Cythemias

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.

Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.

Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.

Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.

The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.

The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).

Malignant blood disorders

In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).

In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.

When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).

In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).

The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).

Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.

The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.

Non-malignant blood disorders

In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).

Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.

“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.

“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.

Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.

Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.

Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.

The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.

The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).

Malignant blood disorders

In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).

In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.

When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).

In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).

The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).

Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.

The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.

Non-malignant blood disorders

In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).

Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.

“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.

“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.

Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.

Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.

Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.

The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.

The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).

Malignant blood disorders

In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).

In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.

When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).

In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).

The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).

Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.

The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.

Non-malignant blood disorders

In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).

Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.

“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.

“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Mast cells

Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).

The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.

Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.

The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.

The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.

Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.

With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.

Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.

Response

The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.

The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.

The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.

Responses occurred in all subgroups, which included patients who were positive for KIT D816V.

The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.

The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.

Survival

The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.

The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.

The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.

Safety

The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).

Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).

Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.

Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).

Compassionate use

The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.

The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.

The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.

Mast cells

Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).

The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.

Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.

The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.

The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.

Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.

With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.

Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.

Response

The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.

The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.

The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.

Responses occurred in all subgroups, which included patients who were positive for KIT D816V.

The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.

The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.

Survival

The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.

The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.

The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.

Safety

The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).

Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).

Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.

Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).

Compassionate use

The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.

The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.

The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.

Mast cells

Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).

The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.

Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.

Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.

The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.

The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.

Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.

With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.

Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.

Response

The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.

The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.

The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.

Responses occurred in all subgroups, which included patients who were positive for KIT D816V.

The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.

The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.

Survival

The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.

The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.

The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.

Safety

The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).

Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).

Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.

Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).

Compassionate use

The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.

The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.

The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.

Aspirin tablets

Photo by Sage Ross

Results of a retrospective study suggest that patients with low-risk essential thrombocythemia (ET) may benefit from a genotype-based approach to

antiplatelet therapy.

The study showed that, overall, neither CALR-mutated nor JAK2V617F-positive patients derived a significant benefit from treatment with low-dose aspirin.

JAK2V617F-positive patients had a somewhat lower risk of thrombosis while on the therapy than during observation.

But CALR-mutated patients had a significantly increased risk of major bleeding and no decrease in the risk of thrombosis while on antiplatelet therapy.

Carlos Besses, MD, PhD, of Hospital del Mar in Barcelona, Spain, and his colleagues reported these results in haematologica.

The researchers evaluated 433 patients with low-risk ET—271 with CALR mutations and 162 with JAK2V617F. In all, 353 patients received low-dose aspirin (81-100 mg/day), but the treatment was withdrawn in 50 patients (permanently in 46 of them).

Two hundred and thirty-one patients received cytoreductive therapy, including hydroxyurea (n=143), anagrelide (n=66), interferon (n=18), and busulfan (n=4).

The projected time from diagnosis to the start of cytoreductive therapy was significantly shorter in patients with CALR-mutated ET than in JAK2V617F-positive patients—a median of 5.0 years and 9.8 years, respectively (P=0.002). The most common reason for cytoreduction in CALR-mutated patients was extreme thrombocytosis.

Thrombosis

After 2215 person-years of follow-up free from cytoreduction, there were 25 arterial or venous thrombotic events.

Fourteen thrombotic events occurred while patients were receiving low-dose aspirin, and 11 occurred while patients were under observation only. The incidence rates were 10.7 and 12.1 events x 1000 person-years, respectively (P=0.7).

Among CALR-mutated patients, there were more thrombotic events during antiplatelet therapy than during observation—9.7 and 6.9 events x 1000 person-years, respectively (P=0.6).

Among JAK2V617F-positive patients, there were fewer thrombotic events during antiplatelet therapy than during observation, but the difference was not significant—11.6 and 21.1 events x 1000 person-years, respectively (P=0.3).

Coexistence of the JAK2V617F mutation and cardiovascular risk factors increased the risk of thrombosis, even after the researchers adjusted for treatment with low-dose aspirin. The incidence rate ratio (IRR) was 9.8 (P=0.02).

Bleeding

After 2215 person-years of follow-up free from cytoreduction, there were 17 major bleeding episodes.

Thirteen occurred while patients were on antiplatelet therapy, and 4 occurred while patients were on observation. The incidence rates were 9.9 and 4.6 events x 1000 person-years, respectively (P=0.2).

There was no significant difference in major bleeding episodes between the treatment groups for JAK2V617F-positive patients.

But CALR-mutated patients had a significantly higher rate of major bleeding while on antiplatelet therapy than on observation—12.9 and 1.8 events per 1000 person-years, respectively (P=0.03).

In CALR-mutated patients, antiplatelet therapy was associated with a tendency toward an increased risk of bleeding (IRR: 6.9, P=0.06), but extreme thrombocytosis was not (IRR: 2.7, P=0.1).

In JAK2V617F-positive patients, extreme thrombocytosis was associated with an increased risk of bleeding (IRR: 9.8, P=0.002), but antiplatelet therapy was not (IRR: 0.9, P=0.9).

Potential treatment recommendations

The researchers said this retrospective study suggests a genotype-based approach to antiplatelet therapy may be effective for patients with low-risk ET. However, this needs to be confirmed in prospective trials.

The failure of antiplatelet therapy to prevent thrombosis in CALR-mutated patients and their increased need for cytoreductive therapy suggest these patients require a different approach from that used in JAK2V617F-positive patients.

The researchers said the data suggest that patients with CALR-mutated ET who have a low risk of thrombosis and no symptoms should simply be observed. And CALR-mutated patients with symptoms or marked thrombocytosis should receive cytoreductive therapy, as it poses a lower risk of bleeding than antiplatelet therapy.

Patients with JAK2V617F-positive ET should receive antiplatelet therapy rather than undergoing observation, as antiplatelet therapy may reduce the risk of thrombosis in these patients and does not pose an increased risk of bleeding.

However, in JAK2V617F-positive patients with concomitant cardiovascular risk factors and/or leukocytosis, antiplatelet therapy may not be sufficient. These patients might be candidates for cytoreductive therapy, especially if they have marked thrombocytosis.

Aspirin tablets

Photo by Sage Ross

Results of a retrospective study suggest that patients with low-risk essential thrombocythemia (ET) may benefit from a genotype-based approach to

antiplatelet therapy.

The study showed that, overall, neither CALR-mutated nor JAK2V617F-positive patients derived a significant benefit from treatment with low-dose aspirin.

JAK2V617F-positive patients had a somewhat lower risk of thrombosis while on the therapy than during observation.

But CALR-mutated patients had a significantly increased risk of major bleeding and no decrease in the risk of thrombosis while on antiplatelet therapy.

Carlos Besses, MD, PhD, of Hospital del Mar in Barcelona, Spain, and his colleagues reported these results in haematologica.

The researchers evaluated 433 patients with low-risk ET—271 with CALR mutations and 162 with JAK2V617F. In all, 353 patients received low-dose aspirin (81-100 mg/day), but the treatment was withdrawn in 50 patients (permanently in 46 of them).

Two hundred and thirty-one patients received cytoreductive therapy, including hydroxyurea (n=143), anagrelide (n=66), interferon (n=18), and busulfan (n=4).

The projected time from diagnosis to the start of cytoreductive therapy was significantly shorter in patients with CALR-mutated ET than in JAK2V617F-positive patients—a median of 5.0 years and 9.8 years, respectively (P=0.002). The most common reason for cytoreduction in CALR-mutated patients was extreme thrombocytosis.

Thrombosis

After 2215 person-years of follow-up free from cytoreduction, there were 25 arterial or venous thrombotic events.

Fourteen thrombotic events occurred while patients were receiving low-dose aspirin, and 11 occurred while patients were under observation only. The incidence rates were 10.7 and 12.1 events x 1000 person-years, respectively (P=0.7).

Among CALR-mutated patients, there were more thrombotic events during antiplatelet therapy than during observation—9.7 and 6.9 events x 1000 person-years, respectively (P=0.6).

Among JAK2V617F-positive patients, there were fewer thrombotic events during antiplatelet therapy than during observation, but the difference was not significant—11.6 and 21.1 events x 1000 person-years, respectively (P=0.3).

Coexistence of the JAK2V617F mutation and cardiovascular risk factors increased the risk of thrombosis, even after the researchers adjusted for treatment with low-dose aspirin. The incidence rate ratio (IRR) was 9.8 (P=0.02).

Bleeding

After 2215 person-years of follow-up free from cytoreduction, there were 17 major bleeding episodes.

Thirteen occurred while patients were on antiplatelet therapy, and 4 occurred while patients were on observation. The incidence rates were 9.9 and 4.6 events x 1000 person-years, respectively (P=0.2).

There was no significant difference in major bleeding episodes between the treatment groups for JAK2V617F-positive patients.

But CALR-mutated patients had a significantly higher rate of major bleeding while on antiplatelet therapy than on observation—12.9 and 1.8 events per 1000 person-years, respectively (P=0.03).

In CALR-mutated patients, antiplatelet therapy was associated with a tendency toward an increased risk of bleeding (IRR: 6.9, P=0.06), but extreme thrombocytosis was not (IRR: 2.7, P=0.1).

In JAK2V617F-positive patients, extreme thrombocytosis was associated with an increased risk of bleeding (IRR: 9.8, P=0.002), but antiplatelet therapy was not (IRR: 0.9, P=0.9).

Potential treatment recommendations

The researchers said this retrospective study suggests a genotype-based approach to antiplatelet therapy may be effective for patients with low-risk ET. However, this needs to be confirmed in prospective trials.

The failure of antiplatelet therapy to prevent thrombosis in CALR-mutated patients and their increased need for cytoreductive therapy suggest these patients require a different approach from that used in JAK2V617F-positive patients.

The researchers said the data suggest that patients with CALR-mutated ET who have a low risk of thrombosis and no symptoms should simply be observed. And CALR-mutated patients with symptoms or marked thrombocytosis should receive cytoreductive therapy, as it poses a lower risk of bleeding than antiplatelet therapy.

Patients with JAK2V617F-positive ET should receive antiplatelet therapy rather than undergoing observation, as antiplatelet therapy may reduce the risk of thrombosis in these patients and does not pose an increased risk of bleeding.

However, in JAK2V617F-positive patients with concomitant cardiovascular risk factors and/or leukocytosis, antiplatelet therapy may not be sufficient. These patients might be candidates for cytoreductive therapy, especially if they have marked thrombocytosis.

Aspirin tablets

Photo by Sage Ross

Results of a retrospective study suggest that patients with low-risk essential thrombocythemia (ET) may benefit from a genotype-based approach to

antiplatelet therapy.

The study showed that, overall, neither CALR-mutated nor JAK2V617F-positive patients derived a significant benefit from treatment with low-dose aspirin.

JAK2V617F-positive patients had a somewhat lower risk of thrombosis while on the therapy than during observation.

But CALR-mutated patients had a significantly increased risk of major bleeding and no decrease in the risk of thrombosis while on antiplatelet therapy.

Carlos Besses, MD, PhD, of Hospital del Mar in Barcelona, Spain, and his colleagues reported these results in haematologica.

The researchers evaluated 433 patients with low-risk ET—271 with CALR mutations and 162 with JAK2V617F. In all, 353 patients received low-dose aspirin (81-100 mg/day), but the treatment was withdrawn in 50 patients (permanently in 46 of them).

Two hundred and thirty-one patients received cytoreductive therapy, including hydroxyurea (n=143), anagrelide (n=66), interferon (n=18), and busulfan (n=4).

The projected time from diagnosis to the start of cytoreductive therapy was significantly shorter in patients with CALR-mutated ET than in JAK2V617F-positive patients—a median of 5.0 years and 9.8 years, respectively (P=0.002). The most common reason for cytoreduction in CALR-mutated patients was extreme thrombocytosis.

Thrombosis

After 2215 person-years of follow-up free from cytoreduction, there were 25 arterial or venous thrombotic events.

Fourteen thrombotic events occurred while patients were receiving low-dose aspirin, and 11 occurred while patients were under observation only. The incidence rates were 10.7 and 12.1 events x 1000 person-years, respectively (P=0.7).

Among CALR-mutated patients, there were more thrombotic events during antiplatelet therapy than during observation—9.7 and 6.9 events x 1000 person-years, respectively (P=0.6).

Among JAK2V617F-positive patients, there were fewer thrombotic events during antiplatelet therapy than during observation, but the difference was not significant—11.6 and 21.1 events x 1000 person-years, respectively (P=0.3).

Coexistence of the JAK2V617F mutation and cardiovascular risk factors increased the risk of thrombosis, even after the researchers adjusted for treatment with low-dose aspirin. The incidence rate ratio (IRR) was 9.8 (P=0.02).

Bleeding

After 2215 person-years of follow-up free from cytoreduction, there were 17 major bleeding episodes.

Thirteen occurred while patients were on antiplatelet therapy, and 4 occurred while patients were on observation. The incidence rates were 9.9 and 4.6 events x 1000 person-years, respectively (P=0.2).

There was no significant difference in major bleeding episodes between the treatment groups for JAK2V617F-positive patients.

But CALR-mutated patients had a significantly higher rate of major bleeding while on antiplatelet therapy than on observation—12.9 and 1.8 events per 1000 person-years, respectively (P=0.03).

In CALR-mutated patients, antiplatelet therapy was associated with a tendency toward an increased risk of bleeding (IRR: 6.9, P=0.06), but extreme thrombocytosis was not (IRR: 2.7, P=0.1).

In JAK2V617F-positive patients, extreme thrombocytosis was associated with an increased risk of bleeding (IRR: 9.8, P=0.002), but antiplatelet therapy was not (IRR: 0.9, P=0.9).

Potential treatment recommendations

The researchers said this retrospective study suggests a genotype-based approach to antiplatelet therapy may be effective for patients with low-risk ET. However, this needs to be confirmed in prospective trials.

The failure of antiplatelet therapy to prevent thrombosis in CALR-mutated patients and their increased need for cytoreductive therapy suggest these patients require a different approach from that used in JAK2V617F-positive patients.

The researchers said the data suggest that patients with CALR-mutated ET who have a low risk of thrombosis and no symptoms should simply be observed. And CALR-mutated patients with symptoms or marked thrombocytosis should receive cytoreductive therapy, as it poses a lower risk of bleeding than antiplatelet therapy.

Patients with JAK2V617F-positive ET should receive antiplatelet therapy rather than undergoing observation, as antiplatelet therapy may reduce the risk of thrombosis in these patients and does not pose an increased risk of bleeding.

However, in JAK2V617F-positive patients with concomitant cardiovascular risk factors and/or leukocytosis, antiplatelet therapy may not be sufficient. These patients might be candidates for cytoreductive therapy, especially if they have marked thrombocytosis.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.

Micrograph showing MF

The US Food and Drug Administration (FDA) has placed a full clinical hold on trials conducted under the investigational new drug application for pacritinib, a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The hold means all patients currently on pacritinib must stop taking the drug immediately, and no patients can be enrolled on a pacritinib trial or start pacritinib as initial or crossover treatment.

In addition, CTI BioPharma has withdrawn the new drug application for pacritinib while the company reviews data from the phase 3 PERSIST-2 trial.

The FDA’s decision to place a full clinical hold on pacritinib trials was due to interim results from PERSIST-2. The aim of this trial was to compare pacritinib to best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The overall survival results from PERSIST-2 indicate that pacritinib had a detrimental effect on survival, which is consistent with results from the PERSIST-1 trial. The deaths in pacritinib-treated patients on PERSIST-2 include intracranial hemorrhage, cardiac failure, and cardiac arrest.

Based on these results, the FDA has made recommendations for CTI BioPharma that supersede the agency’s previous recommendations.

On February 4, 2016, the FDA placed a partial clinical hold on pacritinib trials and made related recommendations for CTI BioPharma, advising that the company modify trial protocols and take other actions in compliance with the partial clinical hold.

Now that pacritinib trials are on full clinical hold, the FDA is recommending that CTI BioPharma conduct dose exploration studies for pacritinib in patients with MF and submit final study reports and datasets for PERSIST-1 and PERSIST-2.

The FDA is also recommending that CTI BioPharma provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, make certain modifications to protocols, and request a meeting with the FDA prior to submitting a response to the full clinical hold.

CTI BioPharma said all clinical investigators worldwide have been notified of the hold.

Micrograph showing MF

The US Food and Drug Administration (FDA) has placed a full clinical hold on trials conducted under the investigational new drug application for pacritinib, a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The hold means all patients currently on pacritinib must stop taking the drug immediately, and no patients can be enrolled on a pacritinib trial or start pacritinib as initial or crossover treatment.

In addition, CTI BioPharma has withdrawn the new drug application for pacritinib while the company reviews data from the phase 3 PERSIST-2 trial.

The FDA’s decision to place a full clinical hold on pacritinib trials was due to interim results from PERSIST-2. The aim of this trial was to compare pacritinib to best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The overall survival results from PERSIST-2 indicate that pacritinib had a detrimental effect on survival, which is consistent with results from the PERSIST-1 trial. The deaths in pacritinib-treated patients on PERSIST-2 include intracranial hemorrhage, cardiac failure, and cardiac arrest.

Based on these results, the FDA has made recommendations for CTI BioPharma that supersede the agency’s previous recommendations.

On February 4, 2016, the FDA placed a partial clinical hold on pacritinib trials and made related recommendations for CTI BioPharma, advising that the company modify trial protocols and take other actions in compliance with the partial clinical hold.

Now that pacritinib trials are on full clinical hold, the FDA is recommending that CTI BioPharma conduct dose exploration studies for pacritinib in patients with MF and submit final study reports and datasets for PERSIST-1 and PERSIST-2.

The FDA is also recommending that CTI BioPharma provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, make certain modifications to protocols, and request a meeting with the FDA prior to submitting a response to the full clinical hold.

CTI BioPharma said all clinical investigators worldwide have been notified of the hold.

Micrograph showing MF

The US Food and Drug Administration (FDA) has placed a full clinical hold on trials conducted under the investigational new drug application for pacritinib, a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The hold means all patients currently on pacritinib must stop taking the drug immediately, and no patients can be enrolled on a pacritinib trial or start pacritinib as initial or crossover treatment.

In addition, CTI BioPharma has withdrawn the new drug application for pacritinib while the company reviews data from the phase 3 PERSIST-2 trial.

The FDA’s decision to place a full clinical hold on pacritinib trials was due to interim results from PERSIST-2. The aim of this trial was to compare pacritinib to best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The overall survival results from PERSIST-2 indicate that pacritinib had a detrimental effect on survival, which is consistent with results from the PERSIST-1 trial. The deaths in pacritinib-treated patients on PERSIST-2 include intracranial hemorrhage, cardiac failure, and cardiac arrest.

Based on these results, the FDA has made recommendations for CTI BioPharma that supersede the agency’s previous recommendations.

On February 4, 2016, the FDA placed a partial clinical hold on pacritinib trials and made related recommendations for CTI BioPharma, advising that the company modify trial protocols and take other actions in compliance with the partial clinical hold.

Now that pacritinib trials are on full clinical hold, the FDA is recommending that CTI BioPharma conduct dose exploration studies for pacritinib in patients with MF and submit final study reports and datasets for PERSIST-1 and PERSIST-2.

The FDA is also recommending that CTI BioPharma provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, make certain modifications to protocols, and request a meeting with the FDA prior to submitting a response to the full clinical hold.

CTI BioPharma said all clinical investigators worldwide have been notified of the hold.

Micrograph showing primary MF

The US Food and Drug Administration (FDA) has placed a partial clinical hold on trials conducted under the investigational new drug

(IND) application for pacritinib.

Pacritinib is a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The partial clinical hold impacts part of the clinical work currently being conducted under the pacritinib IND and will also affect planned clinical trials.

The FDA said the reasons for the partial clinical hold are excess mortality and other adverse events in pacritinib-treated patients (compared to the control arm) in the PERSIST-1 trial.

The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment.

Under the partial clinical hold, investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment must stop using pacritinib.

In addition, the FDA has recommended that CTI BioPharma make certain modifications to protocols, provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, and take certain other actions.

CTI BioPharma said it intends to implement the FDA’s recommendations, and all clinical investigators worldwide have been notified of the partial clinical hold.

Just before the FDA notified CTI BioPharma of the partial clinical hold, the company completed enrollment in the phase 3 PERSIST-2 trial.

In PERSIST-2, researchers are comparing the efficacy and safety of pacritinib and best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Under the partial clinical hold, patients on this trial who are currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.

Micrograph showing primary MF

The US Food and Drug Administration (FDA) has placed a partial clinical hold on trials conducted under the investigational new drug

(IND) application for pacritinib.

Pacritinib is a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The partial clinical hold impacts part of the clinical work currently being conducted under the pacritinib IND and will also affect planned clinical trials.

The FDA said the reasons for the partial clinical hold are excess mortality and other adverse events in pacritinib-treated patients (compared to the control arm) in the PERSIST-1 trial.

The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment.

Under the partial clinical hold, investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment must stop using pacritinib.

In addition, the FDA has recommended that CTI BioPharma make certain modifications to protocols, provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, and take certain other actions.

CTI BioPharma said it intends to implement the FDA’s recommendations, and all clinical investigators worldwide have been notified of the partial clinical hold.

Just before the FDA notified CTI BioPharma of the partial clinical hold, the company completed enrollment in the phase 3 PERSIST-2 trial.

In PERSIST-2, researchers are comparing the efficacy and safety of pacritinib and best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Under the partial clinical hold, patients on this trial who are currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.

Micrograph showing primary MF

The US Food and Drug Administration (FDA) has placed a partial clinical hold on trials conducted under the investigational new drug

(IND) application for pacritinib.

Pacritinib is a JAK2/FLT3 inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis (MF).

The partial clinical hold impacts part of the clinical work currently being conducted under the pacritinib IND and will also affect planned clinical trials.

The FDA said the reasons for the partial clinical hold are excess mortality and other adverse events in pacritinib-treated patients (compared to the control arm) in the PERSIST-1 trial.

The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment.

Under the partial clinical hold, investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment must stop using pacritinib.

In addition, the FDA has recommended that CTI BioPharma make certain modifications to protocols, provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, and take certain other actions.

CTI BioPharma said it intends to implement the FDA’s recommendations, and all clinical investigators worldwide have been notified of the partial clinical hold.

Just before the FDA notified CTI BioPharma of the partial clinical hold, the company completed enrollment in the phase 3 PERSIST-2 trial.

In PERSIST-2, researchers are comparing the efficacy and safety of pacritinib and best available therapy in patients with thrombocytopenia and primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

Under the partial clinical hold, patients on this trial who are currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.