HT Staff

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Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.

Emicizumab is given as a once-weekly subcutaneous injection.

“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.

“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”

Trial results

The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).

The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.

A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).

Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.

There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”

Cord blood donation

The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.

Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.

It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.

However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.

Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.

Dilanubicel also has orphan drug designation from the FDA.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

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

Trials of dilanubicel

The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.

The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m²), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).

Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.

The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.

The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.

At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.

The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.

At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.

At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.

There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.

Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.

The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).

Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.

Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.

Cord blood donation

The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.

Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.

It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.

However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.

Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.

Dilanubicel also has orphan drug designation from the FDA.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

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

Trials of dilanubicel

The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.

The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m²), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).

Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.

The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.

The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.

At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.

The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.

At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.

At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.

There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.

Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.

The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).

Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.

Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.

Cord blood donation

The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.

Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.

It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.

However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.

Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.

Dilanubicel also has orphan drug designation from the FDA.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

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

Trials of dilanubicel

The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.

The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m²), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).

Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.

The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.

The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.

At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.

The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.

At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.

At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.

There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.

Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.

The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).

Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.

Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

Micrograph showing MM

MorphoSys AG has decided to stop developing MOR202 as a treatment for multiple myeloma (MM).

However, MorphoSys said it will complete the ongoing phase 1/2a trial of MOR202, and I-Mab Biopharma will continue developing MOR202 as an MM therapy for the Greater China region.

MOR202 is a human monoclonal HuCAL antibody directed against CD38, a validated target in MM.

MorphoSys is testing MOR202 in combination with other drugs in a phase 1/2a trial of patients with relapsed/refractory MM (NCT01421186).

The patients were assigned to receive MOR202 plus dexamethasone (Dex), MOR202 plus lenalidomide (Len) and Dex, or MOR202 plus pomalidomide (Pom) and Dex.

Results from this study were presented at the 2016 Annual Meeting of the German, Austrian and Swiss Societies for Hematology and Medical Oncology.

Data were reported for 38 patients—18 who had received MOR202 plus Dex, 7 who had received MOR202 plus Pom and Dex, and 13 who had received MOR202 plus Len and Dex.

The researchers said the maximum-tolerated dose of MOR202, alone or in combination, had not yet been reached. However, the data suggested MOR202 can be safely administered as a 2-hour intravenous infusion at doses up to 16 mg/kg.

The most frequent grade 3 or higher adverse events observed were hematologic in nature (leukopenia, lymphopenia, neutropenia, thrombocytopenia, and anemia).

One patient discontinued treatment due to an adverse event (decrease in platelet count) that may have been caused by MOR202 or Dex. One patient developed a transient anti-MOR202 antibody response.

There were no treatment-related deaths.

Efficacy data were available for 31 of the 38 patients. Fifteen patients responded (2 with complete responses). There were 7 responses in the Len/Dex arm, 5 in the Dex arm, and 3 in the Pom/Dex arm. Twelve responses were ongoing for up to 56 weeks.

MorphoSys said it expects to present final results from this study at an upcoming medical conference.

MorphoSys also said it will continue to support I-Mab Biopharma’s development of MOR202 in Greater China (China, Taiwan, Hong Kong, and Macao).

In November 2017, MorphoSys and I-Mab entered into an exclusive regional licensing agreement to develop and commercialize MOR202 in Greater China. I-Mab assumed exclusive responsibility for all subsequent development and commercialization of MOR202 in the agreed territory.

Micrograph showing MM

MorphoSys AG has decided to stop developing MOR202 as a treatment for multiple myeloma (MM).

However, MorphoSys said it will complete the ongoing phase 1/2a trial of MOR202, and I-Mab Biopharma will continue developing MOR202 as an MM therapy for the Greater China region.

MOR202 is a human monoclonal HuCAL antibody directed against CD38, a validated target in MM.

MorphoSys is testing MOR202 in combination with other drugs in a phase 1/2a trial of patients with relapsed/refractory MM (NCT01421186).

The patients were assigned to receive MOR202 plus dexamethasone (Dex), MOR202 plus lenalidomide (Len) and Dex, or MOR202 plus pomalidomide (Pom) and Dex.

Results from this study were presented at the 2016 Annual Meeting of the German, Austrian and Swiss Societies for Hematology and Medical Oncology.

Data were reported for 38 patients—18 who had received MOR202 plus Dex, 7 who had received MOR202 plus Pom and Dex, and 13 who had received MOR202 plus Len and Dex.

The researchers said the maximum-tolerated dose of MOR202, alone or in combination, had not yet been reached. However, the data suggested MOR202 can be safely administered as a 2-hour intravenous infusion at doses up to 16 mg/kg.

The most frequent grade 3 or higher adverse events observed were hematologic in nature (leukopenia, lymphopenia, neutropenia, thrombocytopenia, and anemia).

One patient discontinued treatment due to an adverse event (decrease in platelet count) that may have been caused by MOR202 or Dex. One patient developed a transient anti-MOR202 antibody response.

There were no treatment-related deaths.

Efficacy data were available for 31 of the 38 patients. Fifteen patients responded (2 with complete responses). There were 7 responses in the Len/Dex arm, 5 in the Dex arm, and 3 in the Pom/Dex arm. Twelve responses were ongoing for up to 56 weeks.

MorphoSys said it expects to present final results from this study at an upcoming medical conference.

MorphoSys also said it will continue to support I-Mab Biopharma’s development of MOR202 in Greater China (China, Taiwan, Hong Kong, and Macao).

In November 2017, MorphoSys and I-Mab entered into an exclusive regional licensing agreement to develop and commercialize MOR202 in Greater China. I-Mab assumed exclusive responsibility for all subsequent development and commercialization of MOR202 in the agreed territory.

Micrograph showing MM

MorphoSys AG has decided to stop developing MOR202 as a treatment for multiple myeloma (MM).

However, MorphoSys said it will complete the ongoing phase 1/2a trial of MOR202, and I-Mab Biopharma will continue developing MOR202 as an MM therapy for the Greater China region.

MOR202 is a human monoclonal HuCAL antibody directed against CD38, a validated target in MM.

MorphoSys is testing MOR202 in combination with other drugs in a phase 1/2a trial of patients with relapsed/refractory MM (NCT01421186).

The patients were assigned to receive MOR202 plus dexamethasone (Dex), MOR202 plus lenalidomide (Len) and Dex, or MOR202 plus pomalidomide (Pom) and Dex.

Results from this study were presented at the 2016 Annual Meeting of the German, Austrian and Swiss Societies for Hematology and Medical Oncology.

Data were reported for 38 patients—18 who had received MOR202 plus Dex, 7 who had received MOR202 plus Pom and Dex, and 13 who had received MOR202 plus Len and Dex.

The researchers said the maximum-tolerated dose of MOR202, alone or in combination, had not yet been reached. However, the data suggested MOR202 can be safely administered as a 2-hour intravenous infusion at doses up to 16 mg/kg.

The most frequent grade 3 or higher adverse events observed were hematologic in nature (leukopenia, lymphopenia, neutropenia, thrombocytopenia, and anemia).

One patient discontinued treatment due to an adverse event (decrease in platelet count) that may have been caused by MOR202 or Dex. One patient developed a transient anti-MOR202 antibody response.

There were no treatment-related deaths.

Efficacy data were available for 31 of the 38 patients. Fifteen patients responded (2 with complete responses). There were 7 responses in the Len/Dex arm, 5 in the Dex arm, and 3 in the Pom/Dex arm. Twelve responses were ongoing for up to 56 weeks.

MorphoSys said it expects to present final results from this study at an upcoming medical conference.

MorphoSys also said it will continue to support I-Mab Biopharma’s development of MOR202 in Greater China (China, Taiwan, Hong Kong, and Macao).

In November 2017, MorphoSys and I-Mab entered into an exclusive regional licensing agreement to develop and commercialize MOR202 in Greater China. I-Mab assumed exclusive responsibility for all subsequent development and commercialization of MOR202 in the agreed territory.

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.

Lab mouse

Researchers say they have discovered how hypoxia increases the risk of thrombosis.

The team noted that the cellular response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF1).

The researchers were able to show that HIF1 downregulates expression of protein S (PS), a natural anticoagulant, which increases the risk of thrombosis.

“Our earlier work found that PS inhibits a key clotting protein, factor IXa,” said Rinku Majumder, PhD, of LSU Health Sciences Center in New Orleans, Louisiana.

“We knew that PS deficiency could occur in hypoxia but not why. With this study, our group identified the gene regulatory mechanism by which oxygen concentration controls PS production.”

Dr Majumder and her colleagues described this discovery in a letter published in Blood.

Because PS is primarily produced in the liver, the researchers cultured human hepatocarcinoma cells in normoxic and hypoxic conditions and then measured levels of PS.

The team found that increasing hypoxia reduced PS levels and increased stability of the HIF1α subunit of HIF1. The researchers said this inverse relationship between HIF1α and PS levels suggests HIF1 might regulate PS expression, and this theory was confirmed via experiments with mice.

Dr Majumder and her colleagues pointed out that an oxygen-dependent signaling system degrades HIF1α, and oxygen deficiency prevents HIF1α degradation. The HIF1α P564A mutant (HIF1α dPA) is resistant to degradation, which results in elevated HIF1 even in normoxic conditions.

The researchers conducted experiments with knockout mice expressing HIF1α dPA in the liver, HIF1α liver-specific knockout mice, and control mice.

When compared to PS levels in liver samples from control mice (100%), PS levels were elevated in liver samples from the HIF1α liver-specific knockout mice (220%) and reduced in samples from the HIF1α dPA mice (50%).

PS messenger RNA was 2-fold higher in HIF1α knockout mice than in controls. In HIF1α dPA mice, PS messenger RNA was 0.3-fold that of controls.

PS levels in plasma from HIF1α knockout mice were double the levels of controls, while PS levels in plasma from HIF1α dPA mice were half that of controls.

Plasma from HIF1α knockout mice produced 5-fold less thrombin and plasma from HIF1α dPA mice produced 1.5-fold more thrombin than control plasma.

Subsequent experiments confirmed that the variations in thrombin generation were due to changes in plasma PS levels, the researchers said.

The team concluded that stabilization of HIF1 in the liver, which is a normal response to hypoxia, is associated with reduced PS expression. This results in lower plasma PS levels and an increased risk of thrombosis.