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FDA approves biosimilar filgrastim
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).
Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.
The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.
The full approved indication for Nivestym is as follows:
- To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
- To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
- To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
- For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
- For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
For more details on Nivestym, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).
Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.
The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.
The full approved indication for Nivestym is as follows:
- To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
- To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
- To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
- For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
- For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
For more details on Nivestym, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).
Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.
The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.
The full approved indication for Nivestym is as follows:
- To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
- To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
- To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
- For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
- For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
For more details on Nivestym, see the full prescribing information.
Tool may reveal optimal time for SCT in MF
A new tool can help patients with myelofibrosis (MF) decide when to pursue stem cell transplant (SCT), according to the MPN Research Foundation.
The SCT Spectrum Transplant Timing tool (SSTT) is an online MF risk calculator.
It is designed to inform patients of their risk status in a timely manner so they can be proactive in speaking to their doctors about SCT.
“There is an optimal time to start SCT, simply because the odds of success soar in our favor when we start early rather than late in the game,” said Zhenya Senyak, editor of MPN Forum, an MF patient, and creator of the SSTT.
“The SCT Spectrum Timing Tool can help inform the timing of that decision.”
The SSTT incorporates the Dynamic International Prognostic Scoring System (DIPSS), asking patients about their age, white blood cell count, hemoglobin level, peripheral blood blast percentage, and constitutional symptoms.
Patients’ answers are used to create a color signal that indicates their current MF risk level. Accompanying information explains what the risk level means, provides median survival times for that level, and alerts patients of the relative urgency of SCT.
Patients can review these results with their hematologist to ensure accuracy and incorporate risk factors not measured by the SSTT.
The SSTT also includes resources to support SCT discussions between patients and hematologists.
Senyak created SSTT with help from the MPN SCT Transplantation Timing Taskforce, a group of 18 MPN and transplant specialists, patient advocates, and SCT survivors. The work was sponsored by the MPN Research Foundation.
“The decision of whether or not to pursue a stem cell transplant is incredibly fraught for any person,” said Ruben Mesa, MD, a member of the MPN SCT Transplantation Timing Taskforce.
“Our hope in assisting with this effort is to lend our knowledge and experience to create a guide to assist with patient-doctor communication around this very complicated issue.”
A new tool can help patients with myelofibrosis (MF) decide when to pursue stem cell transplant (SCT), according to the MPN Research Foundation.
The SCT Spectrum Transplant Timing tool (SSTT) is an online MF risk calculator.
It is designed to inform patients of their risk status in a timely manner so they can be proactive in speaking to their doctors about SCT.
“There is an optimal time to start SCT, simply because the odds of success soar in our favor when we start early rather than late in the game,” said Zhenya Senyak, editor of MPN Forum, an MF patient, and creator of the SSTT.
“The SCT Spectrum Timing Tool can help inform the timing of that decision.”
The SSTT incorporates the Dynamic International Prognostic Scoring System (DIPSS), asking patients about their age, white blood cell count, hemoglobin level, peripheral blood blast percentage, and constitutional symptoms.
Patients’ answers are used to create a color signal that indicates their current MF risk level. Accompanying information explains what the risk level means, provides median survival times for that level, and alerts patients of the relative urgency of SCT.
Patients can review these results with their hematologist to ensure accuracy and incorporate risk factors not measured by the SSTT.
The SSTT also includes resources to support SCT discussions between patients and hematologists.
Senyak created SSTT with help from the MPN SCT Transplantation Timing Taskforce, a group of 18 MPN and transplant specialists, patient advocates, and SCT survivors. The work was sponsored by the MPN Research Foundation.
“The decision of whether or not to pursue a stem cell transplant is incredibly fraught for any person,” said Ruben Mesa, MD, a member of the MPN SCT Transplantation Timing Taskforce.
“Our hope in assisting with this effort is to lend our knowledge and experience to create a guide to assist with patient-doctor communication around this very complicated issue.”
A new tool can help patients with myelofibrosis (MF) decide when to pursue stem cell transplant (SCT), according to the MPN Research Foundation.
The SCT Spectrum Transplant Timing tool (SSTT) is an online MF risk calculator.
It is designed to inform patients of their risk status in a timely manner so they can be proactive in speaking to their doctors about SCT.
“There is an optimal time to start SCT, simply because the odds of success soar in our favor when we start early rather than late in the game,” said Zhenya Senyak, editor of MPN Forum, an MF patient, and creator of the SSTT.
“The SCT Spectrum Timing Tool can help inform the timing of that decision.”
The SSTT incorporates the Dynamic International Prognostic Scoring System (DIPSS), asking patients about their age, white blood cell count, hemoglobin level, peripheral blood blast percentage, and constitutional symptoms.
Patients’ answers are used to create a color signal that indicates their current MF risk level. Accompanying information explains what the risk level means, provides median survival times for that level, and alerts patients of the relative urgency of SCT.
Patients can review these results with their hematologist to ensure accuracy and incorporate risk factors not measured by the SSTT.
The SSTT also includes resources to support SCT discussions between patients and hematologists.
Senyak created SSTT with help from the MPN SCT Transplantation Timing Taskforce, a group of 18 MPN and transplant specialists, patient advocates, and SCT survivors. The work was sponsored by the MPN Research Foundation.
“The decision of whether or not to pursue a stem cell transplant is incredibly fraught for any person,” said Ruben Mesa, MD, a member of the MPN SCT Transplantation Timing Taskforce.
“Our hope in assisting with this effort is to lend our knowledge and experience to create a guide to assist with patient-doctor communication around this very complicated issue.”
FDA grants UCB product orphan designation
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan 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.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan 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.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan 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.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Product receives orphan designation for use in HSCT
The US Food and Drug Administration (FDA) has granted orphan drug designation to dilanubicel (NLA101) for the reduction of morbidity and mortality associated with hematopoietic stem cell transplant (HSCT).
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 HSCT 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.
Phase 2 trials
The orphan drug designation for dilanubicel was 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 HSCT protocol, minus dilanubicel. There were no significant differences between the 2 cohorts with regard to baseline characteristics.
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.
“Dilanubicel has shown encouraging initial activity as a novel cell therapy in patients with hematologic malignancies receiving a cord blood transplant,” said President and CEO of Nohla Therapeutics Katie Fanning.
“We believe the addition of dilanubicel has the potential to make a meaningful difference for these patients, and we look forward to having the top-line results from the fully enrolled, randomized, phase 2b trial later this year.”
The phase 2b trial (NCT01690520) 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.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the 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.
The US Food and Drug Administration (FDA) has granted orphan drug designation to dilanubicel (NLA101) for the reduction of morbidity and mortality associated with hematopoietic stem cell transplant (HSCT).
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 HSCT 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.
Phase 2 trials
The orphan drug designation for dilanubicel was 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 HSCT protocol, minus dilanubicel. There were no significant differences between the 2 cohorts with regard to baseline characteristics.
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.
“Dilanubicel has shown encouraging initial activity as a novel cell therapy in patients with hematologic malignancies receiving a cord blood transplant,” said President and CEO of Nohla Therapeutics Katie Fanning.
“We believe the addition of dilanubicel has the potential to make a meaningful difference for these patients, and we look forward to having the top-line results from the fully enrolled, randomized, phase 2b trial later this year.”
The phase 2b trial (NCT01690520) 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.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the 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.
The US Food and Drug Administration (FDA) has granted orphan drug designation to dilanubicel (NLA101) for the reduction of morbidity and mortality associated with hematopoietic stem cell transplant (HSCT).
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 HSCT 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.
Phase 2 trials
The orphan drug designation for dilanubicel was 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 HSCT protocol, minus dilanubicel. There were no significant differences between the 2 cohorts with regard to baseline characteristics.
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.
“Dilanubicel has shown encouraging initial activity as a novel cell therapy in patients with hematologic malignancies receiving a cord blood transplant,” said President and CEO of Nohla Therapeutics Katie Fanning.
“We believe the addition of dilanubicel has the potential to make a meaningful difference for these patients, and we look forward to having the top-line results from the fully enrolled, randomized, phase 2b trial later this year.”
The phase 2b trial (NCT01690520) 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.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the 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.
New approach to AE reporting needed, group says
A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.
The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.
The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.
“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.
“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”
Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.
First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.
The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.
Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.
The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.
The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.
Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.
Additional details and recommendations are available in the full report.
A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.
The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.
The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.
“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.
“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”
Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.
First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.
The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.
Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.
The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.
The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.
Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.
Additional details and recommendations are available in the full report.
A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.
The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.
The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.
“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.
“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”
Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.
First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.
The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.
Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.
The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.
The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.
Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.
Additional details and recommendations are available in the full report.
Transplant strategy not viable for aggressive B-NHL
Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.
Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with 90Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).
However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.
The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).
Patients were treated with 0.4 mCi/kg 90Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.
Patients also received fludarabine at 30 mg/m2 on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.
In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.
The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.
However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.
Long-term survival
In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.
The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.
The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.
The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.
Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.
Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.
Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.
Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.
The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.
The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.
The researchers concluded that 90Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.
Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.
Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with 90Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).
However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.
The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).
Patients were treated with 0.4 mCi/kg 90Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.
Patients also received fludarabine at 30 mg/m2 on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.
In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.
The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.
However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.
Long-term survival
In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.
The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.
The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.
The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.
Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.
Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.
Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.
Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.
The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.
The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.
The researchers concluded that 90Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.
Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.
Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with 90Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).
However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.
The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).
Patients were treated with 0.4 mCi/kg 90Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.
Patients also received fludarabine at 30 mg/m2 on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.
In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.
The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.
However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.
Long-term survival
In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.
The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.
The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.
The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.
Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.
Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.
Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.
Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.
The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.
The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.
The researchers concluded that 90Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.
A ‘highly effective’ strategy for haplo-HSCT
STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).
The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.
Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.
In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.
Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).
The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.
Patients and transplant characteristics
Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.
Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).
The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).
About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.
The median CD34 dose was 22.0 x 106/kg, and the median α/β T-cell dose was 0.4 x 105/kg.
The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).
The median follow-up was 536 days (range, 32-1252).
Engraftment and survival
The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.
Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.
The cumulative incidence of transplant-related mortality was 8.7%.
There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.
“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.
The rate of disease-free survival and overall survival were both 87.6%.
GVHD and adverse events
Dr Pagliara said there were low rates of acute GVHD in the first 100 days.
The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.
Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.
Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.
“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.
Nine patients (15.2%) had at least 1 adverse event (AE).
AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.
There were no severe AEs attributed to BPX-501.
STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).
The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.
Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.
In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.
Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).
The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.
Patients and transplant characteristics
Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.
Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).
The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).
About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.
The median CD34 dose was 22.0 x 106/kg, and the median α/β T-cell dose was 0.4 x 105/kg.
The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).
The median follow-up was 536 days (range, 32-1252).
Engraftment and survival
The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.
Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.
The cumulative incidence of transplant-related mortality was 8.7%.
There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.
“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.
The rate of disease-free survival and overall survival were both 87.6%.
GVHD and adverse events
Dr Pagliara said there were low rates of acute GVHD in the first 100 days.
The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.
Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.
Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.
“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.
Nine patients (15.2%) had at least 1 adverse event (AE).
AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.
There were no severe AEs attributed to BPX-501.
STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).
The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.
Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.
In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.
Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).
The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.
Patients and transplant characteristics
Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.
Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).
The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).
About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.
The median CD34 dose was 22.0 x 106/kg, and the median α/β T-cell dose was 0.4 x 105/kg.
The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).
The median follow-up was 536 days (range, 32-1252).
Engraftment and survival
The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.
Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.
The cumulative incidence of transplant-related mortality was 8.7%.
There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.
“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.
The rate of disease-free survival and overall survival were both 87.6%.
GVHD and adverse events
Dr Pagliara said there were low rates of acute GVHD in the first 100 days.
The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.
Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.
Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.
“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.
Nine patients (15.2%) had at least 1 adverse event (AE).
AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.
There were no severe AEs attributed to BPX-501.
Inhibitor elicits responses in cGVHD
STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.
KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.
There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.
Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.
This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.
The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).
Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.
The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.
All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.
Treatment duration
The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.
Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.
Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.
Safety
“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”
Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).
Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).
Response
The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.
In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.
“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”
“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”
Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.
Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.
In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.
Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.
There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.
Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.
Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.
Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.
STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.
KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.
There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.
Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.
This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.
The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).
Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.
The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.
All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.
Treatment duration
The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.
Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.
Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.
Safety
“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”
Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).
Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).
Response
The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.
In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.
“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”
“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”
Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.
Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.
In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.
Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.
There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.
Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.
Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.
Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.
STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.
KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.
There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.
Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.
This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.
The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).
Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.
The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.
All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.
Treatment duration
The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.
Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.
Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.
Safety
“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”
Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).
Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).
Response
The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.
In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.
“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”
“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”
Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.
Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.
In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.
Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.
There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.
Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.
Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.
Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.
‘Excellent’ survival with HCT despite early treatment failure in FL
Autologous and allogeneic hematopoietic stem cell transplantation (HCT) both offer excellent long-term survival in follicular lymphoma (FL) patients who experience early treatment failure, an analysis of a large transplant registry suggests.
Five-year survival rates exceeded 70% for patients who received autologous or matched sibling donor (MSD) transplants, according to the analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. The database included 440 patients who underwent a procedure between 2002 and 2014.
“Until better risk-stratification tools are available for FL, auto-HCT and MSD allo-HCT should be considered as effective treatment options with excellent long-term survival for high-risk patients as defined by early treatment failure,” Sonali M. Smith, MD, of the University of Chicago, and co-investigators wrote in the journal Cancer.
Early treatment failure in FL is associated with worse overall survival. In the National LymphoCare Study (NLCS), patients who received upfront R-CHOP therapy and progressed within 24 months had a 5-year overall survival of 50%, versus 90% for patients without early progression.
By contrast, survival figures in the present study are “provocatively higher” than those in the NLCS, in which only 8 out of 110 patients underwent HCT, Dr Smith and co-authors said.
Dr Smith’s study showed that with a median follow-up of 69 to 73 months, adjusted probability of 5-year overall survival was 70% for autologous and 73% for MSD HCT, versus 49% for matched unrelated donor HCT (P=0.0008).
Ryan C. Lynch, MD, and Ajay K. Gopal, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, said that the finding “convincingly demonstrates” the benefit of transplant in the setting of early treatment failure.
“Select patients (particularly younger patients) with chemoresponsive disease who understand the risk-benefit ratio in comparison with currently approved and experimental therapies still remain good candidates for autologous HCT,” Drs Lynch and Gopal said in an editorial.
“For older patients or patients with comorbidities, we would continue to recommend clinical trials or treatment with an approved PI3K inhibitor,” they added.
The study by Dr Smith and colleagues is not the first to show a benefit of HCT in this clinical scenario. In a recent NLCS/CIBMTR analysis of FL patients, 5-year overall survival was 73% for those undergoing autologous HCT done within a year of early treatment failure, versus 60% for those who did not (P=0.05).
The two studies “collectively suggest that transplantation should be considered in this high-risk group of patients with early relapse,” Dr Smith and co-authors wrote.
Autologous and allogeneic hematopoietic stem cell transplantation (HCT) both offer excellent long-term survival in follicular lymphoma (FL) patients who experience early treatment failure, an analysis of a large transplant registry suggests.
Five-year survival rates exceeded 70% for patients who received autologous or matched sibling donor (MSD) transplants, according to the analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. The database included 440 patients who underwent a procedure between 2002 and 2014.
“Until better risk-stratification tools are available for FL, auto-HCT and MSD allo-HCT should be considered as effective treatment options with excellent long-term survival for high-risk patients as defined by early treatment failure,” Sonali M. Smith, MD, of the University of Chicago, and co-investigators wrote in the journal Cancer.
Early treatment failure in FL is associated with worse overall survival. In the National LymphoCare Study (NLCS), patients who received upfront R-CHOP therapy and progressed within 24 months had a 5-year overall survival of 50%, versus 90% for patients without early progression.
By contrast, survival figures in the present study are “provocatively higher” than those in the NLCS, in which only 8 out of 110 patients underwent HCT, Dr Smith and co-authors said.
Dr Smith’s study showed that with a median follow-up of 69 to 73 months, adjusted probability of 5-year overall survival was 70% for autologous and 73% for MSD HCT, versus 49% for matched unrelated donor HCT (P=0.0008).
Ryan C. Lynch, MD, and Ajay K. Gopal, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, said that the finding “convincingly demonstrates” the benefit of transplant in the setting of early treatment failure.
“Select patients (particularly younger patients) with chemoresponsive disease who understand the risk-benefit ratio in comparison with currently approved and experimental therapies still remain good candidates for autologous HCT,” Drs Lynch and Gopal said in an editorial.
“For older patients or patients with comorbidities, we would continue to recommend clinical trials or treatment with an approved PI3K inhibitor,” they added.
The study by Dr Smith and colleagues is not the first to show a benefit of HCT in this clinical scenario. In a recent NLCS/CIBMTR analysis of FL patients, 5-year overall survival was 73% for those undergoing autologous HCT done within a year of early treatment failure, versus 60% for those who did not (P=0.05).
The two studies “collectively suggest that transplantation should be considered in this high-risk group of patients with early relapse,” Dr Smith and co-authors wrote.
Autologous and allogeneic hematopoietic stem cell transplantation (HCT) both offer excellent long-term survival in follicular lymphoma (FL) patients who experience early treatment failure, an analysis of a large transplant registry suggests.
Five-year survival rates exceeded 70% for patients who received autologous or matched sibling donor (MSD) transplants, according to the analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. The database included 440 patients who underwent a procedure between 2002 and 2014.
“Until better risk-stratification tools are available for FL, auto-HCT and MSD allo-HCT should be considered as effective treatment options with excellent long-term survival for high-risk patients as defined by early treatment failure,” Sonali M. Smith, MD, of the University of Chicago, and co-investigators wrote in the journal Cancer.
Early treatment failure in FL is associated with worse overall survival. In the National LymphoCare Study (NLCS), patients who received upfront R-CHOP therapy and progressed within 24 months had a 5-year overall survival of 50%, versus 90% for patients without early progression.
By contrast, survival figures in the present study are “provocatively higher” than those in the NLCS, in which only 8 out of 110 patients underwent HCT, Dr Smith and co-authors said.
Dr Smith’s study showed that with a median follow-up of 69 to 73 months, adjusted probability of 5-year overall survival was 70% for autologous and 73% for MSD HCT, versus 49% for matched unrelated donor HCT (P=0.0008).
Ryan C. Lynch, MD, and Ajay K. Gopal, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, said that the finding “convincingly demonstrates” the benefit of transplant in the setting of early treatment failure.
“Select patients (particularly younger patients) with chemoresponsive disease who understand the risk-benefit ratio in comparison with currently approved and experimental therapies still remain good candidates for autologous HCT,” Drs Lynch and Gopal said in an editorial.
“For older patients or patients with comorbidities, we would continue to recommend clinical trials or treatment with an approved PI3K inhibitor,” they added.
The study by Dr Smith and colleagues is not the first to show a benefit of HCT in this clinical scenario. In a recent NLCS/CIBMTR analysis of FL patients, 5-year overall survival was 73% for those undergoing autologous HCT done within a year of early treatment failure, versus 60% for those who did not (P=0.05).
The two studies “collectively suggest that transplantation should be considered in this high-risk group of patients with early relapse,” Dr Smith and co-authors wrote.
Dasatinib outcomes similar to imatinib in pediatric Ph+ ALL
Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.
But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.
Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.
The investigators believe the incidence of cranial relapse may explain the results of AALL0622.
“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.
AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.
In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.
Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.
As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.
In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.
For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.
In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.
However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.
HSCT
AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.
Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.
Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.
Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.
Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).
Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.
The investigators reported their findings in The Journal of Clinical Oncology.
Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.
But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.
Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.
The investigators believe the incidence of cranial relapse may explain the results of AALL0622.
“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.
AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.
In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.
Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.
As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.
In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.
For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.
In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.
However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.
HSCT
AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.
Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.
Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.
Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.
Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).
Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.
The investigators reported their findings in The Journal of Clinical Oncology.
Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.
But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.
Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.
The investigators believe the incidence of cranial relapse may explain the results of AALL0622.
“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.
AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.
In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.
Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.
As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.
In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.
For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.
In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.
However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.
HSCT
AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.
Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.
Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.
Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.
Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).
Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.
The investigators reported their findings in The Journal of Clinical Oncology.