Cythemias

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

Rusfertide, a first-in-class mimetic of hepcidin, shows high efficacy in the treatment of erythrocytosis polycythemia vera (PV), with substantial improvements in hematocrit levels that can potentially eliminate the need for phlebotomies that are typically required – but usually ineffective.

“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.

“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.

PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.

To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.

To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.

“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”

For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.

During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.

The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).

The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.

Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.

At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).

Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).

Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).

Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.

Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).

In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.

The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.

Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.

Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.

“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”

“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”

Overall, she agreed that the responses are remarkably positive.

“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”

In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”

The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.

Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”

Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”

“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.

In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.

The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.

Rusfertide, a first-in-class mimetic of hepcidin, shows high efficacy in the treatment of erythrocytosis polycythemia vera (PV), with substantial improvements in hematocrit levels that can potentially eliminate the need for phlebotomies that are typically required – but usually ineffective.

“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.

“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.

PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.

To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.

To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.

“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”

For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.

During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.

The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).

The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.

Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.

At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).

Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).

Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).

Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.

Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).

In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.

The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.

Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.

Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.

“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”

“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”

Overall, she agreed that the responses are remarkably positive.

“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”

In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”

The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.

Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”

Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”

“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.

In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.

The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.

Rusfertide, a first-in-class mimetic of hepcidin, shows high efficacy in the treatment of erythrocytosis polycythemia vera (PV), with substantial improvements in hematocrit levels that can potentially eliminate the need for phlebotomies that are typically required – but usually ineffective.

“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.

“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.

PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.

To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.

To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.

“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”

For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.

During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.

The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).

The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.

Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.

At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).

Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).

Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).

Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.

Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).

In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.

The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.

Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.

Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.

“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”

“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”

Overall, she agreed that the responses are remarkably positive.

“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”

In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”

The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.

Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”

Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”

“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.

In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.

The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.

In a webinar designed to guide physicians in the care of hematology patients during the COVID-19 pandemic, three world experts on thalassemia and sickle cell disease (SCD) provided on-the-ground information from physicians who were dealing with the height of the crisis in their countries.

The webinar was organized by the European Hematology Association (EHA) and the Thalassemia International Federation (TIF).

Moderator Francesco Cerisoli, MD, head of research and mentoring at EHA, led the discussion with three guest speakers: Maria-Domenica Cappellini, MD, PhD, professor of hematology at the University of Milan; Androulla Eleftheriou, MD, executive director of TIF in Cyprus; and Raffaella Colombatti , MD, of the University of Padova in Italy, coordinator of the Red Cell Reserve Working Group of the Italian Association of Pediatric Hematology and Oncology.
 

Italian experience with thalassemia and COVID-19

Dr. Cappellini discussed the Italian experience with 11 thalassemia patients followed by a network survey who developed COVID-19 in the northern part of Italy, where the pandemic has been most widespread.

There are no published data focusing specifically on SARS-CoV-2 infection in patients with thalassemic syndromes, but patients with preexisting comorbidities are likely to be more severely affected by SARS-CoV-2, according to Dr. Cappellini.

Of particular concern is the fact that patients with thalassemia, especially older ones, are frequently splenectomized, which renders them more vulnerable to bacterial infections and can trigger life-threatening sepsis. However, splenectomy is not known to increase the risk of viral infection or severe viral illness. Of additional concern is the fact that many thalassemia patients need routine and frequent transfusions.

Overall, the 11 thalassemia patients who developed COVID-19 experienced only mild to moderate symptoms. This is despite the fact that 72% of the patients were splenectomized, which did not appear to affect the clinical course, and all of the patients had thalassemia-related comorbidities.

Around half of the patients were hospitalized, but none of them required transfer to the ICU. One patient who was treated with chemotherapy for diffuse large B-cell lymphoma in 2019 but is now in remission required more intense ventilation support with the use of continuous positive airway pressure.

Only three patients received specific treatment for COVID-19: one with hydroxychloroquine (HCQ) alone, one with HCQ plus anakinra, and one with HCQ plus ritonavir/darunavir.

Overall, “the number of infected thalassemia patients was lower than expected, likely due to earlier and more vigilant self-isolation compared to the general population,” Dr. Cappellini said. She pointed out that the first early response in February by thalassemia physicians was to warn their patients via email and phone calls about the need for self-isolation and precautions against the pandemic.

Physicians “rapidly reorganized activities, postponing nonessential ones” and managed to provide patients “a safe track at the hospital to receive their life-saving treatment in COVID-19–free areas with health care personnel wearing protective equipment” and assessment of all entering patients for COVID-19 infection, Dr. Cappellini said.
 

Results in additional thalassemia patients and SCD patients

Dr. Eleftheriou described 51 cases of thalassemia patients with SARS-CoV-2 infection reported to TIF as of April 16. Patients were from Cyprus, Italy, the United Kingdom, France, Turkey, Iran, Pakistan, and Indonesia.

Of the 51 patients, 46 presented with mild to moderate symptoms. Five patients had severe respiratory symptoms and required hospitalization, two were hospitalized and discharged, and three died between day 5 and day 15 post hospitalization.

Dr. Colombatti followed with a brief presentation of the intersection of COVID-19 with SCD patients. She presented anecdotal data involving 32 SCD patients who exhibited COVID-19 symptoms. Dr. Colombatti obtained the data via personal communication with Pablo Bartolucci, of Hôpitaux Universitaires Henri Mondor in Créteil, France.

All 32 SCD patients were screened and treated for COVID-19, and 17 of them continued treatment for 10 days. In all, 22 patients were hospitalized, 11 were transferred to the ICU, and 1 died.
 

Ensuring adequate blood supply

Dr. Eleftheriou also discussed the TIF response to the COVID-19 pandemic, which focused on the adequacy of blood supplies for these patients who so often need transfusions.

Dr. Eleftheriou stated that a shortage of blood was reported in 75% of the 62 member countries of the TIF, with 58% reporting severe shortages and 35% reporting moderate to severe shortages.

The shortages resulted in many countries returning to older family/friends donation practices, rare use of whole blood transfusions, and the use of older blood transfusions (older than 28 days).

In addition, physicians have modified their transfusion strategy. They have reduced the amount of blood given to thalassemia patients from two units to one unit during any transfusion, while making arrangements for more frequent transfusions; for example, one transfusion per week but with precautions made to “limit the time spent in the clinic and to control blood supplies while safeguarding that all [thalassemia] patients will be able to get their transfusion,” Dr. Eleftheriou said.

The information in the webinar was provided with the caveat that “no general evidence-based guidance can be derived from this discussion.” There were no other disclosures given.

mlesney@mdedge.com

In a webinar designed to guide physicians in the care of hematology patients during the COVID-19 pandemic, three world experts on thalassemia and sickle cell disease (SCD) provided on-the-ground information from physicians who were dealing with the height of the crisis in their countries.

The webinar was organized by the European Hematology Association (EHA) and the Thalassemia International Federation (TIF).

Moderator Francesco Cerisoli, MD, head of research and mentoring at EHA, led the discussion with three guest speakers: Maria-Domenica Cappellini, MD, PhD, professor of hematology at the University of Milan; Androulla Eleftheriou, MD, executive director of TIF in Cyprus; and Raffaella Colombatti , MD, of the University of Padova in Italy, coordinator of the Red Cell Reserve Working Group of the Italian Association of Pediatric Hematology and Oncology.
 

Italian experience with thalassemia and COVID-19

Dr. Cappellini discussed the Italian experience with 11 thalassemia patients followed by a network survey who developed COVID-19 in the northern part of Italy, where the pandemic has been most widespread.

There are no published data focusing specifically on SARS-CoV-2 infection in patients with thalassemic syndromes, but patients with preexisting comorbidities are likely to be more severely affected by SARS-CoV-2, according to Dr. Cappellini.

Of particular concern is the fact that patients with thalassemia, especially older ones, are frequently splenectomized, which renders them more vulnerable to bacterial infections and can trigger life-threatening sepsis. However, splenectomy is not known to increase the risk of viral infection or severe viral illness. Of additional concern is the fact that many thalassemia patients need routine and frequent transfusions.

Overall, the 11 thalassemia patients who developed COVID-19 experienced only mild to moderate symptoms. This is despite the fact that 72% of the patients were splenectomized, which did not appear to affect the clinical course, and all of the patients had thalassemia-related comorbidities.

Around half of the patients were hospitalized, but none of them required transfer to the ICU. One patient who was treated with chemotherapy for diffuse large B-cell lymphoma in 2019 but is now in remission required more intense ventilation support with the use of continuous positive airway pressure.

Only three patients received specific treatment for COVID-19: one with hydroxychloroquine (HCQ) alone, one with HCQ plus anakinra, and one with HCQ plus ritonavir/darunavir.

Overall, “the number of infected thalassemia patients was lower than expected, likely due to earlier and more vigilant self-isolation compared to the general population,” Dr. Cappellini said. She pointed out that the first early response in February by thalassemia physicians was to warn their patients via email and phone calls about the need for self-isolation and precautions against the pandemic.

Physicians “rapidly reorganized activities, postponing nonessential ones” and managed to provide patients “a safe track at the hospital to receive their life-saving treatment in COVID-19–free areas with health care personnel wearing protective equipment” and assessment of all entering patients for COVID-19 infection, Dr. Cappellini said.
 

Results in additional thalassemia patients and SCD patients

Dr. Eleftheriou described 51 cases of thalassemia patients with SARS-CoV-2 infection reported to TIF as of April 16. Patients were from Cyprus, Italy, the United Kingdom, France, Turkey, Iran, Pakistan, and Indonesia.

Of the 51 patients, 46 presented with mild to moderate symptoms. Five patients had severe respiratory symptoms and required hospitalization, two were hospitalized and discharged, and three died between day 5 and day 15 post hospitalization.

Dr. Colombatti followed with a brief presentation of the intersection of COVID-19 with SCD patients. She presented anecdotal data involving 32 SCD patients who exhibited COVID-19 symptoms. Dr. Colombatti obtained the data via personal communication with Pablo Bartolucci, of Hôpitaux Universitaires Henri Mondor in Créteil, France.

All 32 SCD patients were screened and treated for COVID-19, and 17 of them continued treatment for 10 days. In all, 22 patients were hospitalized, 11 were transferred to the ICU, and 1 died.
 

Ensuring adequate blood supply

Dr. Eleftheriou also discussed the TIF response to the COVID-19 pandemic, which focused on the adequacy of blood supplies for these patients who so often need transfusions.

Dr. Eleftheriou stated that a shortage of blood was reported in 75% of the 62 member countries of the TIF, with 58% reporting severe shortages and 35% reporting moderate to severe shortages.

The shortages resulted in many countries returning to older family/friends donation practices, rare use of whole blood transfusions, and the use of older blood transfusions (older than 28 days).

In addition, physicians have modified their transfusion strategy. They have reduced the amount of blood given to thalassemia patients from two units to one unit during any transfusion, while making arrangements for more frequent transfusions; for example, one transfusion per week but with precautions made to “limit the time spent in the clinic and to control blood supplies while safeguarding that all [thalassemia] patients will be able to get their transfusion,” Dr. Eleftheriou said.

The information in the webinar was provided with the caveat that “no general evidence-based guidance can be derived from this discussion.” There were no other disclosures given.

mlesney@mdedge.com

In a webinar designed to guide physicians in the care of hematology patients during the COVID-19 pandemic, three world experts on thalassemia and sickle cell disease (SCD) provided on-the-ground information from physicians who were dealing with the height of the crisis in their countries.

The webinar was organized by the European Hematology Association (EHA) and the Thalassemia International Federation (TIF).

Moderator Francesco Cerisoli, MD, head of research and mentoring at EHA, led the discussion with three guest speakers: Maria-Domenica Cappellini, MD, PhD, professor of hematology at the University of Milan; Androulla Eleftheriou, MD, executive director of TIF in Cyprus; and Raffaella Colombatti , MD, of the University of Padova in Italy, coordinator of the Red Cell Reserve Working Group of the Italian Association of Pediatric Hematology and Oncology.
 

Italian experience with thalassemia and COVID-19

Dr. Cappellini discussed the Italian experience with 11 thalassemia patients followed by a network survey who developed COVID-19 in the northern part of Italy, where the pandemic has been most widespread.

There are no published data focusing specifically on SARS-CoV-2 infection in patients with thalassemic syndromes, but patients with preexisting comorbidities are likely to be more severely affected by SARS-CoV-2, according to Dr. Cappellini.

Of particular concern is the fact that patients with thalassemia, especially older ones, are frequently splenectomized, which renders them more vulnerable to bacterial infections and can trigger life-threatening sepsis. However, splenectomy is not known to increase the risk of viral infection or severe viral illness. Of additional concern is the fact that many thalassemia patients need routine and frequent transfusions.

Overall, the 11 thalassemia patients who developed COVID-19 experienced only mild to moderate symptoms. This is despite the fact that 72% of the patients were splenectomized, which did not appear to affect the clinical course, and all of the patients had thalassemia-related comorbidities.

Around half of the patients were hospitalized, but none of them required transfer to the ICU. One patient who was treated with chemotherapy for diffuse large B-cell lymphoma in 2019 but is now in remission required more intense ventilation support with the use of continuous positive airway pressure.

Only three patients received specific treatment for COVID-19: one with hydroxychloroquine (HCQ) alone, one with HCQ plus anakinra, and one with HCQ plus ritonavir/darunavir.

Overall, “the number of infected thalassemia patients was lower than expected, likely due to earlier and more vigilant self-isolation compared to the general population,” Dr. Cappellini said. She pointed out that the first early response in February by thalassemia physicians was to warn their patients via email and phone calls about the need for self-isolation and precautions against the pandemic.

Physicians “rapidly reorganized activities, postponing nonessential ones” and managed to provide patients “a safe track at the hospital to receive their life-saving treatment in COVID-19–free areas with health care personnel wearing protective equipment” and assessment of all entering patients for COVID-19 infection, Dr. Cappellini said.
 

Results in additional thalassemia patients and SCD patients

Dr. Eleftheriou described 51 cases of thalassemia patients with SARS-CoV-2 infection reported to TIF as of April 16. Patients were from Cyprus, Italy, the United Kingdom, France, Turkey, Iran, Pakistan, and Indonesia.

Of the 51 patients, 46 presented with mild to moderate symptoms. Five patients had severe respiratory symptoms and required hospitalization, two were hospitalized and discharged, and three died between day 5 and day 15 post hospitalization.

Dr. Colombatti followed with a brief presentation of the intersection of COVID-19 with SCD patients. She presented anecdotal data involving 32 SCD patients who exhibited COVID-19 symptoms. Dr. Colombatti obtained the data via personal communication with Pablo Bartolucci, of Hôpitaux Universitaires Henri Mondor in Créteil, France.

All 32 SCD patients were screened and treated for COVID-19, and 17 of them continued treatment for 10 days. In all, 22 patients were hospitalized, 11 were transferred to the ICU, and 1 died.
 

Ensuring adequate blood supply

Dr. Eleftheriou also discussed the TIF response to the COVID-19 pandemic, which focused on the adequacy of blood supplies for these patients who so often need transfusions.

Dr. Eleftheriou stated that a shortage of blood was reported in 75% of the 62 member countries of the TIF, with 58% reporting severe shortages and 35% reporting moderate to severe shortages.

The shortages resulted in many countries returning to older family/friends donation practices, rare use of whole blood transfusions, and the use of older blood transfusions (older than 28 days).

In addition, physicians have modified their transfusion strategy. They have reduced the amount of blood given to thalassemia patients from two units to one unit during any transfusion, while making arrangements for more frequent transfusions; for example, one transfusion per week but with precautions made to “limit the time spent in the clinic and to control blood supplies while safeguarding that all [thalassemia] patients will be able to get their transfusion,” Dr. Eleftheriou said.

The information in the webinar was provided with the caveat that “no general evidence-based guidance can be derived from this discussion.” There were no other disclosures given.

mlesney@mdedge.com

ORLANDO – The BET inhibitor CPI-0610, given alone or in combination with ruxolitinib, has demonstrated activity in a phase 2 trial of patients with relapsed/refractory myelofibrosis (MF).

144294_Mascarenhas_John_web.jpg

Responses were best among transfusion-dependent patients who received CPI-0610 and ruxolitinib. All but one of these patients experienced symptom improvement.

In the monotherapy group, results were best among transfusion-independent patients. All of these patients had an improvement in Patient Global Impression of Change (PGIC) score, and most had a 50% or greater improvement in total symptom score (TSS).

John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai, New York, presented these results from the phase 2 MANIFEST trial (NCT02158858) at the annual meeting of the American Society of Hematology.

Dr. Mascarenhas presented data on 90 patients – 59 with primary MF, 16 with post–polycythemia vera MF, 13 with post–essential thrombocythemia MF, and 2 whose type of MF was unknown. At baseline, the patients’ median age was 69 years and 76.7% of patients had received at least 6 months of ruxolitinib treatment.

Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. 17, 2019. Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. The median duration of treatment was 11.3 weeks in the monotherapy arm and 25.9 weeks in the combination arm. Responses were assessed at 24 weeks.

“CPI-0610 monotherapy or added on to ruxolitinib in a relapsed/refractory MF population demonstrated antitumor activity, as evidenced by spleen and symptom improvement,” Dr. Mascarenhas said. “Symptom responses were observed in a majority of patients. We treated these patients, and they felt much better. It was impressive.”

Efficacy of monotherapy

There were two evaluable patients who had been transfusion dependent at baseline and received CPI-0610 monotherapy for at least 24 weeks. Neither patient achieved transfusion independence, and neither had a spleen volume reduction of at least 35% (SVR35). One patient had a 50% or greater improvement in TSS, and one had an improvement in PGIC score.

There were seven evaluable patients who were transfusion independent at baseline and received CPI-0610 for at least 24 weeks. None of these patients had an SVR35 response, three of five evaluable patients had a 50% or greater improvement in TSS, and all seven had an improvement in PGIC score.
 

Efficacy of the combination

There were 14 patients who had been transfusion dependent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. Six of these patients had become transfusion independent at week 24.

Among the patients who were transfusion dependent at baseline, 25% (3/12) had an SVR35 response at week 24, 54% (7/13) had a 50% or greater improvement in TSS, and 75% (9/12) had an improvement in PGIC score.

There were 13 evaluable patients who were transfusion independent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. None of these patients had an SVR35 response, 38% had a 50% or greater improvement in TSS, and 69% had an improvement in PGIC score.
 

Safety

“CPI-0610 monotherapy or as an add-on to [ruxolitinib] was generally well tolerated,” Dr. Mascarenhas said. “Thrombocytopenia was asymptomatic, generally reversible, and manageable. There were no other unanticipated safety concerns.”

All 90 patients were evaluable for safety. Hematologic adverse events included thrombocytopenia (23.3%) and anemia (8.9%).

The most common nonhematologic adverse events were diarrhea (32.2%), nausea (22.2%), cough (16.7%), fatigue (14.4%), vomiting (14.4%), and upper respiratory tract infection (14.4%).

Eight patients (8.9%) experienced grade 4 adverse events, but all events resolved. Four events occurred in the monotherapy arm, and one (rash) required dose interruption. Of the four events in the combination arm, one (anemia) was considered treatment related.

There were three fatal adverse events – acute kidney injury, traumatic subdural hematoma, and brain stem hemorrhage. None of these events were considered related to CPI-0610.

Based on these preliminary results, the cohort of transfusion-dependent patients receiving CPI-0610 and ruxolitinib has been expanded. A cohort of ruxolitinib-naive patients receiving CPI-0610 and ruxolitinib has been expanded as well.

The MANIFEST trial is funded by Constellation Pharmaceuticals in collaboration with the Leukemia & Lymphoma Society. Dr. Mascarenhas reported relationships with Incyte, Janssen, CTI Biopharma, Novartis, Roche, Merck, Celgene, Promedior, Merus, and PharmaEssentia.

jensmith@mdedge.com

SOURCE: Mascarenhas J et al. ASH 2019, Abstract 670.
 

ORLANDO – The BET inhibitor CPI-0610, given alone or in combination with ruxolitinib, has demonstrated activity in a phase 2 trial of patients with relapsed/refractory myelofibrosis (MF).

144294_Mascarenhas_John_web.jpg

Responses were best among transfusion-dependent patients who received CPI-0610 and ruxolitinib. All but one of these patients experienced symptom improvement.

In the monotherapy group, results were best among transfusion-independent patients. All of these patients had an improvement in Patient Global Impression of Change (PGIC) score, and most had a 50% or greater improvement in total symptom score (TSS).

John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai, New York, presented these results from the phase 2 MANIFEST trial (NCT02158858) at the annual meeting of the American Society of Hematology.

Dr. Mascarenhas presented data on 90 patients – 59 with primary MF, 16 with post–polycythemia vera MF, 13 with post–essential thrombocythemia MF, and 2 whose type of MF was unknown. At baseline, the patients’ median age was 69 years and 76.7% of patients had received at least 6 months of ruxolitinib treatment.

Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. 17, 2019. Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. The median duration of treatment was 11.3 weeks in the monotherapy arm and 25.9 weeks in the combination arm. Responses were assessed at 24 weeks.

“CPI-0610 monotherapy or added on to ruxolitinib in a relapsed/refractory MF population demonstrated antitumor activity, as evidenced by spleen and symptom improvement,” Dr. Mascarenhas said. “Symptom responses were observed in a majority of patients. We treated these patients, and they felt much better. It was impressive.”

Efficacy of monotherapy

There were two evaluable patients who had been transfusion dependent at baseline and received CPI-0610 monotherapy for at least 24 weeks. Neither patient achieved transfusion independence, and neither had a spleen volume reduction of at least 35% (SVR35). One patient had a 50% or greater improvement in TSS, and one had an improvement in PGIC score.

There were seven evaluable patients who were transfusion independent at baseline and received CPI-0610 for at least 24 weeks. None of these patients had an SVR35 response, three of five evaluable patients had a 50% or greater improvement in TSS, and all seven had an improvement in PGIC score.
 

Efficacy of the combination

There were 14 patients who had been transfusion dependent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. Six of these patients had become transfusion independent at week 24.

Among the patients who were transfusion dependent at baseline, 25% (3/12) had an SVR35 response at week 24, 54% (7/13) had a 50% or greater improvement in TSS, and 75% (9/12) had an improvement in PGIC score.

There were 13 evaluable patients who were transfusion independent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. None of these patients had an SVR35 response, 38% had a 50% or greater improvement in TSS, and 69% had an improvement in PGIC score.
 

Safety

“CPI-0610 monotherapy or as an add-on to [ruxolitinib] was generally well tolerated,” Dr. Mascarenhas said. “Thrombocytopenia was asymptomatic, generally reversible, and manageable. There were no other unanticipated safety concerns.”

All 90 patients were evaluable for safety. Hematologic adverse events included thrombocytopenia (23.3%) and anemia (8.9%).

The most common nonhematologic adverse events were diarrhea (32.2%), nausea (22.2%), cough (16.7%), fatigue (14.4%), vomiting (14.4%), and upper respiratory tract infection (14.4%).

Eight patients (8.9%) experienced grade 4 adverse events, but all events resolved. Four events occurred in the monotherapy arm, and one (rash) required dose interruption. Of the four events in the combination arm, one (anemia) was considered treatment related.

There were three fatal adverse events – acute kidney injury, traumatic subdural hematoma, and brain stem hemorrhage. None of these events were considered related to CPI-0610.

Based on these preliminary results, the cohort of transfusion-dependent patients receiving CPI-0610 and ruxolitinib has been expanded. A cohort of ruxolitinib-naive patients receiving CPI-0610 and ruxolitinib has been expanded as well.

The MANIFEST trial is funded by Constellation Pharmaceuticals in collaboration with the Leukemia & Lymphoma Society. Dr. Mascarenhas reported relationships with Incyte, Janssen, CTI Biopharma, Novartis, Roche, Merck, Celgene, Promedior, Merus, and PharmaEssentia.

jensmith@mdedge.com

SOURCE: Mascarenhas J et al. ASH 2019, Abstract 670.
 

ORLANDO – The BET inhibitor CPI-0610, given alone or in combination with ruxolitinib, has demonstrated activity in a phase 2 trial of patients with relapsed/refractory myelofibrosis (MF).

144294_Mascarenhas_John_web.jpg

Responses were best among transfusion-dependent patients who received CPI-0610 and ruxolitinib. All but one of these patients experienced symptom improvement.

In the monotherapy group, results were best among transfusion-independent patients. All of these patients had an improvement in Patient Global Impression of Change (PGIC) score, and most had a 50% or greater improvement in total symptom score (TSS).

John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai, New York, presented these results from the phase 2 MANIFEST trial (NCT02158858) at the annual meeting of the American Society of Hematology.

Dr. Mascarenhas presented data on 90 patients – 59 with primary MF, 16 with post–polycythemia vera MF, 13 with post–essential thrombocythemia MF, and 2 whose type of MF was unknown. At baseline, the patients’ median age was 69 years and 76.7% of patients had received at least 6 months of ruxolitinib treatment.

Of the 36 patients who received CPI-0610 monotherapy, 34 were still receiving the treatment as of Oct. 17, 2019. Of the 54 patients treated with CPI-0610 and ruxolitinib, 41 were still receiving the combination at that time. The median duration of treatment was 11.3 weeks in the monotherapy arm and 25.9 weeks in the combination arm. Responses were assessed at 24 weeks.

“CPI-0610 monotherapy or added on to ruxolitinib in a relapsed/refractory MF population demonstrated antitumor activity, as evidenced by spleen and symptom improvement,” Dr. Mascarenhas said. “Symptom responses were observed in a majority of patients. We treated these patients, and they felt much better. It was impressive.”

Efficacy of monotherapy

There were two evaluable patients who had been transfusion dependent at baseline and received CPI-0610 monotherapy for at least 24 weeks. Neither patient achieved transfusion independence, and neither had a spleen volume reduction of at least 35% (SVR35). One patient had a 50% or greater improvement in TSS, and one had an improvement in PGIC score.

There were seven evaluable patients who were transfusion independent at baseline and received CPI-0610 for at least 24 weeks. None of these patients had an SVR35 response, three of five evaluable patients had a 50% or greater improvement in TSS, and all seven had an improvement in PGIC score.
 

Efficacy of the combination

There were 14 patients who had been transfusion dependent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. Six of these patients had become transfusion independent at week 24.

Among the patients who were transfusion dependent at baseline, 25% (3/12) had an SVR35 response at week 24, 54% (7/13) had a 50% or greater improvement in TSS, and 75% (9/12) had an improvement in PGIC score.

There were 13 evaluable patients who were transfusion independent at baseline and received CPI-0610 and ruxolitinib for at least 24 weeks. None of these patients had an SVR35 response, 38% had a 50% or greater improvement in TSS, and 69% had an improvement in PGIC score.
 

Safety

“CPI-0610 monotherapy or as an add-on to [ruxolitinib] was generally well tolerated,” Dr. Mascarenhas said. “Thrombocytopenia was asymptomatic, generally reversible, and manageable. There were no other unanticipated safety concerns.”

All 90 patients were evaluable for safety. Hematologic adverse events included thrombocytopenia (23.3%) and anemia (8.9%).

The most common nonhematologic adverse events were diarrhea (32.2%), nausea (22.2%), cough (16.7%), fatigue (14.4%), vomiting (14.4%), and upper respiratory tract infection (14.4%).

Eight patients (8.9%) experienced grade 4 adverse events, but all events resolved. Four events occurred in the monotherapy arm, and one (rash) required dose interruption. Of the four events in the combination arm, one (anemia) was considered treatment related.

There were three fatal adverse events – acute kidney injury, traumatic subdural hematoma, and brain stem hemorrhage. None of these events were considered related to CPI-0610.

Based on these preliminary results, the cohort of transfusion-dependent patients receiving CPI-0610 and ruxolitinib has been expanded. A cohort of ruxolitinib-naive patients receiving CPI-0610 and ruxolitinib has been expanded as well.

The MANIFEST trial is funded by Constellation Pharmaceuticals in collaboration with the Leukemia & Lymphoma Society. Dr. Mascarenhas reported relationships with Incyte, Janssen, CTI Biopharma, Novartis, Roche, Merck, Celgene, Promedior, Merus, and PharmaEssentia.

jensmith@mdedge.com

SOURCE: Mascarenhas J et al. ASH 2019, Abstract 670.
 

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Garcia_Jacqueline_MA_web.jpg

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Garcia_Jacqueline_MA_web.jpg

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Garcia_Jacqueline_MA_web.jpg

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

FDA_icon3_web.jpg

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

[embed:render:related:node:187695]

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

jensmith@mdedge.com

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

FDA_icon3_web.jpg

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

[embed:render:related:node:187695]

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

jensmith@mdedge.com

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

FDA_icon3_web.jpg

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

[embed:render:related:node:187695]

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).

The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”

However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.

Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.

The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.

Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.

Treatment and safety

For the first cycle, patients received decitabine at 20 mg/m² per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.

“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.

Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.

Response and survival

Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.

Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.

Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.

The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.

The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.

Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.

“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”

Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).

The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”

However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.

Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.

The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.

Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.

Treatment and safety

For the first cycle, patients received decitabine at 20 mg/m² per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.

“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.

Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.

Response and survival

Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.

Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.

Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.

The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.

The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.

Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.

“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”

Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).

The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”

However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.

Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.

The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.

Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.

Treatment and safety

For the first cycle, patients received decitabine at 20 mg/m² per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.

“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.

Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.

Response and survival

Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.

Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.

Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.

The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.

The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.

Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.

“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”

Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

Polycythemia_vera_blood_smear_Credit_AFIP_230.jpg

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.

Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.

The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of a CHMP recommendation.

The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).

Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.

PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).

The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.

At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).

At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).

A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).

Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.

There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.

The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.

Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.

CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.

Polycythemia_vera_blood_smear_Credit_AFIP_230.jpg

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.

Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.

The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of a CHMP recommendation.

The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).

Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.

PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).

The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.

At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).

At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).

A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).

Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.

There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.

The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.

Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.

CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.

Polycythemia_vera_blood_smear_Credit_AFIP_230.jpg

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.

Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.

The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of a CHMP recommendation.

The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).

Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.

PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).

The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.

At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).

At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).

A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).

Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.

There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.

The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.

Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.

CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.

gotlib-jason-220.jpg

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.

gotlib-jason-220.jpg

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.

gotlib-jason-220.jpg

SAN DIEGO—The KIT D816V inhibitor avapritinib can improve symptoms of systemic mastocytosis (SM), according to researchers.

Patients treated with avapritinib in a phase 1 trial had an overall response rate (ORR) of 83%, a 41% mean reduction in mastocytosis symptoms from baseline, and a 58% mean reduction in the most bothersome symptom domain.

Most adverse events (AEs) in this trial were grade 1 or 2. However, 66% of patients did have grade 3 or higher treatment-related AEs that necessitated dose reductions.

Jason R. Gotlib, MD, of Stanford University School of Medicine in California, presented these results, from the EXPLORER trial (NCT02561988), at the 2018 ASH Annual Meeting (abstract 351).

Patients and treatment

The trial enrolled 67 patients—90% with advanced SM and 10% with indolent or smoldering SM. The patients’ median age was 62 (range, 34 to 83), and 49% were female.

Patients had received a median of 3 (range, 0 to 3) prior therapies. Sixty percent of patients had received any prior therapy, and 23% had received midostaurin. Thirty-three percent were on steroid therapy at baseline.

Eighty-four percent of patients had the KIT D816V mutation, and 1% had the KIT D816Y mutation. Forty-five percent of patients had mutations in SRSF2, ASXL1, and RUNX1.

In the dose-escalation portion of the trial, patients received avapritinib at 30 mg to 400 mg once daily in continuous 28-day cycles. In the expansion portion of the trial, patients received avapritinib at 200 mg or 300 mg once daily.

Response

There were 29 patients evaluable for response. The ORR was 83% (n=24). The rate of complete response (CR) was 10% (n=3), the rate of CR with partial hematologic recovery (CRh) was 14% (n=4), and the partial response rate was 48% (n=14).

Ten percent (n=3) of patients had clinical improvement, 17% (n=5) had stable disease, and none of the patients progressed.

Among the 10 patients treated at a dose of 200 mg or lower, the ORR was 90% (n=9). The CR rate was 30% (n=3), the rate of CRh was 20% (n=2), and the partial response rate was 30% (n=3). Ten percent (n=1) of patients each had clinical improvement or stable disease.

Dr. Gotlib noted that responses have been durable and deepened over time.

At a median follow-up of 14 months, the median duration of response had not been reached. The 12-month response rate is 76%.

The median time to initial response is 2 months, and the median time to CR/CRh is 9 months.

Safety

Seventy-eight percent of patients (52/67) were still on treatment at last follow-up. Four percent (4/67) discontinued treatment due to related AEs, and 66% (44/67) had grade 3 or higher AEs that prompted dose reductions.

AEs prompting discontinuation included refractory ascites, encephalopathy, and intracranial bleeding. AEs necessitating dose reductions were largely hematologic events.

The most common AEs were periorbital edema (67%), anemia (52%), fatigue (37%), nausea (36%), diarrhea (34%), peripheral edema (34%), thrombocytopenia (31%) vomiting (28%), cognitive effects (28%), and hair color changes (25%).

The most common grade 3/4 AEs were anemia (26%), thrombocytopenia (17%), and neutropenia (10%). There were no treatment-related deaths.

Symptoms

For symptom assessment, patients completed the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF), a patient-reported outcomes (PRO) tool that included eight symptoms:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Spots
• Itching
• Flushing
• Fatigue.

Symptoms were scored on a scale of 1 to 10. Results were analyzed as a total symptom score (TSS) combining all eight items, as a gastrointestinal domain (combining nausea, vomiting, diarrhea, and abdominal pain), and as a skin domain (combining itching, flushing, and spots). Analyses were based on 7-day average scores.

Among the 32 evaluable patients, there was a 41% reduction in TSS from baseline (P=0.043). Among the 16 most symptomatic patients, there was a 46% reduction in TSS from baseline (P=0.038).

In all 32 evaluable patients, there was a 58% reduction from baseline in the score for most bothersome symptom domain (gastrointestinal or skin; P=0.0034). In the 16 most symptomatic patients, there was 63% reduction from baseline (P=0.0038).

“This is the first advanced SM-specific PRO to demonstrate significant improvements in total symptom score,” Dr. Gotlib said. “The clinical activity and initial PRO data do support further evaluation of avapritinib in both advanced and indolent disease.”

Dr. Gotlib noted that the PATHFINDER trial (NCT03580655), a study of avapritinib in advanced SM, is now enrolling. And the PIONEER trial (NCT03731260), a study of avapritinib in patients with indolent or smoldering SM, is scheduled to begin at the end of the year.

The EXPLORER trial was sponsored by Blueprint Medicines Corporation. Dr. Gotlib reported relationships with Blueprint Medicines, Celgene, Incyte, Novartis, Deciphera, Gilead, Promedior, and Kartos.