EHA Congress 2014

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.

Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.

Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.

Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.

Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.

Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.

“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”

To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.

The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.

To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.

The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.

In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.

Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.

“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”

Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.

“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.

“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”

MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.

Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.

Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.

Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.

Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.

Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.

“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”

To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.

The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.

To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.

The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.

In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.

Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.

“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”

Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.

“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.

“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”

MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.

Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.

Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.

Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.

Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.

Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.

“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”

To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.

The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.

To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.

The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.

In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.

Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.

“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”

Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.

“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.

“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”

MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.

All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.

Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.

“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.

“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”

Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.

She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.

Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.

For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.

For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.

Response and relapse

The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).

Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.

“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.

“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”

However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.

Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.

Safety and tolerability

Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.

The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).

There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.

There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.

MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.

All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.

Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.

“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.

“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”

Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.

She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.

Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.

For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.

For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.

Response and relapse

The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).

Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.

“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.

“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”

However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.

Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.

Safety and tolerability

Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.

The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).

There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.

There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.

MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.

All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.

Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.

“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.

“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”

Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.

She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.

Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.

For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.

For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.

Response and relapse

The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).

Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.

“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.

“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”

However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.

Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.

Safety and tolerability

Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.

The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).

There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.

There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.

MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.

Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.

Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.

Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.

"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.

AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).

About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.

An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.

Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.

Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.

Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.

AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.

The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.

Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.

There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.

There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.

"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.

Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.

pwendling@frontlinemedcom.com

MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.

Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.

Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.

Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.

"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.

AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).

About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.

An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.

Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.

Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.

Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.

AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.

The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.

Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.

There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.

There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.

"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.

Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.

pwendling@frontlinemedcom.com

MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.

Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.

Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.

Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.

"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.

AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).

About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.

An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.

Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.

Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.

Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.

AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.

The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.

Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.

There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.

There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.

"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.

Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.

pwendling@frontlinemedcom.com

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

MILAN—Two new studies appear to confirm the prognostic significance of CALR mutations in patients with primary myelofibrosis (PMF).

One study showed that PMF patients with mutated CALR had prolonged overall survival (OS) compared to patients with wild-type CALR. And additional subclonal mutations did not impair the positive impact of CALR mutations.

Another study suggested that indels in exon 9 of CALR are founding driver mutations in PMF. These mutations are independent predictors of clinical course, disease progression, and OS.

Both studies were presented at the 19th Congress of the European Hematology Association (EHA).

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented data on CALR mutations in the context of additional mutations (abstract S1355).

And Elisa Rumi, MD, of the University of Pavia in Italy, presented information on mutated CALR and other founding driver mutations in PMF (abstract S1356).

CALR & other subclonal mutations in PMF

To investigate the prognostic role of CALR mutations in relation to additional subclonal mutations, Dr Guglielmelli and her colleagues analyzed 274 samples from PMF patients.

The team genotyped the samples for mutations in 11 genes: JAK2, CALR, MPL, EZH2, ASXL1, SRSF2, IDH1, IDH2, CBL, TET2, and DNMT3A.

Two hundred and fifty-six patients (93.4%) presented with at least 1 somatic mutation, and 104 (38%) presented with at least 2.

The median follow-up was 3.8 years (range, 0.52-29.20 years). Among all patients, the median OS was 12.2 years (range, 5.6-18.8 years). Eighty-four patients died (30.7%), 44 (16.1%) of them due to leukemia.

The presence of CALR mutations was associated with better OS, independent of IPSS and molecular risk categories (hazard ratio [HR] 0.51, P=0.03). But CALR mutations did not impact the risk of progression to acute leukemia.

Among patients with a low- to intermediate-1-risk IPSS score, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR 0.4, P=0.02). Among patients with intermediate-2 to high risk, those with CALR mutations lived a median of 4.2 years, and those without lived a median of 2.6 years (HR=0.5, P=0.09).

Among patients with high molecular risk, those with CALR mutations lived a median of 17.7 years, and those without lived a median of 4.3 years, (HR=0.3, P=0.008). High molecular risk was defined as at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2.

Among patients in the low-molecular-risk group, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR=0.6, P=0.048).

Dr Guglielmelli said these results confirm the association between CALR mutation and favorable outcomes in PMF. They also show that additional subclonal mutations do not impair the positive impact of CALR mutation, thereby reinforcing the idea that CALR-mutated PMF is a distinct entity in terms of prognosis.

Founding driver mutations in PMF

In another presentation at the EHA Congress, Dr Rumi presented data on founding driver mutations in PMF. She and her colleagues analyzed 617 PMF patients, screening them for JAK2 V617F mutations, indels of CALR exon 9, and MPL exon 10 mutations.

The researchers assessed the impact of these mutations on thrombosis, progression to leukemia, and OS.

Their analysis suggested CALR-mutated PMF patients have a lower risk of thrombosis than JAK2-mutated patients (P=0.021). And this difference retained significance after adjusting for age.

Triple-negative PMF patients had a higher risk of leukemic evolution than CALR-mutated patients (P=0.016) and JAK2-mutated patients (P=0.043).

After adjusting for age, the risk remained significantly higher in triple-negative patients compared to JAK2-mutated patients (P=0.04) and retained borderline significance compared to CALR-mutated patients (P=0.052).

Patients with CALR-mutated PMF had a better OS than JAK2-mutated patients (P<0.001), MPL-mutated patients (P=0.009), and triple-negative patients (P<0.001).

In a multivariate analysis, CALR-mutated patients maintained a better OS than JAK2-mutated patients (P=0.019) and triple-negative patients (P<0.001).

Based on these results, Dr Rumi concluded that mutations in JAK2, CALR, and MPL are independent predictors of clinical course, disease progression, and OS in PMF. So screening patients for these mutations can likely improve upon the risk stratification provided by IPSS.

MILAN—Two new studies appear to confirm the prognostic significance of CALR mutations in patients with primary myelofibrosis (PMF).

One study showed that PMF patients with mutated CALR had prolonged overall survival (OS) compared to patients with wild-type CALR. And additional subclonal mutations did not impair the positive impact of CALR mutations.

Another study suggested that indels in exon 9 of CALR are founding driver mutations in PMF. These mutations are independent predictors of clinical course, disease progression, and OS.

Both studies were presented at the 19th Congress of the European Hematology Association (EHA).

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented data on CALR mutations in the context of additional mutations (abstract S1355).

And Elisa Rumi, MD, of the University of Pavia in Italy, presented information on mutated CALR and other founding driver mutations in PMF (abstract S1356).

CALR & other subclonal mutations in PMF

To investigate the prognostic role of CALR mutations in relation to additional subclonal mutations, Dr Guglielmelli and her colleagues analyzed 274 samples from PMF patients.

The team genotyped the samples for mutations in 11 genes: JAK2, CALR, MPL, EZH2, ASXL1, SRSF2, IDH1, IDH2, CBL, TET2, and DNMT3A.

Two hundred and fifty-six patients (93.4%) presented with at least 1 somatic mutation, and 104 (38%) presented with at least 2.

The median follow-up was 3.8 years (range, 0.52-29.20 years). Among all patients, the median OS was 12.2 years (range, 5.6-18.8 years). Eighty-four patients died (30.7%), 44 (16.1%) of them due to leukemia.

The presence of CALR mutations was associated with better OS, independent of IPSS and molecular risk categories (hazard ratio [HR] 0.51, P=0.03). But CALR mutations did not impact the risk of progression to acute leukemia.

Among patients with a low- to intermediate-1-risk IPSS score, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR 0.4, P=0.02). Among patients with intermediate-2 to high risk, those with CALR mutations lived a median of 4.2 years, and those without lived a median of 2.6 years (HR=0.5, P=0.09).

Among patients with high molecular risk, those with CALR mutations lived a median of 17.7 years, and those without lived a median of 4.3 years, (HR=0.3, P=0.008). High molecular risk was defined as at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2.

Among patients in the low-molecular-risk group, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR=0.6, P=0.048).

Dr Guglielmelli said these results confirm the association between CALR mutation and favorable outcomes in PMF. They also show that additional subclonal mutations do not impair the positive impact of CALR mutation, thereby reinforcing the idea that CALR-mutated PMF is a distinct entity in terms of prognosis.

Founding driver mutations in PMF

In another presentation at the EHA Congress, Dr Rumi presented data on founding driver mutations in PMF. She and her colleagues analyzed 617 PMF patients, screening them for JAK2 V617F mutations, indels of CALR exon 9, and MPL exon 10 mutations.

The researchers assessed the impact of these mutations on thrombosis, progression to leukemia, and OS.

Their analysis suggested CALR-mutated PMF patients have a lower risk of thrombosis than JAK2-mutated patients (P=0.021). And this difference retained significance after adjusting for age.

Triple-negative PMF patients had a higher risk of leukemic evolution than CALR-mutated patients (P=0.016) and JAK2-mutated patients (P=0.043).

After adjusting for age, the risk remained significantly higher in triple-negative patients compared to JAK2-mutated patients (P=0.04) and retained borderline significance compared to CALR-mutated patients (P=0.052).

Patients with CALR-mutated PMF had a better OS than JAK2-mutated patients (P<0.001), MPL-mutated patients (P=0.009), and triple-negative patients (P<0.001).

In a multivariate analysis, CALR-mutated patients maintained a better OS than JAK2-mutated patients (P=0.019) and triple-negative patients (P<0.001).

Based on these results, Dr Rumi concluded that mutations in JAK2, CALR, and MPL are independent predictors of clinical course, disease progression, and OS in PMF. So screening patients for these mutations can likely improve upon the risk stratification provided by IPSS.

MILAN—Two new studies appear to confirm the prognostic significance of CALR mutations in patients with primary myelofibrosis (PMF).

One study showed that PMF patients with mutated CALR had prolonged overall survival (OS) compared to patients with wild-type CALR. And additional subclonal mutations did not impair the positive impact of CALR mutations.

Another study suggested that indels in exon 9 of CALR are founding driver mutations in PMF. These mutations are independent predictors of clinical course, disease progression, and OS.

Both studies were presented at the 19th Congress of the European Hematology Association (EHA).

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented data on CALR mutations in the context of additional mutations (abstract S1355).

And Elisa Rumi, MD, of the University of Pavia in Italy, presented information on mutated CALR and other founding driver mutations in PMF (abstract S1356).

CALR & other subclonal mutations in PMF

To investigate the prognostic role of CALR mutations in relation to additional subclonal mutations, Dr Guglielmelli and her colleagues analyzed 274 samples from PMF patients.

The team genotyped the samples for mutations in 11 genes: JAK2, CALR, MPL, EZH2, ASXL1, SRSF2, IDH1, IDH2, CBL, TET2, and DNMT3A.

Two hundred and fifty-six patients (93.4%) presented with at least 1 somatic mutation, and 104 (38%) presented with at least 2.

The median follow-up was 3.8 years (range, 0.52-29.20 years). Among all patients, the median OS was 12.2 years (range, 5.6-18.8 years). Eighty-four patients died (30.7%), 44 (16.1%) of them due to leukemia.

The presence of CALR mutations was associated with better OS, independent of IPSS and molecular risk categories (hazard ratio [HR] 0.51, P=0.03). But CALR mutations did not impact the risk of progression to acute leukemia.

Among patients with a low- to intermediate-1-risk IPSS score, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR 0.4, P=0.02). Among patients with intermediate-2 to high risk, those with CALR mutations lived a median of 4.2 years, and those without lived a median of 2.6 years (HR=0.5, P=0.09).

Among patients with high molecular risk, those with CALR mutations lived a median of 17.7 years, and those without lived a median of 4.3 years, (HR=0.3, P=0.008). High molecular risk was defined as at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2.

Among patients in the low-molecular-risk group, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR=0.6, P=0.048).

Dr Guglielmelli said these results confirm the association between CALR mutation and favorable outcomes in PMF. They also show that additional subclonal mutations do not impair the positive impact of CALR mutation, thereby reinforcing the idea that CALR-mutated PMF is a distinct entity in terms of prognosis.

Founding driver mutations in PMF

In another presentation at the EHA Congress, Dr Rumi presented data on founding driver mutations in PMF. She and her colleagues analyzed 617 PMF patients, screening them for JAK2 V617F mutations, indels of CALR exon 9, and MPL exon 10 mutations.

The researchers assessed the impact of these mutations on thrombosis, progression to leukemia, and OS.

Their analysis suggested CALR-mutated PMF patients have a lower risk of thrombosis than JAK2-mutated patients (P=0.021). And this difference retained significance after adjusting for age.

Triple-negative PMF patients had a higher risk of leukemic evolution than CALR-mutated patients (P=0.016) and JAK2-mutated patients (P=0.043).

After adjusting for age, the risk remained significantly higher in triple-negative patients compared to JAK2-mutated patients (P=0.04) and retained borderline significance compared to CALR-mutated patients (P=0.052).

Patients with CALR-mutated PMF had a better OS than JAK2-mutated patients (P<0.001), MPL-mutated patients (P=0.009), and triple-negative patients (P<0.001).

In a multivariate analysis, CALR-mutated patients maintained a better OS than JAK2-mutated patients (P=0.019) and triple-negative patients (P<0.001).

Based on these results, Dr Rumi concluded that mutations in JAK2, CALR, and MPL are independent predictors of clinical course, disease progression, and OS in PMF. So screening patients for these mutations can likely improve upon the risk stratification provided by IPSS.

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.