Transplantation

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Cord blood donation

Photo courtesy of NHS

VALENCIA, SPAIN—The expanded umbilical cord blood (UCB) product NiCord can provide clinical benefits in patients with high-risk hematologic malignancies, according to data presented at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation.

NiCord consists of cells from a single UCB unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The data showed that patients transplanted with NiCord had fewer moderate to severe bacterial infections and shorter hospital stays than patients who received standard UCB transplants.

“We saw a significant reduction in serious bacterial infections during the first 100 days in the NiCord group,” said Mitchell Horwitz, MD, of the Duke University School of Medicine in Durham, North Carolina.

“This is encouraging because this type of infection is a major cause of early death following UCB transplantation. We also saw a significant reduction in hospitalization time in the NiCord group, indicating a faster recovery of these patients in comparison to those transplanted with standard umbilical cord blood.”

These results were presented at the meeting as abstract O090. The research was funded by Gamida Cell, the company developing NiCord.

Dr Horwitz and his colleagues analyzed 18 patients with high-risk hematologic malignancies—most with acute leukemia or myelodysplastic syndromes (90%)—who were transplanted with NiCord.

Ten of the patients received NiCord with a second, unmanipulated UCB unit, and 8 patients received NiCord as a single UCB graft.

The researchers compared these patients to 101 patients who received standard single or double UCB transplants at Duke University from January 2005 to March 2015.

Patients in both groups received a total body irradiation-based myeloablative preparative regimen.

The median time to neutrophil engraftment was significantly shorter in the NiCord group than the control group—12.5 days and 27 days, respectively (P<0.001).

All 18 patients in the Nicord group and 100 patients in the control group had at least 1 infection.

Patients in the NiCord group had a significantly lower incidence of grade 2-3 bacterial infections than patients in the control group—22% and 54%, respectively (P=0.015).

However, there was no significant difference between the groups with regard to grade 2-3 viral infections (39% and 35%, respectively, P=0.729), fungal infections (0% and 5%, respectively, P=1.0), or non-microbiologically defined infections (0% and 17%, respectively, P=0.072).

In the first 100 days after transplant, patients in the NiCord group spent significantly more days out of the hospital than patients in the control group. The median number of days for each group was 74 and 53, respectively (P=0.002).

“These results demonstrate that the rapid hematopoietic recovery from NiCord transplantation results in clinical benefit, in comparison to similar site controls,” Dr Horwitz concluded.

Cord blood donation

Photo courtesy of NHS

VALENCIA, SPAIN—The expanded umbilical cord blood (UCB) product NiCord can provide clinical benefits in patients with high-risk hematologic malignancies, according to data presented at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation.

NiCord consists of cells from a single UCB unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The data showed that patients transplanted with NiCord had fewer moderate to severe bacterial infections and shorter hospital stays than patients who received standard UCB transplants.

“We saw a significant reduction in serious bacterial infections during the first 100 days in the NiCord group,” said Mitchell Horwitz, MD, of the Duke University School of Medicine in Durham, North Carolina.

“This is encouraging because this type of infection is a major cause of early death following UCB transplantation. We also saw a significant reduction in hospitalization time in the NiCord group, indicating a faster recovery of these patients in comparison to those transplanted with standard umbilical cord blood.”

These results were presented at the meeting as abstract O090. The research was funded by Gamida Cell, the company developing NiCord.

Dr Horwitz and his colleagues analyzed 18 patients with high-risk hematologic malignancies—most with acute leukemia or myelodysplastic syndromes (90%)—who were transplanted with NiCord.

Ten of the patients received NiCord with a second, unmanipulated UCB unit, and 8 patients received NiCord as a single UCB graft.

The researchers compared these patients to 101 patients who received standard single or double UCB transplants at Duke University from January 2005 to March 2015.

Patients in both groups received a total body irradiation-based myeloablative preparative regimen.

The median time to neutrophil engraftment was significantly shorter in the NiCord group than the control group—12.5 days and 27 days, respectively (P<0.001).

All 18 patients in the Nicord group and 100 patients in the control group had at least 1 infection.

Patients in the NiCord group had a significantly lower incidence of grade 2-3 bacterial infections than patients in the control group—22% and 54%, respectively (P=0.015).

However, there was no significant difference between the groups with regard to grade 2-3 viral infections (39% and 35%, respectively, P=0.729), fungal infections (0% and 5%, respectively, P=1.0), or non-microbiologically defined infections (0% and 17%, respectively, P=0.072).

In the first 100 days after transplant, patients in the NiCord group spent significantly more days out of the hospital than patients in the control group. The median number of days for each group was 74 and 53, respectively (P=0.002).

“These results demonstrate that the rapid hematopoietic recovery from NiCord transplantation results in clinical benefit, in comparison to similar site controls,” Dr Horwitz concluded.

Cord blood donation

Photo courtesy of NHS

VALENCIA, SPAIN—The expanded umbilical cord blood (UCB) product NiCord can provide clinical benefits in patients with high-risk hematologic malignancies, according to data presented at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation.

NiCord consists of cells from a single UCB unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The data showed that patients transplanted with NiCord had fewer moderate to severe bacterial infections and shorter hospital stays than patients who received standard UCB transplants.

“We saw a significant reduction in serious bacterial infections during the first 100 days in the NiCord group,” said Mitchell Horwitz, MD, of the Duke University School of Medicine in Durham, North Carolina.

“This is encouraging because this type of infection is a major cause of early death following UCB transplantation. We also saw a significant reduction in hospitalization time in the NiCord group, indicating a faster recovery of these patients in comparison to those transplanted with standard umbilical cord blood.”

These results were presented at the meeting as abstract O090. The research was funded by Gamida Cell, the company developing NiCord.

Dr Horwitz and his colleagues analyzed 18 patients with high-risk hematologic malignancies—most with acute leukemia or myelodysplastic syndromes (90%)—who were transplanted with NiCord.

Ten of the patients received NiCord with a second, unmanipulated UCB unit, and 8 patients received NiCord as a single UCB graft.

The researchers compared these patients to 101 patients who received standard single or double UCB transplants at Duke University from January 2005 to March 2015.

Patients in both groups received a total body irradiation-based myeloablative preparative regimen.

The median time to neutrophil engraftment was significantly shorter in the NiCord group than the control group—12.5 days and 27 days, respectively (P<0.001).

All 18 patients in the Nicord group and 100 patients in the control group had at least 1 infection.

Patients in the NiCord group had a significantly lower incidence of grade 2-3 bacterial infections than patients in the control group—22% and 54%, respectively (P=0.015).

However, there was no significant difference between the groups with regard to grade 2-3 viral infections (39% and 35%, respectively, P=0.729), fungal infections (0% and 5%, respectively, P=1.0), or non-microbiologically defined infections (0% and 17%, respectively, P=0.072).

In the first 100 days after transplant, patients in the NiCord group spent significantly more days out of the hospital than patients in the control group. The median number of days for each group was 74 and 53, respectively (P=0.002).

“These results demonstrate that the rapid hematopoietic recovery from NiCord transplantation results in clinical benefit, in comparison to similar site controls,” Dr Horwitz concluded.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

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

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) 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 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on 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 a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) 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 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on 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 a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) 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 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on 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 a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Acute myeloid leukemia

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan designation for the radioimmunoconjugate Iomab-B to be used as a conditioning agent for patients with relapsed or refractory acute myeloid leukemia (AML) who are undergoing hematopoietic stem cell transplant (HSCT).

Iomab-B is a radioimmunoconjugate consisting of BC8, a novel murine monoclonal antibody, and the radioisotope iodine-131.

BC8 targets CD45, a pan-leukocytic antigen widely expressed on white blood cells. This makes BC8 potentially useful in targeting white blood cells in preparation for HSCT.

When labeled with radioactive isotopes, BC8 carries radioactivity directly to the site of cancerous growth and bone marrow, while avoiding the effects of radiation on most healthy tissues, according to Actinium Pharmaceuticals, Inc., the company developing Iomab-B.

Actinium said Iomab-B has been tested as a myeloconditioning/myeloablative agent in more than 250 patients with incurable hematologic malignancies.

The company has released data from a phase 1/2 trial of Iomab-B in patients with relapsed/refractory AML who are older than 50.

The data show that patients who received Iomab-B before HSCT (n=27) had higher rates of survival at 1 and 2 years than patients who underwent HSCT with conventional myeloablative conditioning (n=10) or chemotherapy (n=61).

One-year survival rates were 30% in the Iomab-B arm and 10% each in the conventional conditioning and chemotherapy arms. Two-year survival rates were 19%, 0%, and 0%, respectively.

Now, Actinium is planning a phase 3 trial of Iomab-B in relapsed/refractory AML patients over the age of 55.

About orphan designation

The FDA grants orphan designation to drugs intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has approved the use of defibrotide sodium (Defitelio).

The product can now be used to treat adult and pediatric patients who develop hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction after receiving a hematopoietic stem cell transplant (HSCT).

Defibrotide sodium is the first FDA-approved therapy for patients with this rare, potentially fatal complication.

Defibrotide sodium is a product of Jazz Pharmaceuticals, Inc. The company said shipments of the drug to distribution channels will begin within a week.

The recommended dose and schedule for defibrotide sodium is 6.25 mg/kg every 6 hours, given as a 2-hour intravenous infusion, for at least 21 days, and continued until VOD resolution or up to 60 days of treatment.

In vitro defibrotide sodium has profibrinolytic activity. The use of defibrotide sodium is contraindicated in patients receiving concurrent anticoagulants or fibrinolytic therapies. Hemorrhage and hypersensitivity reactions are the major potential adverse reactions.

The FDA previously granted the defibrotide sodium application priority review status, and the drug received orphan drug designation from the FDA for the treatment of hepatic VOD.

Full prescribing information for defibrotide sodium can be found on the FDA website.

Trial results

The FDA’s approval of defibrotide sodium is supported by data in 528 patients treated on 3 studies: a phase 2 trial, a phase 3 trial, and an expanded access study. Data from the expanded access study were presented at the 2015 BMT Tandem Meetings, and data from the phase 3 trial were published in Blood earlier this year.

The 528 patients all had hepatic VOD with multi-organ dysfunction after HSCT. They received defibrotide sodium at 6.25 mg/kg intravenously every 6 hours until resolution of VOD.

The approval was based on survival at day +100 after HSCT. The day +100 survival rates for Study 1 (phase 3, n=102), Study 2 (phase 2, n=75), and Study 3 (expanded access, n=351) were 38%, 44%, and 45%, respectively.

Based on published reports and analyses of patient-level data, the day +100 survival rates were 21% to 31% for patients with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.

The safety of defibrotide sodium to support approval is based on data from 176 patients in the clinical development program for the treatment of VOD with renal and/or pulmonary dysfunction following HSCT.

The most common adverse events (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse events (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%).

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has approved the use of defibrotide sodium (Defitelio).

The product can now be used to treat adult and pediatric patients who develop hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction after receiving a hematopoietic stem cell transplant (HSCT).

Defibrotide sodium is the first FDA-approved therapy for patients with this rare, potentially fatal complication.

Defibrotide sodium is a product of Jazz Pharmaceuticals, Inc. The company said shipments of the drug to distribution channels will begin within a week.

The recommended dose and schedule for defibrotide sodium is 6.25 mg/kg every 6 hours, given as a 2-hour intravenous infusion, for at least 21 days, and continued until VOD resolution or up to 60 days of treatment.

In vitro defibrotide sodium has profibrinolytic activity. The use of defibrotide sodium is contraindicated in patients receiving concurrent anticoagulants or fibrinolytic therapies. Hemorrhage and hypersensitivity reactions are the major potential adverse reactions.

The FDA previously granted the defibrotide sodium application priority review status, and the drug received orphan drug designation from the FDA for the treatment of hepatic VOD.

Full prescribing information for defibrotide sodium can be found on the FDA website.

Trial results

The FDA’s approval of defibrotide sodium is supported by data in 528 patients treated on 3 studies: a phase 2 trial, a phase 3 trial, and an expanded access study. Data from the expanded access study were presented at the 2015 BMT Tandem Meetings, and data from the phase 3 trial were published in Blood earlier this year.

The 528 patients all had hepatic VOD with multi-organ dysfunction after HSCT. They received defibrotide sodium at 6.25 mg/kg intravenously every 6 hours until resolution of VOD.

The approval was based on survival at day +100 after HSCT. The day +100 survival rates for Study 1 (phase 3, n=102), Study 2 (phase 2, n=75), and Study 3 (expanded access, n=351) were 38%, 44%, and 45%, respectively.

Based on published reports and analyses of patient-level data, the day +100 survival rates were 21% to 31% for patients with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.

The safety of defibrotide sodium to support approval is based on data from 176 patients in the clinical development program for the treatment of VOD with renal and/or pulmonary dysfunction following HSCT.

The most common adverse events (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse events (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%).

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has approved the use of defibrotide sodium (Defitelio).

The product can now be used to treat adult and pediatric patients who develop hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction after receiving a hematopoietic stem cell transplant (HSCT).

Defibrotide sodium is the first FDA-approved therapy for patients with this rare, potentially fatal complication.

Defibrotide sodium is a product of Jazz Pharmaceuticals, Inc. The company said shipments of the drug to distribution channels will begin within a week.

The recommended dose and schedule for defibrotide sodium is 6.25 mg/kg every 6 hours, given as a 2-hour intravenous infusion, for at least 21 days, and continued until VOD resolution or up to 60 days of treatment.

In vitro defibrotide sodium has profibrinolytic activity. The use of defibrotide sodium is contraindicated in patients receiving concurrent anticoagulants or fibrinolytic therapies. Hemorrhage and hypersensitivity reactions are the major potential adverse reactions.

The FDA previously granted the defibrotide sodium application priority review status, and the drug received orphan drug designation from the FDA for the treatment of hepatic VOD.

Full prescribing information for defibrotide sodium can be found on the FDA website.

Trial results

The FDA’s approval of defibrotide sodium is supported by data in 528 patients treated on 3 studies: a phase 2 trial, a phase 3 trial, and an expanded access study. Data from the expanded access study were presented at the 2015 BMT Tandem Meetings, and data from the phase 3 trial were published in Blood earlier this year.

The 528 patients all had hepatic VOD with multi-organ dysfunction after HSCT. They received defibrotide sodium at 6.25 mg/kg intravenously every 6 hours until resolution of VOD.

The approval was based on survival at day +100 after HSCT. The day +100 survival rates for Study 1 (phase 3, n=102), Study 2 (phase 2, n=75), and Study 3 (expanded access, n=351) were 38%, 44%, and 45%, respectively.

Based on published reports and analyses of patient-level data, the day +100 survival rates were 21% to 31% for patients with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.

The safety of defibrotide sodium to support approval is based on data from 176 patients in the clinical development program for the treatment of VOD with renal and/or pulmonary dysfunction following HSCT.

The most common adverse events (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse events (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%).

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

Lab mouse

Preclinical data suggest that blocking the Rho-associated coiled-coil kinase 2 (ROCK2) signaling pathway with the ROCK2 inhibitor KD025 can ameliorate chronic graft-versus-host disease (cGVHD).

Previous studies have shown that IL-21 and IL-17, 2 pro-inflammatory cytokines regulated by the ROCK2 signaling pathway, play a key role in cGVHD pathogenesis.

In the new study, targeted ROCK2 inhibition with KD025 had a therapeutic effect on cGVHD cytokines and signaling pathways involved in the pathogenesis of cGVHD.

Bruce R. Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these findings in Blood.

The research was supported by Kadmon Corporation, LLC, the company developing KD025, as well as other sources.

The researchers found that KD025 reversed the clinical and immunological symptoms of cGVHD in 2 murine models: a full major histocompatibility complex (MHC)-mismatch model of multi-organ system cGVHD with bronchiolitis obliterans syndrome and a minor MHC-mismatch model of sclerodermatous GVHD.

Mice treated with KD025 showed improvements in pulmonary function and had a significant decrease in cGVHD pathology in the lung, liver, and spleen, when compared to vehicle-treated animals.

In addition, KD025 treatment did not affect the graft-versus-leukemia effect or immune response to viral pathogens.

In both animal models, KD025 treatment downregulated phosphorylation of STAT3, a pro-inflammatory signaling pathway that plays a key role in the development of cGVHD.

In human cells, KD025 inhibited the production of IL-21, IL-17, and IFN-γ. The drug also decreased STAT3 activity.

In both murine and human cells, KD025 downregulated STAT3 phosphorylation and simultaneously upregulated STAT5 phosphorylation, thereby reducing cGVHD progression.

“These data demonstrate that ROCK2 inhibition decreases cGVHD manifestation in murine and human models, which correlates with a demonstrated effect on molecular signaling pathways responsible for cGVHD pathogenesis,” Dr Blazar said.

Based on these results, Kadmon is planning to initiate a phase 2 study of KD025 for the treatment of cGVHD in mid-2016. The drug has already been tested in phase 1 studies of healthy volunteers.

Lab mouse

Preclinical data suggest that blocking the Rho-associated coiled-coil kinase 2 (ROCK2) signaling pathway with the ROCK2 inhibitor KD025 can ameliorate chronic graft-versus-host disease (cGVHD).

Previous studies have shown that IL-21 and IL-17, 2 pro-inflammatory cytokines regulated by the ROCK2 signaling pathway, play a key role in cGVHD pathogenesis.

In the new study, targeted ROCK2 inhibition with KD025 had a therapeutic effect on cGVHD cytokines and signaling pathways involved in the pathogenesis of cGVHD.

Bruce R. Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these findings in Blood.

The research was supported by Kadmon Corporation, LLC, the company developing KD025, as well as other sources.

The researchers found that KD025 reversed the clinical and immunological symptoms of cGVHD in 2 murine models: a full major histocompatibility complex (MHC)-mismatch model of multi-organ system cGVHD with bronchiolitis obliterans syndrome and a minor MHC-mismatch model of sclerodermatous GVHD.

Mice treated with KD025 showed improvements in pulmonary function and had a significant decrease in cGVHD pathology in the lung, liver, and spleen, when compared to vehicle-treated animals.

In addition, KD025 treatment did not affect the graft-versus-leukemia effect or immune response to viral pathogens.

In both animal models, KD025 treatment downregulated phosphorylation of STAT3, a pro-inflammatory signaling pathway that plays a key role in the development of cGVHD.

In human cells, KD025 inhibited the production of IL-21, IL-17, and IFN-γ. The drug also decreased STAT3 activity.

In both murine and human cells, KD025 downregulated STAT3 phosphorylation and simultaneously upregulated STAT5 phosphorylation, thereby reducing cGVHD progression.

“These data demonstrate that ROCK2 inhibition decreases cGVHD manifestation in murine and human models, which correlates with a demonstrated effect on molecular signaling pathways responsible for cGVHD pathogenesis,” Dr Blazar said.

Based on these results, Kadmon is planning to initiate a phase 2 study of KD025 for the treatment of cGVHD in mid-2016. The drug has already been tested in phase 1 studies of healthy volunteers.

Lab mouse

Preclinical data suggest that blocking the Rho-associated coiled-coil kinase 2 (ROCK2) signaling pathway with the ROCK2 inhibitor KD025 can ameliorate chronic graft-versus-host disease (cGVHD).

Previous studies have shown that IL-21 and IL-17, 2 pro-inflammatory cytokines regulated by the ROCK2 signaling pathway, play a key role in cGVHD pathogenesis.

In the new study, targeted ROCK2 inhibition with KD025 had a therapeutic effect on cGVHD cytokines and signaling pathways involved in the pathogenesis of cGVHD.

Bruce R. Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these findings in Blood.

The research was supported by Kadmon Corporation, LLC, the company developing KD025, as well as other sources.

The researchers found that KD025 reversed the clinical and immunological symptoms of cGVHD in 2 murine models: a full major histocompatibility complex (MHC)-mismatch model of multi-organ system cGVHD with bronchiolitis obliterans syndrome and a minor MHC-mismatch model of sclerodermatous GVHD.

Mice treated with KD025 showed improvements in pulmonary function and had a significant decrease in cGVHD pathology in the lung, liver, and spleen, when compared to vehicle-treated animals.

In addition, KD025 treatment did not affect the graft-versus-leukemia effect or immune response to viral pathogens.

In both animal models, KD025 treatment downregulated phosphorylation of STAT3, a pro-inflammatory signaling pathway that plays a key role in the development of cGVHD.

In human cells, KD025 inhibited the production of IL-21, IL-17, and IFN-γ. The drug also decreased STAT3 activity.

In both murine and human cells, KD025 downregulated STAT3 phosphorylation and simultaneously upregulated STAT5 phosphorylation, thereby reducing cGVHD progression.

“These data demonstrate that ROCK2 inhibition decreases cGVHD manifestation in murine and human models, which correlates with a demonstrated effect on molecular signaling pathways responsible for cGVHD pathogenesis,” Dr Blazar said.

Based on these results, Kadmon is planning to initiate a phase 2 study of KD025 for the treatment of cGVHD in mid-2016. The drug has already been tested in phase 1 studies of healthy volunteers.