Myelodysplastic Syndrome

Winship Cancer Institute

Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.

He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.

Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).

Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.

In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.

“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.

“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”

A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.

He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.

Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”

“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”

According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.

Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.

Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.

He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.

Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.

Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.

In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.

Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.

There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia. 

Winship Cancer Institute

Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.

He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.

Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).

Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.

In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.

“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.

“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”

A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.

He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.

Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”

“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”

According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.

Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.

Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.

He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.

Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.

Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.

In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.

Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.

There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia. 

Winship Cancer Institute

Physician, researcher, and educator H. Jean Khoury, MD, recently passed away.

He died on Monday, May 22, at the age of 50, after a year-long battle with esophageal cancer.

Dr Khoury led the division of hematology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

He was considered an authority on hematologic malignancies, particularly chronic myeloid leukemia (CML), acute leukemia, and myelodysplastic syndromes (MDS).

Dr Khoury joined Winship Cancer Institute in 2004 as director of the Leukemia Service and associate professor in the Emory School of Medicine.

In 2009, he was promoted to professor and director of the Division of Hematology in the Department of Hematology and Medical Oncology, and he was later named to the R. Randall Rollins Chair in Oncology.

“We are all deeply grieving the loss of this remarkable man who gave so much to Winship,” said Walter J. Curran, Jr, MD, Winship Cancer Institute’s executive director.

“His enthusiasm and love for his patients and his commitment to lessening the burden of cancer for all has been unwavering throughout his life.”

A native of Beirut, Lebanon, Dr Khoury came to the Winship Cancer Institute from Washington University in St Louis, Missouri, where he served on the faculty after completing a fellowship in hematology-oncology.

He earned his medical degree from the Université Catholique de Louvain in Brussels, Belgium, and completed a residency in internal medicine at Memorial Medical Center in Savannah, Georgia.

Dr Khoury was recruited to Winship Cancer Institute by Fadlo R. Khuri, MD, former deputy director of the institute and now president of the American University of Beirut. What he first saw in Dr Khoury was someone who was “in the best sense, a disruptive presence.”

“What you always want in a leader is someone who’s not afraid to be wrong, to take risks,” Dr Khuri said. “Being wrong disrupts the pattern, and Jean was very brave. He didn’t like business as usual, and that showed in the way he took about redeveloping the hematology division, the leukemia program, and his interactions with the transplant division, with faculty, and all across Winship.”

According to his colleagues, Dr Khoury’s guiding principle was how to improve his patients’ lives, whether through research discoveries or through compassionate care.

Even after being diagnosed with cancer himself, Dr Khoury continued to see patients and carry on his work in the clinic and his research.

Dr Khoury pioneered the development of personalized treatment for CML patients and better approaches to improve quality of life for survivors. His research focused on drug development in leukemia and MDS, genomic abnormalities in leukemia, development of cost-effective practice models, and outcome analysis of bone marrow transplant.

He conducted several leukemia and transplant clinical trials, including trials that led to the approval of drugs such as imatinib, dasatinib, and nilotinib.

Dr Khoury received the Georgia Cancer Coalition Distinguished Cancer Scholarship, which allowed for establishment of the Hematological Disorders Tissue Bank at Emory, which now contains annotated germline and somatic samples from more than 800 patients with various hematologic disorders.

Dr Khoury died at home with his family by his side. He is survived by his wife, Angela, and 3 children, Mikhail, Iman, and Alya.

In lieu of flowers, the family requests that contributions be made to a new fund at Winship Cancer Institute that will memorialize the life and work of Dr Khoury by supporting a fellowship program that was so meaningful to him.

Contributions, marked in Memory of Dr H. Jean Khoury, can be sent to Winship Cancer Institute of Emory University, Office of Gift Records, Emory University, 1762 Clifton Rd. NE, Suite 1400, Atlanta, GA 30322. Gifts can also be made online.

There will be a memorial service for Dr Khoury on Wednesday, May 31, at 4:30 pm at Glenn Memorial Church, 1652 North Decatur Road in Atlanta, Georgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).

Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).

Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).

Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

[email protected]

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

[email protected]

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

[email protected]

The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.

This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.

The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.

Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.

Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.

[email protected]

On Twitter @maryjodales

The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.

This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.

The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.

Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.

Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.

[email protected]

On Twitter @maryjodales

The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.

This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.

The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.

Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.

Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.

[email protected]

On Twitter @maryjodales

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]