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Ruxolitinib improves disease control in PV
©ASCO/Phil McCarten
CHICAGO—The JAK1/2 inhibitor ruxolitinib may be a “valuable new treatment option” for patients with polycythemia vera (PV) who cannot tolerate or are resistant to hydroxyurea, according to a speaker at the 2014 ASCO Annual Meeting.
Results of the phase 3 RESPONSE trial showed that ruxolitinib can reduce spleen size in these patients and improve hematocrit control without the need for phlebotomy.
And the drug was generally well-tolerated.
“Patients with PV may not have their disease controlled with existing therapies, increasing their risk for cardiovascular complications,” said Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“In the RESPONSE trial, patients treated with ruxolitinib showed better disease control and improved symptom management compared to [patients who received] current therapies.”
Dr Verstovsek presented results from the trial at ASCO as abstract 7026. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The study has enrolled 222 patients with PV that is resistant to or intolerant of hydroxyurea. Patients were randomized to receive either ruxolitinib at a starting dose of 10 mg twice-daily or best available therapy (BAT). The ruxolitinib dose was adjusted as needed throughout the study.
At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
The primary endpoint of the study was the proportion of patients whose hematocrit was controlled without phlebotomy from week 8 through 32 and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at 32 weeks.
Twenty-one percent of patients in the ruxolitinib arm achieved this endpoint, compared to 1% of patients in the BAT arm.
“Ninety-one percent of patients who achieved the primary end point had a confirmed response at 48 weeks,” Dr Verstovsek said.
He also noted that nearly half of ruxolitinib-treated patients had a 50% or greater reduction in debilitating PV symptoms, compared to 5% of those on BAT.
Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness. In addition, a greater proportion of patients in the ruxolitinib arm achieved complete hematologic response when compared to the BAT arm—24% and 9%, respectively.
Ruxolitinib was generally well-tolerated, Dr Verstovsek said, noting that 85% of patients were still receiving the drug at a median follow-up of 81 weeks.
However, 3.6% of patients on ruxolitinib discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
Most adverse events observed in the ruxolitinib arm were grade 1 or 2 and were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis.
Few patients developed grade 3 or 4 cytopenias. Within the first 32 weeks of treatment, grade 3 or 4 hematologic adverse events in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%). Fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received BAT.
The most common non-hematologic adverse events were headache, diarrhea, and fatigue, which were mainly grade 1 or 2. Dr Verstovsek noted that herpes zoster infection was higher in the ruxolitinib arm than in the BAT arm.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis. Global regulatory filings for PV are underway based on the RESPONSE data. 
©ASCO/Phil McCarten
CHICAGO—The JAK1/2 inhibitor ruxolitinib may be a “valuable new treatment option” for patients with polycythemia vera (PV) who cannot tolerate or are resistant to hydroxyurea, according to a speaker at the 2014 ASCO Annual Meeting.
Results of the phase 3 RESPONSE trial showed that ruxolitinib can reduce spleen size in these patients and improve hematocrit control without the need for phlebotomy.
And the drug was generally well-tolerated.
“Patients with PV may not have their disease controlled with existing therapies, increasing their risk for cardiovascular complications,” said Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“In the RESPONSE trial, patients treated with ruxolitinib showed better disease control and improved symptom management compared to [patients who received] current therapies.”
Dr Verstovsek presented results from the trial at ASCO as abstract 7026. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The study has enrolled 222 patients with PV that is resistant to or intolerant of hydroxyurea. Patients were randomized to receive either ruxolitinib at a starting dose of 10 mg twice-daily or best available therapy (BAT). The ruxolitinib dose was adjusted as needed throughout the study.
At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
The primary endpoint of the study was the proportion of patients whose hematocrit was controlled without phlebotomy from week 8 through 32 and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at 32 weeks.
Twenty-one percent of patients in the ruxolitinib arm achieved this endpoint, compared to 1% of patients in the BAT arm.
“Ninety-one percent of patients who achieved the primary end point had a confirmed response at 48 weeks,” Dr Verstovsek said.
He also noted that nearly half of ruxolitinib-treated patients had a 50% or greater reduction in debilitating PV symptoms, compared to 5% of those on BAT.
Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness. In addition, a greater proportion of patients in the ruxolitinib arm achieved complete hematologic response when compared to the BAT arm—24% and 9%, respectively.
Ruxolitinib was generally well-tolerated, Dr Verstovsek said, noting that 85% of patients were still receiving the drug at a median follow-up of 81 weeks.
However, 3.6% of patients on ruxolitinib discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
Most adverse events observed in the ruxolitinib arm were grade 1 or 2 and were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis.
Few patients developed grade 3 or 4 cytopenias. Within the first 32 weeks of treatment, grade 3 or 4 hematologic adverse events in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%). Fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received BAT.
The most common non-hematologic adverse events were headache, diarrhea, and fatigue, which were mainly grade 1 or 2. Dr Verstovsek noted that herpes zoster infection was higher in the ruxolitinib arm than in the BAT arm.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis. Global regulatory filings for PV are underway based on the RESPONSE data.
©ASCO/Phil McCarten
CHICAGO—The JAK1/2 inhibitor ruxolitinib may be a “valuable new treatment option” for patients with polycythemia vera (PV) who cannot tolerate or are resistant to hydroxyurea, according to a speaker at the 2014 ASCO Annual Meeting.
Results of the phase 3 RESPONSE trial showed that ruxolitinib can reduce spleen size in these patients and improve hematocrit control without the need for phlebotomy.
And the drug was generally well-tolerated.
“Patients with PV may not have their disease controlled with existing therapies, increasing their risk for cardiovascular complications,” said Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“In the RESPONSE trial, patients treated with ruxolitinib showed better disease control and improved symptom management compared to [patients who received] current therapies.”
Dr Verstovsek presented results from the trial at ASCO as abstract 7026. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The study has enrolled 222 patients with PV that is resistant to or intolerant of hydroxyurea. Patients were randomized to receive either ruxolitinib at a starting dose of 10 mg twice-daily or best available therapy (BAT). The ruxolitinib dose was adjusted as needed throughout the study.
At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
The primary endpoint of the study was the proportion of patients whose hematocrit was controlled without phlebotomy from week 8 through 32 and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at 32 weeks.
Twenty-one percent of patients in the ruxolitinib arm achieved this endpoint, compared to 1% of patients in the BAT arm.
“Ninety-one percent of patients who achieved the primary end point had a confirmed response at 48 weeks,” Dr Verstovsek said.
He also noted that nearly half of ruxolitinib-treated patients had a 50% or greater reduction in debilitating PV symptoms, compared to 5% of those on BAT.
Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness. In addition, a greater proportion of patients in the ruxolitinib arm achieved complete hematologic response when compared to the BAT arm—24% and 9%, respectively.
Ruxolitinib was generally well-tolerated, Dr Verstovsek said, noting that 85% of patients were still receiving the drug at a median follow-up of 81 weeks.
However, 3.6% of patients on ruxolitinib discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
Most adverse events observed in the ruxolitinib arm were grade 1 or 2 and were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis.
Few patients developed grade 3 or 4 cytopenias. Within the first 32 weeks of treatment, grade 3 or 4 hematologic adverse events in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%). Fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received BAT.
The most common non-hematologic adverse events were headache, diarrhea, and fatigue, which were mainly grade 1 or 2. Dr Verstovsek noted that herpes zoster infection was higher in the ruxolitinib arm than in the BAT arm.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis. Global regulatory filings for PV are underway based on the RESPONSE data.
Elderly males with DLBCL require increased rituximab dosing
©ASCO/Phil McCarten
CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.
Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.
He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).
Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.
New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.
Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.
Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).
To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.
The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m2 per treatment cycle, and a group of 148 males received 500 mg/m2 per treatment cycle.
The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.
The higher dose of rituximab given to elderly males did not result in increased toxicity.
Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.
A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.
“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in] elderly males,” Dr Pfreundschuh concluded.
He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.
©ASCO/Phil McCarten
CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.
Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.
He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).
Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.
New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.
Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.
Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).
To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.
The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m2 per treatment cycle, and a group of 148 males received 500 mg/m2 per treatment cycle.
The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.
The higher dose of rituximab given to elderly males did not result in increased toxicity.
Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.
A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.
“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in] elderly males,” Dr Pfreundschuh concluded.
He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.
©ASCO/Phil McCarten
CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.
Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.
He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).
Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.
New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.
Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.
Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).
To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.
The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m2 per treatment cycle, and a group of 148 males received 500 mg/m2 per treatment cycle.
The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.
The higher dose of rituximab given to elderly males did not result in increased toxicity.
Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.
A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.
“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in] elderly males,” Dr Pfreundschuh concluded.
He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.
Switch to nilotinib improves deep molecular response in CML
©ASCO/Phil McCarten
CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.
Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.
But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.
“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.
“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”
Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).
The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.
With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.
“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”
MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).
“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.
However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”
By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.
The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.
“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”
©ASCO/Phil McCarten
CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.
Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.
But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.
“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.
“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”
Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).
The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.
With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.
“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”
MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).
“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.
However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”
By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.
The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.
“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”
©ASCO/Phil McCarten
CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.
Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.
But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.
“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.
“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”
Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).
The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.
With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.
“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”
MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).
“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.
However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”
By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.
The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.
“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”
CAR T-cell therapy successfully used frontline as consolidation in CLL
©ASCO/Todd Buchanan
CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.
In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.
Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.
Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.
Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.
Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.
After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.
Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.
The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.
“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.
“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”
ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.
“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”
She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”
©ASCO/Todd Buchanan
CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.
In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.
Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.
Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.
Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.
Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.
After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.
Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.
The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.
“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.
“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”
ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.
“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”
She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”
©ASCO/Todd Buchanan
CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.
In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.
Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.
Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.
Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.
Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.
After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.
Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.
The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.
“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.
“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”
ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.
“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”
She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”
Lenalidomide combination improves QOL in newly diagnosed MM
©ASCO/Scott Morgan
CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and
lowers toxicity without significant loss of response, results of a phase 3 study suggest.
Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.
Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.
“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.
So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.
The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.
Patients received melphalan at 9 mg/m2 and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m2 and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.
MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.
Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.
The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.
The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).
The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.
Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).
The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.
“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”
Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”
©ASCO/Scott Morgan
CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and
lowers toxicity without significant loss of response, results of a phase 3 study suggest.
Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.
Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.
“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.
So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.
The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.
Patients received melphalan at 9 mg/m2 and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m2 and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.
MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.
Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.
The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.
The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).
The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.
Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).
The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.
“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”
Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”
©ASCO/Scott Morgan
CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and
lowers toxicity without significant loss of response, results of a phase 3 study suggest.
Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.
Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.
“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.
So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.
The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.
Patients received melphalan at 9 mg/m2 and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m2 and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.
MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.
Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.
The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.
The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).
The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.
Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).
The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.
“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”
Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”
Novel agent shows promising activity in heavily pretreated NHL
©ASCO/Rodney White
CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.
“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.
Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.
“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.
He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.
The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.
The patients received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2. Dosing at 60 mg/m2 twice weekly is ongoing, and the maximum-tolerated dose has not been reached.
Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.
“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”
The length of response was up to 632 days in the DLBCL group.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.
“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.
There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”
Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.
Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.
©ASCO/Rodney White
CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.
“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.
Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.
“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.
He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.
The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.
The patients received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2. Dosing at 60 mg/m2 twice weekly is ongoing, and the maximum-tolerated dose has not been reached.
Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.
“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”
The length of response was up to 632 days in the DLBCL group.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.
“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.
There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”
Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.
Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.
©ASCO/Rodney White
CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.
“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.
Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.
“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.
He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.
The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.
The patients received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2. Dosing at 60 mg/m2 twice weekly is ongoing, and the maximum-tolerated dose has not been reached.
Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.
“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”
The length of response was up to 632 days in the DLBCL group.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.
“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.
There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”
Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.
Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.
JAK inhibitor ruxolitinib improves treatment landscape in MF
CHICAGO—Two phase 3 studies demonstrate the effectiveness of the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in treating patients with myelofibrosis (MF), according to presentations at the 2011 ASCO Annual Meeting.
Ruxolitinib has the potential to change the treatment landscape in MF, said Alessandro Vannucchi, MD, of the University of Florence, who reported the results of the COMFORT-II trial.
Srdan Verostovsek, MD, PhD, of the MD Anderson Cancer Center, presented results from COMFORT-I.
COMFORT-II
In the COMFORT-II trial, ruxolitinib produced a volumetric spleen size reduction of 35% or greater in 28.5% of MF patients at 48 weeks. None of the patients receiving best available therapy (BAT) experienced such a reduction, Dr Vannucchi said.
At week 24, 31.9% of ruxolitinib-treated patients had a 35% or greater volumetric spleen size reduction, compared to none of the BAT-treated patients. Ruxolitinib also showed a marked improvement in overall quality of life measures, functioning, and symptoms relative to the BAT arm.
This open-label, phase 3 study included 146 patients randomized to ruxolitinib starting at doses of 15 or 20 mg twice daily and 73 patients randomized to BAT, which was administered at doses and schedules determined by the investigator.
Two-thirds of the BAT patients received at least one medication, and one-third received no medication. The most commonly administered agents were hydroxyurea (47% of patients) and glucocorticoids (16% of patients).
All study participants had intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.
The safety profile of ruxolitinib was consistent with previous studies, Dr Vannucchi said. The most common grade 3 or higher adverse events in the ruxolitinib arm were anemia and thrombocytopenia. In the BAT arm, the most common events were anemia, thrombocytopenia, pneumonia, and dyspnea.
COMFORT-I
The COMFORT-I trial enrolled 309 patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. They were randomly assigned to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients).
Ruxolitinib was dosed at 15 mg or 20 mg, depending on the baseline platelet count. Patients in the placebo arm could cross over to the ruxolitinib arm upon disease progression, and nearly a quarter of patients did cross over (11% prior to week 24 and 13% after week 24).
The median follow-up was 32 weeks. A significantly higher proportion of patients on the ruxolitinib arm (41.9%) attained the primary endpoint of at least a 35% reduction in spleen volume after 24 weeks of therapy compared with placebo patients (0.7%), Dr Verstovsek reported.
Ruxolitinib was also more effective than placebo for improving symptom burden, as 45.9% of patients in the ruxolitinib had at least a 50% improvement in symptom burden, compared to 5.3% of placebo-treated patients.
Symptoms that significantly improved with ruxolitinib included abdominal discomfort, pain under the left ribs, early satiety, night sweats, itching, bone or muscle pain, and inactivity.
“Data from the COMFORT studies indicate that ruxolitinib has the potential to significantly improve the current treatment landscape for most patients with MF,” Dr Vannucchi said. 
CHICAGO—Two phase 3 studies demonstrate the effectiveness of the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in treating patients with myelofibrosis (MF), according to presentations at the 2011 ASCO Annual Meeting.
Ruxolitinib has the potential to change the treatment landscape in MF, said Alessandro Vannucchi, MD, of the University of Florence, who reported the results of the COMFORT-II trial.
Srdan Verostovsek, MD, PhD, of the MD Anderson Cancer Center, presented results from COMFORT-I.
COMFORT-II
In the COMFORT-II trial, ruxolitinib produced a volumetric spleen size reduction of 35% or greater in 28.5% of MF patients at 48 weeks. None of the patients receiving best available therapy (BAT) experienced such a reduction, Dr Vannucchi said.
At week 24, 31.9% of ruxolitinib-treated patients had a 35% or greater volumetric spleen size reduction, compared to none of the BAT-treated patients. Ruxolitinib also showed a marked improvement in overall quality of life measures, functioning, and symptoms relative to the BAT arm.
This open-label, phase 3 study included 146 patients randomized to ruxolitinib starting at doses of 15 or 20 mg twice daily and 73 patients randomized to BAT, which was administered at doses and schedules determined by the investigator.
Two-thirds of the BAT patients received at least one medication, and one-third received no medication. The most commonly administered agents were hydroxyurea (47% of patients) and glucocorticoids (16% of patients).
All study participants had intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.
The safety profile of ruxolitinib was consistent with previous studies, Dr Vannucchi said. The most common grade 3 or higher adverse events in the ruxolitinib arm were anemia and thrombocytopenia. In the BAT arm, the most common events were anemia, thrombocytopenia, pneumonia, and dyspnea.
COMFORT-I
The COMFORT-I trial enrolled 309 patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. They were randomly assigned to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients).
Ruxolitinib was dosed at 15 mg or 20 mg, depending on the baseline platelet count. Patients in the placebo arm could cross over to the ruxolitinib arm upon disease progression, and nearly a quarter of patients did cross over (11% prior to week 24 and 13% after week 24).
The median follow-up was 32 weeks. A significantly higher proportion of patients on the ruxolitinib arm (41.9%) attained the primary endpoint of at least a 35% reduction in spleen volume after 24 weeks of therapy compared with placebo patients (0.7%), Dr Verstovsek reported.
Ruxolitinib was also more effective than placebo for improving symptom burden, as 45.9% of patients in the ruxolitinib had at least a 50% improvement in symptom burden, compared to 5.3% of placebo-treated patients.
Symptoms that significantly improved with ruxolitinib included abdominal discomfort, pain under the left ribs, early satiety, night sweats, itching, bone or muscle pain, and inactivity.
“Data from the COMFORT studies indicate that ruxolitinib has the potential to significantly improve the current treatment landscape for most patients with MF,” Dr Vannucchi said.
CHICAGO—Two phase 3 studies demonstrate the effectiveness of the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in treating patients with myelofibrosis (MF), according to presentations at the 2011 ASCO Annual Meeting.
Ruxolitinib has the potential to change the treatment landscape in MF, said Alessandro Vannucchi, MD, of the University of Florence, who reported the results of the COMFORT-II trial.
Srdan Verostovsek, MD, PhD, of the MD Anderson Cancer Center, presented results from COMFORT-I.
COMFORT-II
In the COMFORT-II trial, ruxolitinib produced a volumetric spleen size reduction of 35% or greater in 28.5% of MF patients at 48 weeks. None of the patients receiving best available therapy (BAT) experienced such a reduction, Dr Vannucchi said.
At week 24, 31.9% of ruxolitinib-treated patients had a 35% or greater volumetric spleen size reduction, compared to none of the BAT-treated patients. Ruxolitinib also showed a marked improvement in overall quality of life measures, functioning, and symptoms relative to the BAT arm.
This open-label, phase 3 study included 146 patients randomized to ruxolitinib starting at doses of 15 or 20 mg twice daily and 73 patients randomized to BAT, which was administered at doses and schedules determined by the investigator.
Two-thirds of the BAT patients received at least one medication, and one-third received no medication. The most commonly administered agents were hydroxyurea (47% of patients) and glucocorticoids (16% of patients).
All study participants had intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.
The safety profile of ruxolitinib was consistent with previous studies, Dr Vannucchi said. The most common grade 3 or higher adverse events in the ruxolitinib arm were anemia and thrombocytopenia. In the BAT arm, the most common events were anemia, thrombocytopenia, pneumonia, and dyspnea.
COMFORT-I
The COMFORT-I trial enrolled 309 patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. They were randomly assigned to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients).
Ruxolitinib was dosed at 15 mg or 20 mg, depending on the baseline platelet count. Patients in the placebo arm could cross over to the ruxolitinib arm upon disease progression, and nearly a quarter of patients did cross over (11% prior to week 24 and 13% after week 24).
The median follow-up was 32 weeks. A significantly higher proportion of patients on the ruxolitinib arm (41.9%) attained the primary endpoint of at least a 35% reduction in spleen volume after 24 weeks of therapy compared with placebo patients (0.7%), Dr Verstovsek reported.
Ruxolitinib was also more effective than placebo for improving symptom burden, as 45.9% of patients in the ruxolitinib had at least a 50% improvement in symptom burden, compared to 5.3% of placebo-treated patients.
Symptoms that significantly improved with ruxolitinib included abdominal discomfort, pain under the left ribs, early satiety, night sweats, itching, bone or muscle pain, and inactivity.
“Data from the COMFORT studies indicate that ruxolitinib has the potential to significantly improve the current treatment landscape for most patients with MF,” Dr Vannucchi said.
Fostamatinib successfully targets the B-cell receptor
NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.
The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.
Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.
“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”
Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.
Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.
The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.
Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.
“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.
The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.
“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.
NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.
The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.
Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.
“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”
Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.
Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.
The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.
Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.
“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.
The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.
“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.
NEW YORK—Fostamatinib, a potent, specific inhibitor of spleen tyrosine kinase (Syk), shows promise as a targeted therapy for non-Hodgkin’s lymphoma (NHL) and leukemia.
The B-cell receptor is present on both normal B cells and malignant B cells. Signaling through this receptor is necessary for B-cell maturation and survival. A subset of aggressive lymphomas, as well as follicular lymphomas, appear to rely on signaling from this receptor for survival, said Jonathan Friedberg, MD, of the University of Rochester in New York, at the Chemotherapy Foundation Symposium held November 10-13, 2009.
Syk mediates and amplifies the B-cell receptor signal and initiates downstream events. Inhibition of Syk results in lymphoma cell death in vitro, he said.
“Syk is expressed in aggressive B-cell lines. Altered B-cell receptor signaling distinguishes follicular lymphoma cells from non-malignant B cells,” said Dr Friedberg. “Syk activity is increased in follicular lymphoma cells compared to normal cells.”
Fostamatinib is an orally available drug that has been shown to be safe in healthy human volunteers and is active in the treatment of rheumatoid arthritis and idiopathic thrombocytopenic purpura (ITP). A study of 19 ITP patients found the drug was well tolerated and yielded a 75% response rate.
Dr Friedberg presented the results of the first phase 1/2 trial of fostamatinib in heavily pretreated patients with relapsed/refractory NHL. The phase 1 study evaluated 200 mg and 250 mg twice-daily doses of fostamatinib in 13 patients, median age 74 years. The dose-limiting toxicities were neutropenia, thrombocytopenia, and diarrhea. The 200 mg twice-daily dose was chosen for phase 2 testing.
The phase 2 study enrolled 68 patients with relapsed/refractory disease, including diffuse large B-cell lymphoma (DLBCL) (23 patients), follicular lymphoma (21 patients), and other NHLs (24 patients). The other NHLs mainly included patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The drug was well tolerated, he said. Adverse events were mainly grade 1 or 2. The most common toxicities included diarrhea, fatigue, cytopenias, nausea, and hypertension. He noted that 20% of patients developed hypertension, which was easily controlled. Five patients developed febrile neutropenia and 1 patient had pancytopenia.
Response rates were 21% for DLBCL patients, 10% for follicular lymphoma patients, 55% for CLL/SLL. Stable disease was observed in an additional 22 patients. Median progression-free survival was 4.2 months and response duration exceeded 4 months.
“Some patients had bulky lymphadenopathy that resolved completely with this agent,” said Dr Friedberg. “As the lymphocyte count increased, the lymph nodes melted away.” White blood cell counts normalized in almost all CLL patients, he noted.
The future development of the drug is likely to include rational combinations with other agents. Ongoing laboratory studies are evaluating fostamatinib with mTOR inhibitors, rituximab, proteasome inhibitors, and chemotherapeutic agents.
“Additional clinical trials are planned to identify lymphomas dependent upon the BCR pathway, and to confirm the exciting effects of this truly targeted therapy for B-cell lymphomas and leukemia,” he said.