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Persistent lymphocytosis with ibrutinib does not indicate early relapse
Persistent lymphocytosis lasting more than 12 months in patients with chronic lymphocytic leukemia undergoing treatment with ibrutinib is not associated with a greater likelihood of early relapse.
A prospective observational study in 85 relapsed or refractory patients with chronic lymphocytic leukemia treated with ibrutinib showed lymphocytosis occurred in 77% in patients, persisting at 12 months in 20% of patients.
Dr. Jennifer A. Woyach of Ohio State University, Columbus, and her colleagues found no significant differences in progression-free survival between patients who responded to treatment but showed persistent lymphocytosis, and those with a partial or complete response to treatment without lymphocytosis.
They also found no significant differences in gene expression profiles in persistent lymphocytosis, suggesting that the lymphocytosis most likely represented the movement of quiescent cells (Blood 2014;123:1810-17).
Two authors were unpaid consultants for, three were paid consultants for, and two were employees of Pharmacyclics. One author received research funding from Janssen. The study was funded by the Four Winds Foundation, the Leukemia and Lymphoma Society, and several other organizations. Ibrutinib was provided by Pharmacyclics for in vitro experiments.
As more treatments targeting B-cell receptors became available, it was important for physicians to understand that lymphocytosis associated with this treatment was not indicative of treatment resistance or disease aggressiveness. The study by Woyach et al. provides the proof of principle that prolonged lymphocytosis produced by ibrutinib is composed of quiescent leukemic cells and provides a biological rationale in support of the current revisions of CLL [chronic lymphocytic leukemia] response criteria.
Dr. Davide Rossi and Dr. Gianluca Gaidano of the Amedeo Avogadro University of Eastern Piedmont, Alessandria, Italy, provided these comments in an editorial accompanying Dr. Woyach’s study (Blood 2014;123:1772-4). They declared that had no conflicts of interest.
Dr. Jennifer A. Woyach,
As more treatments targeting B-cell receptors became available, it was important for physicians to understand that lymphocytosis associated with this treatment was not indicative of treatment resistance or disease aggressiveness. The study by Woyach et al. provides the proof of principle that prolonged lymphocytosis produced by ibrutinib is composed of quiescent leukemic cells and provides a biological rationale in support of the current revisions of CLL [chronic lymphocytic leukemia] response criteria.
Dr. Davide Rossi and Dr. Gianluca Gaidano of the Amedeo Avogadro University of Eastern Piedmont, Alessandria, Italy, provided these comments in an editorial accompanying Dr. Woyach’s study (Blood 2014;123:1772-4). They declared that had no conflicts of interest.
As more treatments targeting B-cell receptors became available, it was important for physicians to understand that lymphocytosis associated with this treatment was not indicative of treatment resistance or disease aggressiveness. The study by Woyach et al. provides the proof of principle that prolonged lymphocytosis produced by ibrutinib is composed of quiescent leukemic cells and provides a biological rationale in support of the current revisions of CLL [chronic lymphocytic leukemia] response criteria.
Dr. Davide Rossi and Dr. Gianluca Gaidano of the Amedeo Avogadro University of Eastern Piedmont, Alessandria, Italy, provided these comments in an editorial accompanying Dr. Woyach’s study (Blood 2014;123:1772-4). They declared that had no conflicts of interest.
Persistent lymphocytosis lasting more than 12 months in patients with chronic lymphocytic leukemia undergoing treatment with ibrutinib is not associated with a greater likelihood of early relapse.
A prospective observational study in 85 relapsed or refractory patients with chronic lymphocytic leukemia treated with ibrutinib showed lymphocytosis occurred in 77% in patients, persisting at 12 months in 20% of patients.
Dr. Jennifer A. Woyach of Ohio State University, Columbus, and her colleagues found no significant differences in progression-free survival between patients who responded to treatment but showed persistent lymphocytosis, and those with a partial or complete response to treatment without lymphocytosis.
They also found no significant differences in gene expression profiles in persistent lymphocytosis, suggesting that the lymphocytosis most likely represented the movement of quiescent cells (Blood 2014;123:1810-17).
Two authors were unpaid consultants for, three were paid consultants for, and two were employees of Pharmacyclics. One author received research funding from Janssen. The study was funded by the Four Winds Foundation, the Leukemia and Lymphoma Society, and several other organizations. Ibrutinib was provided by Pharmacyclics for in vitro experiments.
Persistent lymphocytosis lasting more than 12 months in patients with chronic lymphocytic leukemia undergoing treatment with ibrutinib is not associated with a greater likelihood of early relapse.
A prospective observational study in 85 relapsed or refractory patients with chronic lymphocytic leukemia treated with ibrutinib showed lymphocytosis occurred in 77% in patients, persisting at 12 months in 20% of patients.
Dr. Jennifer A. Woyach of Ohio State University, Columbus, and her colleagues found no significant differences in progression-free survival between patients who responded to treatment but showed persistent lymphocytosis, and those with a partial or complete response to treatment without lymphocytosis.
They also found no significant differences in gene expression profiles in persistent lymphocytosis, suggesting that the lymphocytosis most likely represented the movement of quiescent cells (Blood 2014;123:1810-17).
Two authors were unpaid consultants for, three were paid consultants for, and two were employees of Pharmacyclics. One author received research funding from Janssen. The study was funded by the Four Winds Foundation, the Leukemia and Lymphoma Society, and several other organizations. Ibrutinib was provided by Pharmacyclics for in vitro experiments.
Dr. Jennifer A. Woyach,
Dr. Jennifer A. Woyach,
FROM BLOOD
Major finding: Patients with chronic lymphocytic leukemia who experienced persistent lymphocytosis associated with ibrutinib treatment did not have a greater likelihood of early relapse.
Data source: Prospective observational cohort study in 85 patients with relapsed or refractory chronic lymphocytic leukemia undergoing treatment with ibrutinib.
Disclosures: Two authors were unpaid consultants and three were paid consultants for Pharmacyclics, and two authors were employees of the company. One author received research funding from Janssen. The study was funded by the Four Winds Foundation, the Leukemia and Lymphoma Society, and several other organizations. Ibrutinib was provided by Pharmacyclics for in vitro experiments.
Idelalisib and rituximab extends survival in CLL patients
Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to published results from Study 116.
The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).
The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported at the annual meeting of the American Society of Hematology in December. The final results of the study were published online January 22 in the New England Journal of Medicine.
Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).
The investigators evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m2 in week 1, 500 mg/m2 every 2 weeks for four doses, followed by 500 mg/m2 every 4 weeks for three more doses.
Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to published results from Study 116.
The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).
The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported at the annual meeting of the American Society of Hematology in December. The final results of the study were published online January 22 in the New England Journal of Medicine.
Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).
The investigators evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m2 in week 1, 500 mg/m2 every 2 weeks for four doses, followed by 500 mg/m2 every 4 weeks for three more doses.
Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to published results from Study 116.
The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).
The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported at the annual meeting of the American Society of Hematology in December. The final results of the study were published online January 22 in the New England Journal of Medicine.
Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).
The investigators evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m2 in week 1, 500 mg/m2 every 2 weeks for four doses, followed by 500 mg/m2 every 4 weeks for three more doses.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
ONO-4059 makes waves in heavily pretreated CLL
NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.
The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.
Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.
All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.
"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.
ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.
No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.
ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.
Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.
One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.
"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.
Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.
ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.
The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.
ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.
No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.
Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.
NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.
The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.
Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.
All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.
"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.
ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.
No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.
ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.
Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.
One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.
"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.
Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.
ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.
The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.
ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.
No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.
Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.
NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.
The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.
Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.
All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.
"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.
ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.
No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.
ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.
Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.
One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.
"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.
Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.
ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.
The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.
ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.
No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.
Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.
AT ASH 2013
Major finding: The response rate was 89% overall and 71% for patients with 17p deletion.
Data source: A prospective, phase I dose-escalation study in 18 patients with relapsed/refractory or high-risk CLL.
Disclosures: Dr. Salles reported honoraria from Janssen, Gilead, and Celgene. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.
FDA provides steps to obtain ponatinib following suspension
The Food and Drug Administration has provided information on how health care professionals can ensure that patients who have benefitted from the leukemia drug ponatinib continue to have access to the treatment.
Less than a week after the agency announced that marketing and sales of the drug had been suspended because of the risk of life-threatening blood clots and severe narrowing of blood vessels associated with treatment, the FDA posted instructions on how to obtain emergency access to ponatinib through an Investigational New Drug (IND) application. This process entails contacting the FDA to obtain an emergency IND number for each patient who would benefit from continuing treatment and providing the manufacturer with that number to get ponatinib (Iclusig).
Health care professionals can obtain INDs for multiple patients during one phone call and should contact the agency at least 48-72 hours before the drug is needed, according to an FDA announcement.
The statement noted that health care professionals "may continue to use Iclusig for patients who they determine are responding to the drug and for whom the potential benefits outweigh the risks."
Ponatinib is a kinase inhibitor marketed by ARIAD Pharmaceuticals. It was approved in December 2012 for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults.
Serious adverse events associated with ponatinib should be reported online to the FDA or by phone at 800-332-0178. Information about the IND program is available online. The FDA’s emergency IND telephone number is 301-796-7550 (between 8 a.m. and 4:30 p.m. EST, weekdays and 866-300-4374 after 4:30 p.m. EST. More information on how to obtain an IND for patients on ponatinib is available at http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm.
The Food and Drug Administration has provided information on how health care professionals can ensure that patients who have benefitted from the leukemia drug ponatinib continue to have access to the treatment.
Less than a week after the agency announced that marketing and sales of the drug had been suspended because of the risk of life-threatening blood clots and severe narrowing of blood vessels associated with treatment, the FDA posted instructions on how to obtain emergency access to ponatinib through an Investigational New Drug (IND) application. This process entails contacting the FDA to obtain an emergency IND number for each patient who would benefit from continuing treatment and providing the manufacturer with that number to get ponatinib (Iclusig).
Health care professionals can obtain INDs for multiple patients during one phone call and should contact the agency at least 48-72 hours before the drug is needed, according to an FDA announcement.
The statement noted that health care professionals "may continue to use Iclusig for patients who they determine are responding to the drug and for whom the potential benefits outweigh the risks."
Ponatinib is a kinase inhibitor marketed by ARIAD Pharmaceuticals. It was approved in December 2012 for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults.
Serious adverse events associated with ponatinib should be reported online to the FDA or by phone at 800-332-0178. Information about the IND program is available online. The FDA’s emergency IND telephone number is 301-796-7550 (between 8 a.m. and 4:30 p.m. EST, weekdays and 866-300-4374 after 4:30 p.m. EST. More information on how to obtain an IND for patients on ponatinib is available at http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm.
The Food and Drug Administration has provided information on how health care professionals can ensure that patients who have benefitted from the leukemia drug ponatinib continue to have access to the treatment.
Less than a week after the agency announced that marketing and sales of the drug had been suspended because of the risk of life-threatening blood clots and severe narrowing of blood vessels associated with treatment, the FDA posted instructions on how to obtain emergency access to ponatinib through an Investigational New Drug (IND) application. This process entails contacting the FDA to obtain an emergency IND number for each patient who would benefit from continuing treatment and providing the manufacturer with that number to get ponatinib (Iclusig).
Health care professionals can obtain INDs for multiple patients during one phone call and should contact the agency at least 48-72 hours before the drug is needed, according to an FDA announcement.
The statement noted that health care professionals "may continue to use Iclusig for patients who they determine are responding to the drug and for whom the potential benefits outweigh the risks."
Ponatinib is a kinase inhibitor marketed by ARIAD Pharmaceuticals. It was approved in December 2012 for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults.
Serious adverse events associated with ponatinib should be reported online to the FDA or by phone at 800-332-0178. Information about the IND program is available online. The FDA’s emergency IND telephone number is 301-796-7550 (between 8 a.m. and 4:30 p.m. EST, weekdays and 866-300-4374 after 4:30 p.m. EST. More information on how to obtain an IND for patients on ponatinib is available at http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm.
