Transplantation

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

Image from PLOS ONE

The US Food and Drug Administration (FDA) has granted orphan drug designation to KD025 for the treatment of chronic graft-versus-host disease (cGVHD).

KD025 is a Rho-associated coiled-coil kinase (ROCK) inhibitor being developed by Kadmon Holdings, Inc.

The drug is currently under investigation in a phase 2 trial of adults with steroid-dependent or steroid-refractory cGVHD and active disease.

This dose-finding study has enrolled 48 patients divided into 3 cohorts in which patients receive KD025 at 200 mg once daily, 200 mg twice daily, or 400 mg once daily. The patients were enrolled sequentially following a safety assessment of each cohort.

In July, Kadmon Holdings, Inc. released a preliminary analysis of data from the lowest-dose cohort (n=17, 200 mg once daily).

The overall response rate in this cohort was 71% (12/17). Of responders remaining on KD025 through week 24, 89% (8/9) sustained responses. Sixty-seven percent (8/12) of responders saw an improvement in symptoms, as measured by the Lee cGVHD Symptom Scale score.

In addition to the 12 responders, 3 patients had stable disease and were still on KD025 through week 24.  So an overall clinical benefit (response and stable disease) occurred in 88% (15/17) of patients.

Sixty-seven percent (8/12) of responders had a reduction in steroid doses, and 67% (4/6) of responders on tacrolimus had a reduction in tacrolimus doses.

There were no drug-related serious adverse events or drug-related elevations in liver function tests reported.

Kadmon Holdings, Inc. plans to present additional data from this study toward the end of this year.

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.

Image from PLOS ONE

The US Food and Drug Administration (FDA) has granted orphan drug designation to KD025 for the treatment of chronic graft-versus-host disease (cGVHD).

KD025 is a Rho-associated coiled-coil kinase (ROCK) inhibitor being developed by Kadmon Holdings, Inc.

The drug is currently under investigation in a phase 2 trial of adults with steroid-dependent or steroid-refractory cGVHD and active disease.

This dose-finding study has enrolled 48 patients divided into 3 cohorts in which patients receive KD025 at 200 mg once daily, 200 mg twice daily, or 400 mg once daily. The patients were enrolled sequentially following a safety assessment of each cohort.

In July, Kadmon Holdings, Inc. released a preliminary analysis of data from the lowest-dose cohort (n=17, 200 mg once daily).

The overall response rate in this cohort was 71% (12/17). Of responders remaining on KD025 through week 24, 89% (8/9) sustained responses. Sixty-seven percent (8/12) of responders saw an improvement in symptoms, as measured by the Lee cGVHD Symptom Scale score.

In addition to the 12 responders, 3 patients had stable disease and were still on KD025 through week 24.  So an overall clinical benefit (response and stable disease) occurred in 88% (15/17) of patients.

Sixty-seven percent (8/12) of responders had a reduction in steroid doses, and 67% (4/6) of responders on tacrolimus had a reduction in tacrolimus doses.

There were no drug-related serious adverse events or drug-related elevations in liver function tests reported.

Kadmon Holdings, Inc. plans to present additional data from this study toward the end of this year.

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.

Image from PLOS ONE

The US Food and Drug Administration (FDA) has granted orphan drug designation to KD025 for the treatment of chronic graft-versus-host disease (cGVHD).

KD025 is a Rho-associated coiled-coil kinase (ROCK) inhibitor being developed by Kadmon Holdings, Inc.

The drug is currently under investigation in a phase 2 trial of adults with steroid-dependent or steroid-refractory cGVHD and active disease.

This dose-finding study has enrolled 48 patients divided into 3 cohorts in which patients receive KD025 at 200 mg once daily, 200 mg twice daily, or 400 mg once daily. The patients were enrolled sequentially following a safety assessment of each cohort.

In July, Kadmon Holdings, Inc. released a preliminary analysis of data from the lowest-dose cohort (n=17, 200 mg once daily).

The overall response rate in this cohort was 71% (12/17). Of responders remaining on KD025 through week 24, 89% (8/9) sustained responses. Sixty-seven percent (8/12) of responders saw an improvement in symptoms, as measured by the Lee cGVHD Symptom Scale score.

In addition to the 12 responders, 3 patients had stable disease and were still on KD025 through week 24.  So an overall clinical benefit (response and stable disease) occurred in 88% (15/17) of patients.

Sixty-seven percent (8/12) of responders had a reduction in steroid doses, and 67% (4/6) of responders on tacrolimus had a reduction in tacrolimus doses.

There were no drug-related serious adverse events or drug-related elevations in liver function tests reported.

Kadmon Holdings, Inc. plans to present additional data from this study toward the end of this year.

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.

Photo by Einar Fredriksen

A 2-drug combination sets a new standard for prevention of acute graft-versus-host disease (GVHD), according to an author of a new study.

The combination—sirolimus and KY1005—completely protected nonhuman primates from acute GVHD and significantly prolonged survival in the animals.

The combination controlled the expansion of effector T cells (Teffs) while augmenting the proportion of regulatory T cells (Tregs) in the primates’ bloodstreams, allowing transplanted stem cells to reconstitute the animals’ immune systems.

Researchers reported these results in Science Translational Medicine. The work was funded by Kymab, the company developing KY1005.

“KY1005, in combination with sirolimus, sets a new standard for [acute] GVHD prevention,” said study author Leslie Kean, MD, PhD, of Seattle Children’s Research Institute in Washington.

“These results in the complex and clinically relevant animal model suggest this regimen is an exceptional candidate for clinical translation.”

Dr Kean and her colleagues noted that no existing treatments for GVHD can successfully strike the delicate balance between controlling Teffs and maintaining the protective function of Tregs.

So the team decided to combine 2 treatments that partially suppress Teffs—sirolimus and KY1005, a monoclonal antibody that blocks a T-cell receptor ligand called OX40L.

The researchers tested the combination in rhesus macaques undergoing allogeneic hematopoietic stem cell transplant (HSCT). The team compared the combination to each agent alone, as well as to no prophylaxis.

KY1005 was given at a dose of 10 mg/kg, starting 2 days before HSCT and continuing once weekly until planned discontinuation on day 54.  Sirolimus was given daily for the entire study period as an intramuscular formulation, with doses adjusted to achieve a serum trough concentration of 5 to 15 ng/mL.

Animals treated with both sirolimus and KY1005 survived—free from GVHD—for more than 100 days after HSCT, which was significantly longer than any other group (P<0.01).

In comparison, untreated animals succumbed to GVHD within 8 days of HSCT. And the median GVHD-free survival times were 14 days for the sirolimus group and 19.5 days for the KY1005 group.

The researchers also noted that untreated animals experienced “a rapid decline” in Tregs over the study period. They had a significant decrease in the ratio of Tregs to conventional T cells (Tconv)—2.0 ± 0.4 before HSCT and 0.6 ± 0.1 at last analysis (P<0.001).

When given alone, both KY1005 and sirolimus protected animals from this drop in the Treg/Tconv ratio.

But the combination regimen significantly augmented the Treg/Tconv ratio—1.30 ± 0.30 before HSCT and 1.82 ± 0.43 at last analysis (P<0.05).

Because sirolimus is already used as GVHD prophylaxis and KY1005 is in phase 1 testing as a psoriasis treatment, the researchers believe the combination is a strong candidate for clinical testing.

Photo by Einar Fredriksen

A 2-drug combination sets a new standard for prevention of acute graft-versus-host disease (GVHD), according to an author of a new study.

The combination—sirolimus and KY1005—completely protected nonhuman primates from acute GVHD and significantly prolonged survival in the animals.

The combination controlled the expansion of effector T cells (Teffs) while augmenting the proportion of regulatory T cells (Tregs) in the primates’ bloodstreams, allowing transplanted stem cells to reconstitute the animals’ immune systems.

Researchers reported these results in Science Translational Medicine. The work was funded by Kymab, the company developing KY1005.

“KY1005, in combination with sirolimus, sets a new standard for [acute] GVHD prevention,” said study author Leslie Kean, MD, PhD, of Seattle Children’s Research Institute in Washington.

“These results in the complex and clinically relevant animal model suggest this regimen is an exceptional candidate for clinical translation.”

Dr Kean and her colleagues noted that no existing treatments for GVHD can successfully strike the delicate balance between controlling Teffs and maintaining the protective function of Tregs.

So the team decided to combine 2 treatments that partially suppress Teffs—sirolimus and KY1005, a monoclonal antibody that blocks a T-cell receptor ligand called OX40L.

The researchers tested the combination in rhesus macaques undergoing allogeneic hematopoietic stem cell transplant (HSCT). The team compared the combination to each agent alone, as well as to no prophylaxis.

KY1005 was given at a dose of 10 mg/kg, starting 2 days before HSCT and continuing once weekly until planned discontinuation on day 54.  Sirolimus was given daily for the entire study period as an intramuscular formulation, with doses adjusted to achieve a serum trough concentration of 5 to 15 ng/mL.

Animals treated with both sirolimus and KY1005 survived—free from GVHD—for more than 100 days after HSCT, which was significantly longer than any other group (P<0.01).

In comparison, untreated animals succumbed to GVHD within 8 days of HSCT. And the median GVHD-free survival times were 14 days for the sirolimus group and 19.5 days for the KY1005 group.

The researchers also noted that untreated animals experienced “a rapid decline” in Tregs over the study period. They had a significant decrease in the ratio of Tregs to conventional T cells (Tconv)—2.0 ± 0.4 before HSCT and 0.6 ± 0.1 at last analysis (P<0.001).

When given alone, both KY1005 and sirolimus protected animals from this drop in the Treg/Tconv ratio.

But the combination regimen significantly augmented the Treg/Tconv ratio—1.30 ± 0.30 before HSCT and 1.82 ± 0.43 at last analysis (P<0.05).

Because sirolimus is already used as GVHD prophylaxis and KY1005 is in phase 1 testing as a psoriasis treatment, the researchers believe the combination is a strong candidate for clinical testing.

Photo by Einar Fredriksen

A 2-drug combination sets a new standard for prevention of acute graft-versus-host disease (GVHD), according to an author of a new study.

The combination—sirolimus and KY1005—completely protected nonhuman primates from acute GVHD and significantly prolonged survival in the animals.

The combination controlled the expansion of effector T cells (Teffs) while augmenting the proportion of regulatory T cells (Tregs) in the primates’ bloodstreams, allowing transplanted stem cells to reconstitute the animals’ immune systems.

Researchers reported these results in Science Translational Medicine. The work was funded by Kymab, the company developing KY1005.

“KY1005, in combination with sirolimus, sets a new standard for [acute] GVHD prevention,” said study author Leslie Kean, MD, PhD, of Seattle Children’s Research Institute in Washington.

“These results in the complex and clinically relevant animal model suggest this regimen is an exceptional candidate for clinical translation.”

Dr Kean and her colleagues noted that no existing treatments for GVHD can successfully strike the delicate balance between controlling Teffs and maintaining the protective function of Tregs.

So the team decided to combine 2 treatments that partially suppress Teffs—sirolimus and KY1005, a monoclonal antibody that blocks a T-cell receptor ligand called OX40L.

The researchers tested the combination in rhesus macaques undergoing allogeneic hematopoietic stem cell transplant (HSCT). The team compared the combination to each agent alone, as well as to no prophylaxis.

KY1005 was given at a dose of 10 mg/kg, starting 2 days before HSCT and continuing once weekly until planned discontinuation on day 54.  Sirolimus was given daily for the entire study period as an intramuscular formulation, with doses adjusted to achieve a serum trough concentration of 5 to 15 ng/mL.

Animals treated with both sirolimus and KY1005 survived—free from GVHD—for more than 100 days after HSCT, which was significantly longer than any other group (P<0.01).

In comparison, untreated animals succumbed to GVHD within 8 days of HSCT. And the median GVHD-free survival times were 14 days for the sirolimus group and 19.5 days for the KY1005 group.

The researchers also noted that untreated animals experienced “a rapid decline” in Tregs over the study period. They had a significant decrease in the ratio of Tregs to conventional T cells (Tconv)—2.0 ± 0.4 before HSCT and 0.6 ± 0.1 at last analysis (P<0.001).

When given alone, both KY1005 and sirolimus protected animals from this drop in the Treg/Tconv ratio.

But the combination regimen significantly augmented the Treg/Tconv ratio—1.30 ± 0.30 before HSCT and 1.82 ± 0.43 at last analysis (P<0.05).

Because sirolimus is already used as GVHD prophylaxis and KY1005 is in phase 1 testing as a psoriasis treatment, the researchers believe the combination is a strong candidate for clinical testing.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

CMV infection

The US Food and Drug Administration (FDA) has granted orphan drug designation to ATA230 for the treatment of cytomegalovirus (CMV) viremia and disease in immunocompromised patients.

ATA230 is an allogeneic, cytotoxic T-lymphocyte (CTL) product targeting antigens expressed by CMV.

The product is under investigation in phase 2 trials of patients with CMV viremia and disease who are refractory or resistant to antiviral treatment.

Atara Biotherapeutics, Inc., the company developing ATA230, said it will evaluate development plans for this therapy with the FDA and other global health authorities after beginning phase 3 studies of another product, ATA129.

The company said it decided to prioritize ATA129, which is being developed to treat patients with Epstein-Barr-virus-associated post-transplant lymphoproliferative disorder.

Phase 2 trial of ATA230

Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.

The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.

Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.

At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.

Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.

Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.

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.

CMV infection

The US Food and Drug Administration (FDA) has granted orphan drug designation to ATA230 for the treatment of cytomegalovirus (CMV) viremia and disease in immunocompromised patients.

ATA230 is an allogeneic, cytotoxic T-lymphocyte (CTL) product targeting antigens expressed by CMV.

The product is under investigation in phase 2 trials of patients with CMV viremia and disease who are refractory or resistant to antiviral treatment.

Atara Biotherapeutics, Inc., the company developing ATA230, said it will evaluate development plans for this therapy with the FDA and other global health authorities after beginning phase 3 studies of another product, ATA129.

The company said it decided to prioritize ATA129, which is being developed to treat patients with Epstein-Barr-virus-associated post-transplant lymphoproliferative disorder.

Phase 2 trial of ATA230

Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.

The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.

Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.

At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.

Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.

Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.

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.

CMV infection

The US Food and Drug Administration (FDA) has granted orphan drug designation to ATA230 for the treatment of cytomegalovirus (CMV) viremia and disease in immunocompromised patients.

ATA230 is an allogeneic, cytotoxic T-lymphocyte (CTL) product targeting antigens expressed by CMV.

The product is under investigation in phase 2 trials of patients with CMV viremia and disease who are refractory or resistant to antiviral treatment.

Atara Biotherapeutics, Inc., the company developing ATA230, said it will evaluate development plans for this therapy with the FDA and other global health authorities after beginning phase 3 studies of another product, ATA129.

The company said it decided to prioritize ATA129, which is being developed to treat patients with Epstein-Barr-virus-associated post-transplant lymphoproliferative disorder.

Phase 2 trial of ATA230

Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.

The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.

Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.

At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.

Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.

Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.

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.

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has granted orphan drug designation to ApoGraft™ as prophylaxis for acute and chronic graft-versus-host disease (GVHD) in transplant recipients.

ApoGraft is a mobilized peripheral blood cell product collected via apheresis from a matched, related donor. The product is exposed to the apoptotic mediator Fas ligand prior to transplantation.

ApoGraft was designed to eliminate immune responses after transplantation of foreign cells and tissues.

ApoGraft is being developed by Cellect Biotechnology Ltd.

The company is testing ApoGraft as acute GVHD prophylaxis in a phase 1/2 trial.

The trial is currently enrolling patients with hemato-oncology disorders who are eligible for allogeneic, HLA-matched hematopoietic stem cell transplant (HSCT).

The study is expected to have 4 cohorts, each consisting of 3 patients.

The difference between the cohorts is the amount of apoptotic mediator Fas ligand (APO010) to which the graft is exposed during incubation prior to ApoGraft transplantation and HSCT:

• 10 ng/mL APO010 in Cohort 1
• 25 ng/mL APO010 in Cohort 2
• 50 ng/mL APO010 in Cohort 3
• 100 ng/mL APO010 in Cohort 4.

The study is expected to progress from one cohort to the next based on an independent data safety monitoring board review and analysis of safety data.

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.

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has granted orphan drug designation to ApoGraft™ as prophylaxis for acute and chronic graft-versus-host disease (GVHD) in transplant recipients.

ApoGraft is a mobilized peripheral blood cell product collected via apheresis from a matched, related donor. The product is exposed to the apoptotic mediator Fas ligand prior to transplantation.

ApoGraft was designed to eliminate immune responses after transplantation of foreign cells and tissues.

ApoGraft is being developed by Cellect Biotechnology Ltd.

The company is testing ApoGraft as acute GVHD prophylaxis in a phase 1/2 trial.

The trial is currently enrolling patients with hemato-oncology disorders who are eligible for allogeneic, HLA-matched hematopoietic stem cell transplant (HSCT).

The study is expected to have 4 cohorts, each consisting of 3 patients.

The difference between the cohorts is the amount of apoptotic mediator Fas ligand (APO010) to which the graft is exposed during incubation prior to ApoGraft transplantation and HSCT:

• 10 ng/mL APO010 in Cohort 1
• 25 ng/mL APO010 in Cohort 2
• 50 ng/mL APO010 in Cohort 3
• 100 ng/mL APO010 in Cohort 4.

The study is expected to progress from one cohort to the next based on an independent data safety monitoring board review and analysis of safety data.

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.

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has granted orphan drug designation to ApoGraft™ as prophylaxis for acute and chronic graft-versus-host disease (GVHD) in transplant recipients.

ApoGraft is a mobilized peripheral blood cell product collected via apheresis from a matched, related donor. The product is exposed to the apoptotic mediator Fas ligand prior to transplantation.

ApoGraft was designed to eliminate immune responses after transplantation of foreign cells and tissues.

ApoGraft is being developed by Cellect Biotechnology Ltd.

The company is testing ApoGraft as acute GVHD prophylaxis in a phase 1/2 trial.

The trial is currently enrolling patients with hemato-oncology disorders who are eligible for allogeneic, HLA-matched hematopoietic stem cell transplant (HSCT).

The study is expected to have 4 cohorts, each consisting of 3 patients.

The difference between the cohorts is the amount of apoptotic mediator Fas ligand (APO010) to which the graft is exposed during incubation prior to ApoGraft transplantation and HSCT:

• 10 ng/mL APO010 in Cohort 1
• 25 ng/mL APO010 in Cohort 2
• 50 ng/mL APO010 in Cohort 3
• 100 ng/mL APO010 in Cohort 4.

The study is expected to progress from one cohort to the next based on an independent data safety monitoring board review and analysis of safety data.

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.

Fred Hutch News Service

Researchers say they have created nanoparticles loaded with messenger RNA (mRNA) that can give cells the ability to fight cancers and other diseases.

To use these freeze-dried nanocarriers, the team added water and introduced the resulting mixture to cells.

The nanocarriers were able to target T cells and hematopoietic stem cells (HSCs), delivering mRNA directly to the cells and triggering short-term gene expression.

The T cells were then able to fight leukemia and lymphoma in vitro and in vivo. And the HSCs demonstrated improvements in growth and regenerative potential.

Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Nature Communications.

“We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation,” Dr Stephan said.

The researchers surrounded the nanocarrier with a negatively charged envelope with a targeting ligand attached to the surface so the carrier homes and binds to a particular cell type. When this happens, the cell engulfs the carrier, which can be loaded with different types of manmade mRNA.

The researchers mixed the freeze-dried nanocarriers with water and samples of cells. Within 4 hours, cells started showing signs that editing had taken effect.

The team noted that boosters can be given if needed. And the nanocarriers are made from a dissolving biomaterial, so they are removed from the body like other cell waste.

Testing the carriers

Dr Stephan and his colleagues tested their nanocarriers in 3 ways.

First, the researchers tested nanoparticles carrying a gene-editing tool to T cells that snipped out their natural T-cell receptors and was paired with genes encoding a chimeric antigen receptor (CAR).

The resulting CAR T cells maintained their ability to proliferate and successfully eliminated leukemia cells.

Next, the researchers tested nanocarriers targeted to CAR T cells and containing foxo1 mRNA. This prompted the T cells to develop into a type of memory cell with enhanced antitumor activity.

The team found these CAR T cells induced “substantial disease regression” and prolonged survival in a mouse model of B-cell lymphoma.

Finally, the researchers tested nanocarriers targeted to HSCs. The carriers were equipped with mRNA that “induced key regulators of self-renewal,” accelerating the growth and regenerative potential of the HSCs in vitro.

Future possibilities

Dr Stephan and his colleagues noted that these nanocarriers are built on existing technology and can be used by individuals without knowledge of nanotechnology. Therefore, the team hopes the nanocarriers will be an off-the-shelf way for cell-therapy engineers to develop new approaches to treat diseases.

The researchers believe the nanocarriers could replace electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. The team noted that up to 60 times more cells survive the introduction of the nanocarriers than survive electroporation.

“You can imagine taking the nanoparticles, injecting them into a patient, and then you don’t have to culture cells at all anymore,” Dr Stephan said.

He is now looking for commercial partners to move the technology toward additional applications and into clinical trials. 

Fred Hutch News Service

Researchers say they have created nanoparticles loaded with messenger RNA (mRNA) that can give cells the ability to fight cancers and other diseases.

To use these freeze-dried nanocarriers, the team added water and introduced the resulting mixture to cells.

The nanocarriers were able to target T cells and hematopoietic stem cells (HSCs), delivering mRNA directly to the cells and triggering short-term gene expression.

The T cells were then able to fight leukemia and lymphoma in vitro and in vivo. And the HSCs demonstrated improvements in growth and regenerative potential.

Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Nature Communications.

“We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation,” Dr Stephan said.

The researchers surrounded the nanocarrier with a negatively charged envelope with a targeting ligand attached to the surface so the carrier homes and binds to a particular cell type. When this happens, the cell engulfs the carrier, which can be loaded with different types of manmade mRNA.

The researchers mixed the freeze-dried nanocarriers with water and samples of cells. Within 4 hours, cells started showing signs that editing had taken effect.

The team noted that boosters can be given if needed. And the nanocarriers are made from a dissolving biomaterial, so they are removed from the body like other cell waste.

Testing the carriers

Dr Stephan and his colleagues tested their nanocarriers in 3 ways.

First, the researchers tested nanoparticles carrying a gene-editing tool to T cells that snipped out their natural T-cell receptors and was paired with genes encoding a chimeric antigen receptor (CAR).

The resulting CAR T cells maintained their ability to proliferate and successfully eliminated leukemia cells.

Next, the researchers tested nanocarriers targeted to CAR T cells and containing foxo1 mRNA. This prompted the T cells to develop into a type of memory cell with enhanced antitumor activity.

The team found these CAR T cells induced “substantial disease regression” and prolonged survival in a mouse model of B-cell lymphoma.

Finally, the researchers tested nanocarriers targeted to HSCs. The carriers were equipped with mRNA that “induced key regulators of self-renewal,” accelerating the growth and regenerative potential of the HSCs in vitro.

Future possibilities

Dr Stephan and his colleagues noted that these nanocarriers are built on existing technology and can be used by individuals without knowledge of nanotechnology. Therefore, the team hopes the nanocarriers will be an off-the-shelf way for cell-therapy engineers to develop new approaches to treat diseases.

The researchers believe the nanocarriers could replace electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. The team noted that up to 60 times more cells survive the introduction of the nanocarriers than survive electroporation.

“You can imagine taking the nanoparticles, injecting them into a patient, and then you don’t have to culture cells at all anymore,” Dr Stephan said.

He is now looking for commercial partners to move the technology toward additional applications and into clinical trials. 

Fred Hutch News Service

Researchers say they have created nanoparticles loaded with messenger RNA (mRNA) that can give cells the ability to fight cancers and other diseases.

To use these freeze-dried nanocarriers, the team added water and introduced the resulting mixture to cells.

The nanocarriers were able to target T cells and hematopoietic stem cells (HSCs), delivering mRNA directly to the cells and triggering short-term gene expression.

The T cells were then able to fight leukemia and lymphoma in vitro and in vivo. And the HSCs demonstrated improvements in growth and regenerative potential.

Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Nature Communications.

“We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation,” Dr Stephan said.

The researchers surrounded the nanocarrier with a negatively charged envelope with a targeting ligand attached to the surface so the carrier homes and binds to a particular cell type. When this happens, the cell engulfs the carrier, which can be loaded with different types of manmade mRNA.

The researchers mixed the freeze-dried nanocarriers with water and samples of cells. Within 4 hours, cells started showing signs that editing had taken effect.

The team noted that boosters can be given if needed. And the nanocarriers are made from a dissolving biomaterial, so they are removed from the body like other cell waste.

Testing the carriers

Dr Stephan and his colleagues tested their nanocarriers in 3 ways.

First, the researchers tested nanoparticles carrying a gene-editing tool to T cells that snipped out their natural T-cell receptors and was paired with genes encoding a chimeric antigen receptor (CAR).

The resulting CAR T cells maintained their ability to proliferate and successfully eliminated leukemia cells.

Next, the researchers tested nanocarriers targeted to CAR T cells and containing foxo1 mRNA. This prompted the T cells to develop into a type of memory cell with enhanced antitumor activity.

The team found these CAR T cells induced “substantial disease regression” and prolonged survival in a mouse model of B-cell lymphoma.

Finally, the researchers tested nanocarriers targeted to HSCs. The carriers were equipped with mRNA that “induced key regulators of self-renewal,” accelerating the growth and regenerative potential of the HSCs in vitro.

Future possibilities

Dr Stephan and his colleagues noted that these nanocarriers are built on existing technology and can be used by individuals without knowledge of nanotechnology. Therefore, the team hopes the nanocarriers will be an off-the-shelf way for cell-therapy engineers to develop new approaches to treat diseases.

The researchers believe the nanocarriers could replace electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. The team noted that up to 60 times more cells survive the introduction of the nanocarriers than survive electroporation.

“You can imagine taking the nanoparticles, injecting them into a patient, and then you don’t have to culture cells at all anymore,” Dr Stephan said.

He is now looking for commercial partners to move the technology toward additional applications and into clinical trials. 

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

Photo by Chad McNeeley

New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.

Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.

There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.

“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.

“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”

This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.

Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.

“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”

The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.

Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.

In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.

“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.

He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The researchers see potential applications in HSCTs, for both donors and recipients.

In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.

HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”

Photo courtesy of Celgene

Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.

A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.

Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.

The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).

Patient demographics and disease-related characteristics were generally balanced between the treatment groups.

The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.

Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).

PFS and OS

Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.

The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).

The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),

At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.

Safety

Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.

Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).

There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.

The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.

The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.

“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.

“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”

Photo courtesy of Celgene

Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.

A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.

Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.

The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).

Patient demographics and disease-related characteristics were generally balanced between the treatment groups.

The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.

Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).

PFS and OS

Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.

The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).

The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),

At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.

Safety

Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.

Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).

There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.

The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.

The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.

“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.

“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”

Photo courtesy of Celgene

Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.

A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.

Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.

The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).

Patient demographics and disease-related characteristics were generally balanced between the treatment groups.

The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.

Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).

PFS and OS

Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.

The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).

The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),

At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.

Safety

Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.

Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).

There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.

The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.

The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.

“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.

“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”