Jen Smith

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.

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.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.

MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).

The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.

A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.

But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.

“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . .  remains a clinical and economic burden,” Dr Minniti noted.

“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”

With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.

Patient characteristics and treatment

The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).

Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm² (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm² (range, 2.51-14.66).

The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).

For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.

Adverse events

There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.

Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.

For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.

Effects on ulcer size

Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).

Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.

One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.

The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.

Effects on pain and blood flow

One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.

There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).

Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).

“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”

Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).

Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”