AML

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.

In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.

Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.

“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.

Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.

Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m² per day or idarubicin 12 mg/m² per day for 3 days, plus cytarabine 200 mg/m² per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.

After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.

The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.

The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.

A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.

All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.

Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).

Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.

The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.

Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.

Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.

In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).

The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.

The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.

The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.

SOURCE: Stein EM et al. ASH 2018, Abstract 560.

SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.

In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.

Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.

“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.

Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.

Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m² per day or idarubicin 12 mg/m² per day for 3 days, plus cytarabine 200 mg/m² per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.

After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.

The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.

The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.

A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.

All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.

Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).

Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.

The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.

Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.

Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.

In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).

The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.

The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.

The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.

SOURCE: Stein EM et al. ASH 2018, Abstract 560.

SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.

In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.

Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.

“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.

Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.

Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m² per day or idarubicin 12 mg/m² per day for 3 days, plus cytarabine 200 mg/m² per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.

After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.

The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.

The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.

A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.

All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.

Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).

Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.

The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.

Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.

Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.

In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).

The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.

The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.

The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.

SOURCE: Stein EM et al. ASH 2018, Abstract 560.

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3 (FLT3)/AXL inhibitor gilteritinib produced a response rate of more than 90% in newly diagnosed patients with acute myeloid leukemia (AML) with a FLT3 mutation.

The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.

The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.

Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.

Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.

“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.

Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.

[email protected]

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

[email protected]

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).

The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.

The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.

Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.

Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.

The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.

“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”

In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.

In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.

“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.

Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.

In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.

Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.

[email protected]

SOURCE: Burd A et al. ASH 2018, Abstract 559.

SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).

The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.

The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.

Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.

Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.

The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.

“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”

In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.

In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.

“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.

Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.

In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.

Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.

[email protected]

SOURCE: Burd A et al. ASH 2018, Abstract 559.

SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).

The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.

The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.

Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.

Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.

The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.

“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”

In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.

In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.

“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.

Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.

In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.

Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.

[email protected]

SOURCE: Burd A et al. ASH 2018, Abstract 559.

The Food and Drug Administration has issued a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
• Pulmonary infiltrates and pleural effusion.
• Fever.
• Lymphadenopathy.
• Bone pain.
• Peripheral edema with rapid weight gain.
• Pericardial effusion.
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.

Treatment details are not available for the remaining three patients who died, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).

Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).

[email protected]

The Food and Drug Administration has issued a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
• Pulmonary infiltrates and pleural effusion.
• Fever.
• Lymphadenopathy.
• Bone pain.
• Peripheral edema with rapid weight gain.
• Pericardial effusion.
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.

Treatment details are not available for the remaining three patients who died, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).

Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).

[email protected]

The Food and Drug Administration has issued a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
• Pulmonary infiltrates and pleural effusion.
• Fever.
• Lymphadenopathy.
• Bone pain.
• Peripheral edema with rapid weight gain.
• Pericardial effusion.
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.

Treatment details are not available for the remaining three patients who died, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).

Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).

[email protected]

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of  differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.

The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.

Recognizing differentiation syndrome

The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
• Pulmonary infiltrates and pleural effusion
• Fever
• Lymphadenopathy
• Bone pain
• Peripheral edema with rapid weight gain
• Pericardial effusion
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.

Treatment

If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.

Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.

Cases of differentiation syndrome

The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.

Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of  differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.

The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.

Recognizing differentiation syndrome

The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
• Pulmonary infiltrates and pleural effusion
• Fever
• Lymphadenopathy
• Bone pain
• Peripheral edema with rapid weight gain
• Pericardial effusion
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.

Treatment

If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.

Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.

Cases of differentiation syndrome

The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.

Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of  differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.

The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.

Recognizing differentiation syndrome

The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

• Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
• Pulmonary infiltrates and pleural effusion
• Fever
• Lymphadenopathy
• Bone pain
• Peripheral edema with rapid weight gain
• Pericardial effusion
• Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.

Treatment

If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.

Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.

Cases of differentiation syndrome

The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.

Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

[email protected]

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

[email protected]

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

[email protected]

Astellas Pharma

The U.S. Food and Drug Administration (FDA) has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib.

The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect FLT3 mutations in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial (NCT02421939).

The trial enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835, or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit.

Efficacy results are available for 138 patients, with a median follow-up of 4.6 months (range, 2.8 to 15.8).

The complete response (CR) rate was 11.6% (16/138), the rate of CR with partial hematologic recovery (CRh) was 9.4% (13/138), and the rate of CR/CRh was 21% (29/138).

The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion-dependent at baseline, and 33 of these patients (31.1%) became transfusion-independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion-independent at baseline remained transfusion-independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months (range, 0.1 to 42.8).

The most common adverse events were myalgia/arthralgia (42%), transaminase increase (41%), fatigue/malaise (40%), fever (35%), noninfectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), constipation (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%), and vomiting (20%).

Eight percent of patients (n=22) discontinued gilteritinib due to adverse events. The most common were pneumonia (2%), sepsis (2%), and dyspnea (1%).

For more details on the ADMIRAL trial and gilteritinib, see the full prescribing information.

Astellas Pharma

The U.S. Food and Drug Administration (FDA) has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib.

The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect FLT3 mutations in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial (NCT02421939).

The trial enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835, or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit.

Efficacy results are available for 138 patients, with a median follow-up of 4.6 months (range, 2.8 to 15.8).

The complete response (CR) rate was 11.6% (16/138), the rate of CR with partial hematologic recovery (CRh) was 9.4% (13/138), and the rate of CR/CRh was 21% (29/138).

The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion-dependent at baseline, and 33 of these patients (31.1%) became transfusion-independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion-independent at baseline remained transfusion-independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months (range, 0.1 to 42.8).

The most common adverse events were myalgia/arthralgia (42%), transaminase increase (41%), fatigue/malaise (40%), fever (35%), noninfectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), constipation (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%), and vomiting (20%).

Eight percent of patients (n=22) discontinued gilteritinib due to adverse events. The most common were pneumonia (2%), sepsis (2%), and dyspnea (1%).

For more details on the ADMIRAL trial and gilteritinib, see the full prescribing information.

Astellas Pharma

The U.S. Food and Drug Administration (FDA) has approved gilteritinib (Xospata) for use in adults who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test.

The FDA also expanded the approved indication for the LeukoStrat CDx FLT3 Mutation Assay to include use with gilteritinib.

The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect FLT3 mutations in patients with AML.

Gilteritinib, developed by Astellas Pharma, has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain.

The FDA’s approval of gilteritinib was based on an interim analysis of the ADMIRAL trial (NCT02421939).

The trial enrolled adults with relapsed or refractory AML who had a FLT3 ITD, D835, or I836 mutation, according to the LeukoStrat CDx FLT3 Mutation Assay.

Patients received gilteritinib at 120 mg daily until they developed unacceptable toxicity or did not show a clinical benefit.

Efficacy results are available for 138 patients, with a median follow-up of 4.6 months (range, 2.8 to 15.8).

The complete response (CR) rate was 11.6% (16/138), the rate of CR with partial hematologic recovery (CRh) was 9.4% (13/138), and the rate of CR/CRh was 21% (29/138).

The median duration of CR/CRh was 4.6 months.

There were 106 patients who were transfusion-dependent at baseline, and 33 of these patients (31.1%) became transfusion-independent during the post-baseline period.

Seventeen of the 32 patients (53.1%) who were transfusion-independent at baseline remained transfusion-independent.

Safety results are available for 292 patients. The median duration of exposure to gilteritinib in this group was 3 months (range, 0.1 to 42.8).

The most common adverse events were myalgia/arthralgia (42%), transaminase increase (41%), fatigue/malaise (40%), fever (35%), noninfectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), constipation (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%), and vomiting (20%).

Eight percent of patients (n=22) discontinued gilteritinib due to adverse events. The most common were pneumonia (2%), sepsis (2%), and dyspnea (1%).

For more details on the ADMIRAL trial and gilteritinib, see the full prescribing information.