Hematology Times

Photo by Chad McNeeley

The U.S. Food and Drug Administration (FDA) has granted orphan designation to PLX-R18 for the treatment of graft failure and incomplete hematopoietic recovery following hematopoietic stem cell transplant (HSCT).

PLX-R18 consists of placenta-derived, mesenchymal-like adherent stromal cells that are designed to be administered to patients without the need for tissue or genetic matching.

PLX-R18 cells release a combination of therapeutic proteins in response to a damaged or poorly functioning hematopoietic system.

PLX-R18 is currently being evaluated for the treatment of insufficient hematopoietic recovery following HSCT in an ongoing, phase 1 trial (NCT03002519).

The trial is designed to evaluate the safety of intramuscular injections of PLX-R18 cells in 24 subjects with incomplete hematopoietic recovery persisting for at least 4 months after HSCT, with a 12-month follow-up period.

The primary endpoint is safety. Exploratory endpoints include changes in platelet and hemoglobin levels, changes in transfusion frequency, a shift from transfusion dependence to transfusion independence, changes in quality of life, and changes in the serum immunological parameters.

PLX-R18 is being developed by Pluristem Therapeutics, Inc. PLX-R18 also has orphan designation for the treatment of acute radiation syndrome.

About orphan designation

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

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

Photo by Chad McNeeley

The U.S. Food and Drug Administration (FDA) has granted orphan designation to PLX-R18 for the treatment of graft failure and incomplete hematopoietic recovery following hematopoietic stem cell transplant (HSCT).

PLX-R18 consists of placenta-derived, mesenchymal-like adherent stromal cells that are designed to be administered to patients without the need for tissue or genetic matching.

PLX-R18 cells release a combination of therapeutic proteins in response to a damaged or poorly functioning hematopoietic system.

PLX-R18 is currently being evaluated for the treatment of insufficient hematopoietic recovery following HSCT in an ongoing, phase 1 trial (NCT03002519).

The trial is designed to evaluate the safety of intramuscular injections of PLX-R18 cells in 24 subjects with incomplete hematopoietic recovery persisting for at least 4 months after HSCT, with a 12-month follow-up period.

The primary endpoint is safety. Exploratory endpoints include changes in platelet and hemoglobin levels, changes in transfusion frequency, a shift from transfusion dependence to transfusion independence, changes in quality of life, and changes in the serum immunological parameters.

PLX-R18 is being developed by Pluristem Therapeutics, Inc. PLX-R18 also has orphan designation for the treatment of acute radiation syndrome.

About orphan designation

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

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

Photo by Chad McNeeley

The U.S. Food and Drug Administration (FDA) has granted orphan designation to PLX-R18 for the treatment of graft failure and incomplete hematopoietic recovery following hematopoietic stem cell transplant (HSCT).

PLX-R18 consists of placenta-derived, mesenchymal-like adherent stromal cells that are designed to be administered to patients without the need for tissue or genetic matching.

PLX-R18 cells release a combination of therapeutic proteins in response to a damaged or poorly functioning hematopoietic system.

PLX-R18 is currently being evaluated for the treatment of insufficient hematopoietic recovery following HSCT in an ongoing, phase 1 trial (NCT03002519).

The trial is designed to evaluate the safety of intramuscular injections of PLX-R18 cells in 24 subjects with incomplete hematopoietic recovery persisting for at least 4 months after HSCT, with a 12-month follow-up period.

The primary endpoint is safety. Exploratory endpoints include changes in platelet and hemoglobin levels, changes in transfusion frequency, a shift from transfusion dependence to transfusion independence, changes in quality of life, and changes in the serum immunological parameters.

PLX-R18 is being developed by Pluristem Therapeutics, Inc. PLX-R18 also has orphan designation for the treatment of acute radiation syndrome.

About orphan designation

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

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

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Richard Stone, MD

NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.

Dr. Stone also discussed therapies and treatment strategies that are under investigation.

Midostaurin

Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.

Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.

The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.

“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.

Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.

“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”

The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.

Gemtuzumab ozogamicin

The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.

Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.

However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.

Recent studies of the agent suggested use of the agent should be revisited but with lower doses.

Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.

According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.

Overall survival, however, was not significantly superior with gemtuzumab.

A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.

Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.

He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.

CPX-351

CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.

Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.

In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.

Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.

Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”

Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.

Enasidenib and ivosidenib

In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.

Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.

Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.

The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.

Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.

New approaches on the horizon

Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.

Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.

However, he believes the most important is BCL-2 inhibition with venetoclax.

Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.

And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.

Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”

Richard Stone, MD

NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.

Dr. Stone also discussed therapies and treatment strategies that are under investigation.

Midostaurin

Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.

Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.

The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.

“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.

Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.

“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”

The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.

Gemtuzumab ozogamicin

The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.

Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.

However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.

Recent studies of the agent suggested use of the agent should be revisited but with lower doses.

Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.

According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.

Overall survival, however, was not significantly superior with gemtuzumab.

A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.

Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.

He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.

CPX-351

CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.

Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.

In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.

Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.

Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”

Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.

Enasidenib and ivosidenib

In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.

Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.

Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.

The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.

Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.

New approaches on the horizon

Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.

Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.

However, he believes the most important is BCL-2 inhibition with venetoclax.

Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.

And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.

Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”

Richard Stone, MD

NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.

Dr. Stone also discussed therapies and treatment strategies that are under investigation.

Midostaurin

Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.

Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.

The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.

“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.

Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.

“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”

The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.

Gemtuzumab ozogamicin

The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.

Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.

However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.

Recent studies of the agent suggested use of the agent should be revisited but with lower doses.

Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.

According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.

Overall survival, however, was not significantly superior with gemtuzumab.

A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.

Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.

He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.

CPX-351

CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.

Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.

In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.

Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.

Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”

Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.

Enasidenib and ivosidenib

In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.

Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.

Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.

The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.

Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.

New approaches on the horizon

Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.

Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.

However, he believes the most important is BCL-2 inhibition with venetoclax.

Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.

And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.

Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”

Hematologic Malignancies

NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).

Genetics and cytogenetics

Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.

He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.

“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.

He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.

“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”

Achieving CR

Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.

“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”

The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.

“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.

“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.

“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”

Quantitation techniques and MRD

The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.

The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10^-4).

NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10^-4.

In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.

MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.

“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”

The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.

A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.

The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.

Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”

Hematologic Malignancies

NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).

Genetics and cytogenetics

Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.

He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.

“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.

He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.

“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”

Achieving CR

Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.

“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”

The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.

“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.

“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.

“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”

Quantitation techniques and MRD

The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.

The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10^-4).

NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10^-4.

In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.

MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.

“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”

The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.

A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.

The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.

Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”

Hematologic Malignancies

NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).

Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).

Genetics and cytogenetics

Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.

He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.

“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.

He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.

“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”

Achieving CR

Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.

“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”

The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.

“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.

“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.

“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”

Quantitation techniques and MRD

The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.

The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10^-4).

NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10^-4.

In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.

MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.

“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”

The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.

A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.

The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.

Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”

Image by Lance Liotta

The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.

The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.

Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.

The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).

ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.

Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).

Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.

Orphan and SAKIGAKE designations

The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.

To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.

Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.

Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.

Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.

SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.

SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.

Image by Lance Liotta

The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.

The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.

Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.

The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).

ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.

Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).

Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.

Orphan and SAKIGAKE designations

The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.

To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.

Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.

Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.

Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.

SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.

SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.

Image by Lance Liotta

The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.

The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.

Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.

The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).

ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.

Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).

Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.

Orphan and SAKIGAKE designations

The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.

To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.

Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.

Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.

Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.

SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.

SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.

Photo from Business Wire

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).

The approval was based on the phase 3 ECHELON-1 trial.

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD. 

Photo from Business Wire

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).

The approval was based on the phase 3 ECHELON-1 trial.

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD. 

Photo from Business Wire

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment option for CD30-positive Hodgkin lymphoma (HL).

The approval was based on the phase 3 ECHELON-1 trial.

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD. 

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.