardship on antimicrobial use, antimicrobial resistance, the incidence of Clostridium difficile infections, cost, and other endpoints.

The CDC has engaged IHI to define and pilot-test the feasibility of expert-recommended interventions and approaches at eight hospitals through June 2012. The testing could lead to modifications in approaches, perhaps a second round of testing, and an IHI collaborative, says Diane Jacobsen, IHI project manager.

Eventually, Dr. Flanders adds, SHM might offer its own toolkit of resources for hospitals and hospitalists, and mentored implementation along the lines of its other major quality initiatives.

"The biggest thing for hospitalists is awareness of the problem, and then a commitment to appropriate, evidence-based selection and de-escalation of antibiotics," Jacobsen adds.

Continuous positive airway pressure therapy improved several components of the metabolic syndrome along with obstructive sleep apnea in patients who had both disorders, according to a report in the Dec. 15 issue of the New England Journal of Medicine.

In most cases, only one component of the metabolic syndrome improved significantly after CPAP, but that improvement was significant enough to "reverse" the syndrome, said Dr. Surendra K. Sharma of All India Institute of Medical Sciences, New Delhi, and his associates.

© David Cannings-Bushell/iStockphoto

No particular component stood out as being the most responsive to CPAP; statistically significant improvements were seen in systolic BP, diastolic BP, total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides, glycated hemoglobin, weight, and visceral and subcutaneous fat. "These results suggest a significant clinical benefit that will lead to a reduction in cardiovascular risk," they noted.

To examine the effect of CPAP on components of the metabolic syndrome, the researchers recruited 86 patients aged 30-65 years from the sleep laboratory at the institute who had obstructive sleep apnea that was moderate or worse in severity. All the subjects reported excessive daytime somnolence.

A total of 75 study subjects (87%) had the metabolic syndrome, and the remainder had some of the components of the metabolic syndrome.

These patients were randomly assigned to undergo either CPAP or sham CPAP for 3 months, followed by a washout period of 1 month. They then crossed over to receive the other intervention for 3 months.

The sham CPAP was not discernible to the study subjects or the investigators.

The metabolic syndrome resolved in 14 (20%) of the study subjects after CPAP. This was due to decreased blood pressure in five; decreased fasting blood glucose in two; decreased triglycerides in two; increased HDL cholesterol in three; improved triglycerides plus HDL cholesterol in one; and improved triglycerides, HDL cholesterol, and fasting blood glucose in one, Dr. Sharma and his colleagues said. Symptoms of the syndrome developed in three patients who did not have metabolic syndrome at the start of the study.

Overall, CPAP was associated with a mean decrease in systolic BP of 3.9 mm Hg, a mean decrease in diastolic BP of 2.5 mm Hg, a mean decrease in total cholesterol of 13.3 mg/dL, and a mean decrease in triglycerides of 18.7 mg/dL.

CT scans revealed a significant decrease in both visceral and subcutaneous fat, which was accompanied by a decrease in BMI, with CPAP therapy. "These findings could be secondary to a decrease in daytime somnolence and a consequent increase in physical activity after CPAP use at night."

In addition, "we speculate that CPAP has a favorable effect on leptin levels, which have been shown to be elevated in patients with obstructive sleep apnea and to normalize with CPAP therapy," the investigators said (N. Engl. J. Med. 2011;365:2277-86).

In a subgroup analysis involving only the 51 subjects who were most compliant with CPAP, with a mean use of at least 5 hours every night, the improvements in components of the metabolic syndrome were even greater. In particular, systolic BP decreased by 5.6 mm Hg and diastolic BP decreased by 3.3 mm Hg.

This subgroup of patients also showed significant improvement in carotid intima-media thickness, "suggesting a potential role for CPAP therapy in reversing endothelial damage due to obstructive sleep apnea and the metabolic syndrome," Dr. Sharma and his associates said.

Two patients could not tolerate CPAP and one could not tolerate sham CPAP within the first month of treatment, and they withdrew from the study. "Other adverse events reported included skin irritation (in 51% of all patients), nasal bridge discomfort (in 44%), nasal congestion (in 28%), headache (in 26%), and mask leaks (in 30%)."

This study was funded by Pfizer. All investigators reported having no financial conflicts of interest. The investigators received technical support from ResMed Corp. in designing a sham CPAP machine.

Continuous positive airway pressure therapy improved several components of the metabolic syndrome along with obstructive sleep apnea in patients who had both disorders, according to a report in the Dec. 15 issue of the New England Journal of Medicine.

In most cases, only one component of the metabolic syndrome improved significantly after CPAP, but that improvement was significant enough to "reverse" the syndrome, said Dr. Surendra K. Sharma of All India Institute of Medical Sciences, New Delhi, and his associates.

© David Cannings-Bushell/iStockphoto

No particular component stood out as being the most responsive to CPAP; statistically significant improvements were seen in systolic BP, diastolic BP, total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides, glycated hemoglobin, weight, and visceral and subcutaneous fat. "These results suggest a significant clinical benefit that will lead to a reduction in cardiovascular risk," they noted.

To examine the effect of CPAP on components of the metabolic syndrome, the researchers recruited 86 patients aged 30-65 years from the sleep laboratory at the institute who had obstructive sleep apnea that was moderate or worse in severity. All the subjects reported excessive daytime somnolence.

A total of 75 study subjects (87%) had the metabolic syndrome, and the remainder had some of the components of the metabolic syndrome.

These patients were randomly assigned to undergo either CPAP or sham CPAP for 3 months, followed by a washout period of 1 month. They then crossed over to receive the other intervention for 3 months.

The sham CPAP was not discernible to the study subjects or the investigators.

The metabolic syndrome resolved in 14 (20%) of the study subjects after CPAP. This was due to decreased blood pressure in five; decreased fasting blood glucose in two; decreased triglycerides in two; increased HDL cholesterol in three; improved triglycerides plus HDL cholesterol in one; and improved triglycerides, HDL cholesterol, and fasting blood glucose in one, Dr. Sharma and his colleagues said. Symptoms of the syndrome developed in three patients who did not have metabolic syndrome at the start of the study.

Overall, CPAP was associated with a mean decrease in systolic BP of 3.9 mm Hg, a mean decrease in diastolic BP of 2.5 mm Hg, a mean decrease in total cholesterol of 13.3 mg/dL, and a mean decrease in triglycerides of 18.7 mg/dL.

CT scans revealed a significant decrease in both visceral and subcutaneous fat, which was accompanied by a decrease in BMI, with CPAP therapy. "These findings could be secondary to a decrease in daytime somnolence and a consequent increase in physical activity after CPAP use at night."

In addition, "we speculate that CPAP has a favorable effect on leptin levels, which have been shown to be elevated in patients with obstructive sleep apnea and to normalize with CPAP therapy," the investigators said (N. Engl. J. Med. 2011;365:2277-86).

In a subgroup analysis involving only the 51 subjects who were most compliant with CPAP, with a mean use of at least 5 hours every night, the improvements in components of the metabolic syndrome were even greater. In particular, systolic BP decreased by 5.6 mm Hg and diastolic BP decreased by 3.3 mm Hg.

This subgroup of patients also showed significant improvement in carotid intima-media thickness, "suggesting a potential role for CPAP therapy in reversing endothelial damage due to obstructive sleep apnea and the metabolic syndrome," Dr. Sharma and his associates said.

Two patients could not tolerate CPAP and one could not tolerate sham CPAP within the first month of treatment, and they withdrew from the study. "Other adverse events reported included skin irritation (in 51% of all patients), nasal bridge discomfort (in 44%), nasal congestion (in 28%), headache (in 26%), and mask leaks (in 30%)."

This study was funded by Pfizer. All investigators reported having no financial conflicts of interest. The investigators received technical support from ResMed Corp. in designing a sham CPAP machine.

Continuous positive airway pressure therapy improved several components of the metabolic syndrome along with obstructive sleep apnea in patients who had both disorders, according to a report in the Dec. 15 issue of the New England Journal of Medicine.

In most cases, only one component of the metabolic syndrome improved significantly after CPAP, but that improvement was significant enough to "reverse" the syndrome, said Dr. Surendra K. Sharma of All India Institute of Medical Sciences, New Delhi, and his associates.

© David Cannings-Bushell/iStockphoto

No particular component stood out as being the most responsive to CPAP; statistically significant improvements were seen in systolic BP, diastolic BP, total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides, glycated hemoglobin, weight, and visceral and subcutaneous fat. "These results suggest a significant clinical benefit that will lead to a reduction in cardiovascular risk," they noted.

To examine the effect of CPAP on components of the metabolic syndrome, the researchers recruited 86 patients aged 30-65 years from the sleep laboratory at the institute who had obstructive sleep apnea that was moderate or worse in severity. All the subjects reported excessive daytime somnolence.

A total of 75 study subjects (87%) had the metabolic syndrome, and the remainder had some of the components of the metabolic syndrome.

These patients were randomly assigned to undergo either CPAP or sham CPAP for 3 months, followed by a washout period of 1 month. They then crossed over to receive the other intervention for 3 months.

The sham CPAP was not discernible to the study subjects or the investigators.

The metabolic syndrome resolved in 14 (20%) of the study subjects after CPAP. This was due to decreased blood pressure in five; decreased fasting blood glucose in two; decreased triglycerides in two; increased HDL cholesterol in three; improved triglycerides plus HDL cholesterol in one; and improved triglycerides, HDL cholesterol, and fasting blood glucose in one, Dr. Sharma and his colleagues said. Symptoms of the syndrome developed in three patients who did not have metabolic syndrome at the start of the study.

Overall, CPAP was associated with a mean decrease in systolic BP of 3.9 mm Hg, a mean decrease in diastolic BP of 2.5 mm Hg, a mean decrease in total cholesterol of 13.3 mg/dL, and a mean decrease in triglycerides of 18.7 mg/dL.

CT scans revealed a significant decrease in both visceral and subcutaneous fat, which was accompanied by a decrease in BMI, with CPAP therapy. "These findings could be secondary to a decrease in daytime somnolence and a consequent increase in physical activity after CPAP use at night."

In addition, "we speculate that CPAP has a favorable effect on leptin levels, which have been shown to be elevated in patients with obstructive sleep apnea and to normalize with CPAP therapy," the investigators said (N. Engl. J. Med. 2011;365:2277-86).

In a subgroup analysis involving only the 51 subjects who were most compliant with CPAP, with a mean use of at least 5 hours every night, the improvements in components of the metabolic syndrome were even greater. In particular, systolic BP decreased by 5.6 mm Hg and diastolic BP decreased by 3.3 mm Hg.

This subgroup of patients also showed significant improvement in carotid intima-media thickness, "suggesting a potential role for CPAP therapy in reversing endothelial damage due to obstructive sleep apnea and the metabolic syndrome," Dr. Sharma and his associates said.

Two patients could not tolerate CPAP and one could not tolerate sham CPAP within the first month of treatment, and they withdrew from the study. "Other adverse events reported included skin irritation (in 51% of all patients), nasal bridge discomfort (in 44%), nasal congestion (in 28%), headache (in 26%), and mask leaks (in 30%)."

This study was funded by Pfizer. All investigators reported having no financial conflicts of interest. The investigators received technical support from ResMed Corp. in designing a sham CPAP machine.

LAS VEGAS – Although certain characteristics of lymphomatoid papulosis appear be associated with progression to lymphoma, the majority of patients will have a benign course of disease.

The recurrent papulonodular skin eruption lymphomatoid papulosis (LyP) can be a confusing dermatologic entity because it appears malignant histologically, but it usually follows a clinically benign and indolent course (Arch. Dermatol. 1968;97:23-30). And even the 10%-20% of patients who do progress to lymphoma tend to have less aggressive disease, said Dr. Lawrence E. Gibson, professor of dermatology at the Mayo Clinic in Rochester, Minn. The reasons for this disconnect are not yet known.

"Patients with LyP look like lymphoma under the microscope but have clinically indolent cutaneous disease. ... It is an example of a very important clinical-pathological relationship that really needs to be made to help us understand how to treat patients better," he said.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas."

To identify which LyP patients are more likely to progress to lymphoma, Dr. Gibson, Dr. Rokea A. el-Azhary, Dr. Aieska de Souza, and their associates conducted a retrospective analysis of 123 patients seen at the Mayo Clinic between 1991 and 2008. The patients were followed for a mean of 4 years (range, 2 months to 14 years). The 65 males and 58 females had a mean age of 47 years (range, 1-83 years), and a mean of 14 lesions (range, 1-100). Most (88%) of the lesions were papules, with a reported mean duration of 5.5 weeks. Pruritis was present in 38% and scar formation in 58%, the researchers reported (J. Am. Acad. Dermatol. 2011 [doi:10.1016/j.jaad.2011.07.012]).

Hematologic malignancies were present in 17 patients (14%). Of those, 10 were cutaneous lymphomas – 8 mycosis fungoides (MF) and 2 anaplastic large-cell lymphomas (ALCL). Hodgkin lymphoma was present in three patients (including the two with ALCL), multiple myeloma or monoclonal gammopathy in three, and myelodysplastic syndrome in one.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas. They certainly don’t have cytotoxic lymphomas. And if they have lymphoma, they usually have MF. I think that’s somewhat reassuring to us. And for the most part, most of the patients don’t have anything. They have a normal life," Dr. Gibson said at the seminar sponsored by Skin Disease Education Foundation (SDEF).

Of 97 LyP patients for whom original biopsy slides were available, the majority (69) had World Health Organization/European Organization for Research and Treatment of Cancer histologic classification type A, including 35 with immunophenotypic subtype CD8 and 34 with subtype CD4. Another 13 patients had type B lesions (8 CD4, 5 CD8), and 6 had type C, all of which were CD4. The other 9 patients had more than one histologic type (A, B, or C), and/or more than one immunophenotypic subtype (CD4 or CD8). They were designated mixed type.

Clinically, there were no distinguishing features among the subtypes. This finding contrasts with some previous reports that the CD8 subtype might predispose to worse disease outcome (Am. J. Pathol. 1999;155:483-92).

"Our findings indicated that the LyP subtype CD8 does not signify more aggressive disease, a poor prognosis, or an association with malignancy," Dr. Gibson and his colleagues wrote.

Hematologic malignancies were present in 5 of the 9 mixed-type patients (55.5%), compared with 4 of the 34 with A/CD4 (12%), 4 of the 35 A/CD8 (11.5%), 1 of the 8 B/CD4 patients (12.5%), and 1 of the 5 B/CD8 patients (20%). (Two of the 17 malignancies were excluded from analysis because original slides were not available.) The odds ratio for malignancy for the patients with mixed-type LyP versus all other types was a statistically significant 4.33 (P = .03).

In a molecular genetics substudy of 84 LyP lesions from 76 patients, 42 (50%) were positive for clonal T-cell receptor gene rearrangement (TCRGR), 34 (40%) were negative, and 8 (10%) showed equivocal results or had insufficient DNA for analysis. Among the LyP patients who had a hematologic malignancy, 9 of 11 (82%) had positive TCRGR, compared with 30 of 68 (44%) LyP patients without malignancy. That association was also significant, with an odds ratio of 5.7 (P = .02), noted the investigators.

"A positive T-cell receptor gene rearrangement or having more than one type of LyP may have a higher risk of progression to lymphoma, but the evidence is not hard and fast. ... The take-home message is most of these patients do just fine," Dr. Gibson said.

Dr. Gibson stated that he had no relevant financial disclosures or conflicts of interest. SDEF and this news organization are owned by Elsevier.

LAS VEGAS – Although certain characteristics of lymphomatoid papulosis appear be associated with progression to lymphoma, the majority of patients will have a benign course of disease.

The recurrent papulonodular skin eruption lymphomatoid papulosis (LyP) can be a confusing dermatologic entity because it appears malignant histologically, but it usually follows a clinically benign and indolent course (Arch. Dermatol. 1968;97:23-30). And even the 10%-20% of patients who do progress to lymphoma tend to have less aggressive disease, said Dr. Lawrence E. Gibson, professor of dermatology at the Mayo Clinic in Rochester, Minn. The reasons for this disconnect are not yet known.

"Patients with LyP look like lymphoma under the microscope but have clinically indolent cutaneous disease. ... It is an example of a very important clinical-pathological relationship that really needs to be made to help us understand how to treat patients better," he said.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas."

To identify which LyP patients are more likely to progress to lymphoma, Dr. Gibson, Dr. Rokea A. el-Azhary, Dr. Aieska de Souza, and their associates conducted a retrospective analysis of 123 patients seen at the Mayo Clinic between 1991 and 2008. The patients were followed for a mean of 4 years (range, 2 months to 14 years). The 65 males and 58 females had a mean age of 47 years (range, 1-83 years), and a mean of 14 lesions (range, 1-100). Most (88%) of the lesions were papules, with a reported mean duration of 5.5 weeks. Pruritis was present in 38% and scar formation in 58%, the researchers reported (J. Am. Acad. Dermatol. 2011 [doi:10.1016/j.jaad.2011.07.012]).

Hematologic malignancies were present in 17 patients (14%). Of those, 10 were cutaneous lymphomas – 8 mycosis fungoides (MF) and 2 anaplastic large-cell lymphomas (ALCL). Hodgkin lymphoma was present in three patients (including the two with ALCL), multiple myeloma or monoclonal gammopathy in three, and myelodysplastic syndrome in one.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas. They certainly don’t have cytotoxic lymphomas. And if they have lymphoma, they usually have MF. I think that’s somewhat reassuring to us. And for the most part, most of the patients don’t have anything. They have a normal life," Dr. Gibson said at the seminar sponsored by Skin Disease Education Foundation (SDEF).

Of 97 LyP patients for whom original biopsy slides were available, the majority (69) had World Health Organization/European Organization for Research and Treatment of Cancer histologic classification type A, including 35 with immunophenotypic subtype CD8 and 34 with subtype CD4. Another 13 patients had type B lesions (8 CD4, 5 CD8), and 6 had type C, all of which were CD4. The other 9 patients had more than one histologic type (A, B, or C), and/or more than one immunophenotypic subtype (CD4 or CD8). They were designated mixed type.

Clinically, there were no distinguishing features among the subtypes. This finding contrasts with some previous reports that the CD8 subtype might predispose to worse disease outcome (Am. J. Pathol. 1999;155:483-92).

"Our findings indicated that the LyP subtype CD8 does not signify more aggressive disease, a poor prognosis, or an association with malignancy," Dr. Gibson and his colleagues wrote.

Hematologic malignancies were present in 5 of the 9 mixed-type patients (55.5%), compared with 4 of the 34 with A/CD4 (12%), 4 of the 35 A/CD8 (11.5%), 1 of the 8 B/CD4 patients (12.5%), and 1 of the 5 B/CD8 patients (20%). (Two of the 17 malignancies were excluded from analysis because original slides were not available.) The odds ratio for malignancy for the patients with mixed-type LyP versus all other types was a statistically significant 4.33 (P = .03).

In a molecular genetics substudy of 84 LyP lesions from 76 patients, 42 (50%) were positive for clonal T-cell receptor gene rearrangement (TCRGR), 34 (40%) were negative, and 8 (10%) showed equivocal results or had insufficient DNA for analysis. Among the LyP patients who had a hematologic malignancy, 9 of 11 (82%) had positive TCRGR, compared with 30 of 68 (44%) LyP patients without malignancy. That association was also significant, with an odds ratio of 5.7 (P = .02), noted the investigators.

"A positive T-cell receptor gene rearrangement or having more than one type of LyP may have a higher risk of progression to lymphoma, but the evidence is not hard and fast. ... The take-home message is most of these patients do just fine," Dr. Gibson said.

Dr. Gibson stated that he had no relevant financial disclosures or conflicts of interest. SDEF and this news organization are owned by Elsevier.

LAS VEGAS – Although certain characteristics of lymphomatoid papulosis appear be associated with progression to lymphoma, the majority of patients will have a benign course of disease.

The recurrent papulonodular skin eruption lymphomatoid papulosis (LyP) can be a confusing dermatologic entity because it appears malignant histologically, but it usually follows a clinically benign and indolent course (Arch. Dermatol. 1968;97:23-30). And even the 10%-20% of patients who do progress to lymphoma tend to have less aggressive disease, said Dr. Lawrence E. Gibson, professor of dermatology at the Mayo Clinic in Rochester, Minn. The reasons for this disconnect are not yet known.

"Patients with LyP look like lymphoma under the microscope but have clinically indolent cutaneous disease. ... It is an example of a very important clinical-pathological relationship that really needs to be made to help us understand how to treat patients better," he said.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas."

To identify which LyP patients are more likely to progress to lymphoma, Dr. Gibson, Dr. Rokea A. el-Azhary, Dr. Aieska de Souza, and their associates conducted a retrospective analysis of 123 patients seen at the Mayo Clinic between 1991 and 2008. The patients were followed for a mean of 4 years (range, 2 months to 14 years). The 65 males and 58 females had a mean age of 47 years (range, 1-83 years), and a mean of 14 lesions (range, 1-100). Most (88%) of the lesions were papules, with a reported mean duration of 5.5 weeks. Pruritis was present in 38% and scar formation in 58%, the researchers reported (J. Am. Acad. Dermatol. 2011 [doi:10.1016/j.jaad.2011.07.012]).

Hematologic malignancies were present in 17 patients (14%). Of those, 10 were cutaneous lymphomas – 8 mycosis fungoides (MF) and 2 anaplastic large-cell lymphomas (ALCL). Hodgkin lymphoma was present in three patients (including the two with ALCL), multiple myeloma or monoclonal gammopathy in three, and myelodysplastic syndrome in one.

"The bottom line is most of our patients who have LyP do not go on to have aggressive lymphomas. They certainly don’t have cytotoxic lymphomas. And if they have lymphoma, they usually have MF. I think that’s somewhat reassuring to us. And for the most part, most of the patients don’t have anything. They have a normal life," Dr. Gibson said at the seminar sponsored by Skin Disease Education Foundation (SDEF).

Of 97 LyP patients for whom original biopsy slides were available, the majority (69) had World Health Organization/European Organization for Research and Treatment of Cancer histologic classification type A, including 35 with immunophenotypic subtype CD8 and 34 with subtype CD4. Another 13 patients had type B lesions (8 CD4, 5 CD8), and 6 had type C, all of which were CD4. The other 9 patients had more than one histologic type (A, B, or C), and/or more than one immunophenotypic subtype (CD4 or CD8). They were designated mixed type.

Clinically, there were no distinguishing features among the subtypes. This finding contrasts with some previous reports that the CD8 subtype might predispose to worse disease outcome (Am. J. Pathol. 1999;155:483-92).

"Our findings indicated that the LyP subtype CD8 does not signify more aggressive disease, a poor prognosis, or an association with malignancy," Dr. Gibson and his colleagues wrote.

Hematologic malignancies were present in 5 of the 9 mixed-type patients (55.5%), compared with 4 of the 34 with A/CD4 (12%), 4 of the 35 A/CD8 (11.5%), 1 of the 8 B/CD4 patients (12.5%), and 1 of the 5 B/CD8 patients (20%). (Two of the 17 malignancies were excluded from analysis because original slides were not available.) The odds ratio for malignancy for the patients with mixed-type LyP versus all other types was a statistically significant 4.33 (P = .03).

In a molecular genetics substudy of 84 LyP lesions from 76 patients, 42 (50%) were positive for clonal T-cell receptor gene rearrangement (TCRGR), 34 (40%) were negative, and 8 (10%) showed equivocal results or had insufficient DNA for analysis. Among the LyP patients who had a hematologic malignancy, 9 of 11 (82%) had positive TCRGR, compared with 30 of 68 (44%) LyP patients without malignancy. That association was also significant, with an odds ratio of 5.7 (P = .02), noted the investigators.

"A positive T-cell receptor gene rearrangement or having more than one type of LyP may have a higher risk of progression to lymphoma, but the evidence is not hard and fast. ... The take-home message is most of these patients do just fine," Dr. Gibson said.

Dr. Gibson stated that he had no relevant financial disclosures or conflicts of interest. SDEF and this news organization are owned by Elsevier.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.