Hematology Times

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Essential thrombocythemia

New research suggests genomic characteristics of patients with myeloproliferative neoplasms (MPNs) can predict clinical outcomes.

Investigators defined eight genomic subgroups of MPNs, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.

Jacob Grinfeld, MD, of the University of Cambridge in the U.K., and his colleagues described these findings in The New England Journal of Medicine.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other diagnoses.

The investigators performed targeted sequencing for the full coding sequence of 69 genes and genome-wide copy number information in 1,887 patients. Whole-exome sequencing was performed in another 148 patients.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across MPN patients and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations.

In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis revealed eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations.

For example, one subgroup included patients with TP53 mutations. These individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia, compared with the JAK2-heterozygous subgroup (P<0.001).

Because prognosis is “a key determinant” of MPN treatment, genomic subgrouping may one day guide clinical decision-making, the investigators concluded.

To further this cause, they have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

This study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Micrograph showing MM

The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.

With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.

Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.

Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.

Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.

STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.

Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).

Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.

Micrograph showing MM

The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.

With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.

Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.

Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.

Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.

STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.

Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).

Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.

Micrograph showing MM

The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.

With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.

Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.

Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.

Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.

STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.

Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).

Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032