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Expanded UCB product can stand alone
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
SALT LAKE CITY—The expanded umbilical cord blood (UCB) product NiCord can be used as a stand-alone graft, according to research presented at the 2018 BMT Tandem Meetings.
Researchers found that a single NiCord unit provided “robust” engraftment in a phase 1/2 study of patients with high-risk hematologic malignancies.
NiCord recipients had quicker neutrophil and platelet engraftment than matched control subjects who received standard myeloablative UCB transplant (single or double).
Mitchell Horwitz, MD, of the Duke University Medical Center in Durham, North Carolina, presented these results at the meeting as abstract 49.* The research was sponsored by Gamida Cell, the company developing NiCord.
“[NiCord] is an ex vivo expanded cell product that’s derived from an entire unit of umbilical cord blood,” Dr Horwitz explained. “It’s manufactured starting with a CD133-positive selection, which is the progenitor cell population that’s cultured, and a T-cell containing CD133-negative fraction that is provided also at the time of transplant.”
“The culture system contains nicotinamide—that’s the active ingredient in the culture. And that’s supplemented with cytokines—thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor. The culture is 21 days.”
Previous research showed that double UCB transplant including a NiCord unit could provide benefits over standard double UCB transplant. This led Dr Horwitz and his colleagues to wonder if NiCord could be used as a stand-alone graft.
So the team evaluated the safety and efficacy of NiCord alone in 36 adolescents/adults with high-risk hematologic malignancies.
Patients had acute myelogenous leukemia (n=17), acute lymphoblastic leukemia (n=9), myelodysplastic syndrome (n=7), chronic myelogenous leukemia (n=2), and Hodgkin lymphoma (n=1).
Most patients had intermediate (n=15) or high-risk (n=13) disease. They had a median age of 44 (range, 13-63) and a median weight of 75 kg (range, 41-125).
Treatment
For conditioning, 19 patients received thiotepa, busulfan, and fludarabine. Fifteen patients received total body irradiation and fludarabine with or without cyclophosphamide or thiotepa. And 2 patients received clofarabine, fludarabine, and busulfan.
Most patients had a 4/6 human leukocyte antigen (HLA) match (n=26), 8 had a 5/6 HLA match, and 2 had a 6/6 HLA match.
The median total nucleated cell dose was 2.4 x 107/kg prior to expansion of the UCB unit and 3.7 x 107/kg after expansion. The median CD34+ cell dose was 0.2 x 106/kg and 6.3 x 106/kg, respectively.
“CD34 cells were expanded 33-fold in the 3-week culture system,” Dr Horwitz noted. “That translated to a median CD34 dose of 6.3 x 106/kg, a dose comparable to what would be obtained from an adult donor graft.”
Engraftment
There was 1 case of primary graft failure and 2 cases of secondary graft failure. One case of secondary graft failure was associated with an HHV-6 infection, and the other was due to a lethal adenovirus infection.
Of those patients who engrafted, 97% achieved full donor chimerism, and 3% had mixed chimerism.
Dr Horwitz and his colleagues compared engraftment results in the NiCord recipients to results in a cohort of patients from the CIBMTR registry who underwent UCB transplants from 2010 to 2013. They had similar characteristics as the NiCord patients—age, conditioning regimen, disease status, etc.
In total, there were 148 CIBMTR registry patients, 20% of whom received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the CIBMTR matched control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the CIBMTR controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
“There’s a median 10-day reduction in neutrophil recovery [and] 12-day reduction in time to platelet recovery [with NiCord],” Dr Horwitz noted. “There is evidence of robust and durable engraftment with a NiCord unit, with one patient now over 7 years from his first transplant on the pilot trial.”
Relapse, survival, and GVHD
Dr Horwitz reported other outcomes in the NiCord recipients without making comparisons to the CIBMTR matched controls.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the estimated 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The estimated overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute GVHD was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%.
The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the estimated 2-year rate of moderate to severe chronic GVHD was 9.8%.
Dr Horwitz said these “promising results” have led to the launch of a phase 3 registration trial in which researchers are comparing NiCord to standard single or double UCB transplant. The trial is open for accrual.
*Information in the abstract differs from the presentation.
Minihaplo-BMT can cure severe hemoglobinopathies
SALT LAKE CITY—Cure of severe hemoglobinopathies is now possible for most patients, according to a speaker at the 2018 BMT Tandem Meetings.
Results of a small study suggest that nonmyeloablative haploidentical bone marrow transplant (minihaplo-BMT), when used with 400 cGy total body irradiation and post-transplant cyclophosphamide, can cure sickle cell disease (SCD) and beta-thalassemia while conferring limited toxicity.
“This is our second study showing that you can certainly get rid of these conditions using haploidentical donors and, also, that you can cure these conditions with a nonmyeloablative regimen,” said Javier Bolaños-Meade, MD, of Johns Hopkins University in Baltimore, Maryland.
“What we saw [in the current study] is that increasing the total body irradiation from 200 cGy to 400 cGy can overcome the very high rate of graft failure we observed in our prior study.”
However, the results also suggest that major ABO incompatible donors should be avoided.
Dr Bolaños-Meade presented these findings as a late-breaking abstract (LBA3) at this year’s BMT Tandem Meetings.
He began the presentation by pointing out that allogeneic BMT is the only potential cure for SCD and beta-thalassemia. Unfortunately, most of these patients have been excluded from transplant due to a lack of matched donors, concerns over graft-vs-host disease (GVHD), and/or compromised end organ function precluding them from myeloablative conditioning.
With a prior study, Dr Bolaños-Meade and his colleagues found that minihaplo-BMT with post-transplant cyclophosphamide expanded the donor pool and was well tolerated in patients with SCD. However, the rate of secondary graft failure was high, at 43%.
“We hypothesized that increasing the amount of radiation that was given to these patients, making the regimen absolutely more intensive, will help us to overcome this rate of graft failure and retain the tolerability of the regimen,” Dr Bolaños-Meade said.
He and his colleagues tested this theory in 12 patients with SCD and 5 with beta-thalassemia.
The SCD patients had a median age of 26 (range, 6-31), and most (n=8) were female. Ten were African-American, and 2 were of Arab descent.
All SCD patients had at least 2 hospital admissions in the last 2 years, 5 had osteonecrosis, 3 were transfusion-dependent, 2 had a history of acute chest syndrome, and 1 patient had changes in brain magnetic resonance imaging.
The thalassemia patients had a median age of 7 (range, 6-16). Four were female, and all 5 were of Arab descent. All patients were transfusion-dependent from infancy.
Treatment
All patients received antithymocyte globulin (rabbit) at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, fludarabine at 30 mg/m2 on days -6 to -2, cyclophosphamide at 14.5 mg/kg on days -6 and -5, and total body irradiation at 400 cGy on day -1.
Patients received unmanipulated bone marrow that was collected and infused on day 0. Donors included 1 aunt, 4 brothers, 3 sisters, 5 mothers, and 4 fathers. There were 2 major ABO incompatible pairs, 5 minor ABO incompatible pairs, and 10 ABO compatible pairs.
For GVHD prophylaxis, patients received 50 mg/kg/day of cyclophosphamide on days 3 and 4, sirolimus (levels of 5-10 ng/dl) from days 5 to 365, and mycophenolate mofetil at 1 g every 8 hours from days 5 to 35.
Efficacy
All 17 patients are still alive at a median follow-up of 15 months (range, 3-34).
“Of all the patients transplanted, we only observed 1 graft failure,” Dr Bolaños-Meade said. “This is in sharp contrast to the 40% graft failure in our prior study.”
Thirteen patients achieved full donor chimerism, and 3 had mixed chimerism.
Four of the 5 beta-thalassemia patients achieved full donor chimerism, and 1 had mixed chimerism. All 5 patients became transfusion-independent.
Eleven of the 12 SCD patients engrafted, and 9 achieved full donor chimerism.
All but one of the engrafted SCD patients became transfusion-independent. The exception was a mixed chimeric patient who had a major ABO mismatched donor. The patient remains transfusion-dependent more than 30 months after BMT.
“This is the main problem we have seen in all our sickle cell and hemoglobinopathy experiences,” Dr Bolaños-Meade said. “If you have a major ABO incompatibility, and there’s mixed chimerism, you’re asking for trouble.”
Toxicity
All SCD patients had sickle cell crises after antithymocyte globulin. Other toxicities included sirolimus-induced diabetes in 1 patient, worsening of Meniere’s disease in 1 patient, and BK cystitis in 1 patient.
Two patients developed grade 2 acute GVHD, and 1 developed grade 3 acute GVHD. Three patients had chronic GVHD, 2 mild and 1 moderate.
However, all cases of GVHD resolved. And, of the 8 engrafted patients with more than 1 year of follow-up, 6 are off systemic immunosuppression.
SALT LAKE CITY—Cure of severe hemoglobinopathies is now possible for most patients, according to a speaker at the 2018 BMT Tandem Meetings.
Results of a small study suggest that nonmyeloablative haploidentical bone marrow transplant (minihaplo-BMT), when used with 400 cGy total body irradiation and post-transplant cyclophosphamide, can cure sickle cell disease (SCD) and beta-thalassemia while conferring limited toxicity.
“This is our second study showing that you can certainly get rid of these conditions using haploidentical donors and, also, that you can cure these conditions with a nonmyeloablative regimen,” said Javier Bolaños-Meade, MD, of Johns Hopkins University in Baltimore, Maryland.
“What we saw [in the current study] is that increasing the total body irradiation from 200 cGy to 400 cGy can overcome the very high rate of graft failure we observed in our prior study.”
However, the results also suggest that major ABO incompatible donors should be avoided.
Dr Bolaños-Meade presented these findings as a late-breaking abstract (LBA3) at this year’s BMT Tandem Meetings.
He began the presentation by pointing out that allogeneic BMT is the only potential cure for SCD and beta-thalassemia. Unfortunately, most of these patients have been excluded from transplant due to a lack of matched donors, concerns over graft-vs-host disease (GVHD), and/or compromised end organ function precluding them from myeloablative conditioning.
With a prior study, Dr Bolaños-Meade and his colleagues found that minihaplo-BMT with post-transplant cyclophosphamide expanded the donor pool and was well tolerated in patients with SCD. However, the rate of secondary graft failure was high, at 43%.
“We hypothesized that increasing the amount of radiation that was given to these patients, making the regimen absolutely more intensive, will help us to overcome this rate of graft failure and retain the tolerability of the regimen,” Dr Bolaños-Meade said.
He and his colleagues tested this theory in 12 patients with SCD and 5 with beta-thalassemia.
The SCD patients had a median age of 26 (range, 6-31), and most (n=8) were female. Ten were African-American, and 2 were of Arab descent.
All SCD patients had at least 2 hospital admissions in the last 2 years, 5 had osteonecrosis, 3 were transfusion-dependent, 2 had a history of acute chest syndrome, and 1 patient had changes in brain magnetic resonance imaging.
The thalassemia patients had a median age of 7 (range, 6-16). Four were female, and all 5 were of Arab descent. All patients were transfusion-dependent from infancy.
Treatment
All patients received antithymocyte globulin (rabbit) at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, fludarabine at 30 mg/m2 on days -6 to -2, cyclophosphamide at 14.5 mg/kg on days -6 and -5, and total body irradiation at 400 cGy on day -1.
Patients received unmanipulated bone marrow that was collected and infused on day 0. Donors included 1 aunt, 4 brothers, 3 sisters, 5 mothers, and 4 fathers. There were 2 major ABO incompatible pairs, 5 minor ABO incompatible pairs, and 10 ABO compatible pairs.
For GVHD prophylaxis, patients received 50 mg/kg/day of cyclophosphamide on days 3 and 4, sirolimus (levels of 5-10 ng/dl) from days 5 to 365, and mycophenolate mofetil at 1 g every 8 hours from days 5 to 35.
Efficacy
All 17 patients are still alive at a median follow-up of 15 months (range, 3-34).
“Of all the patients transplanted, we only observed 1 graft failure,” Dr Bolaños-Meade said. “This is in sharp contrast to the 40% graft failure in our prior study.”
Thirteen patients achieved full donor chimerism, and 3 had mixed chimerism.
Four of the 5 beta-thalassemia patients achieved full donor chimerism, and 1 had mixed chimerism. All 5 patients became transfusion-independent.
Eleven of the 12 SCD patients engrafted, and 9 achieved full donor chimerism.
All but one of the engrafted SCD patients became transfusion-independent. The exception was a mixed chimeric patient who had a major ABO mismatched donor. The patient remains transfusion-dependent more than 30 months after BMT.
“This is the main problem we have seen in all our sickle cell and hemoglobinopathy experiences,” Dr Bolaños-Meade said. “If you have a major ABO incompatibility, and there’s mixed chimerism, you’re asking for trouble.”
Toxicity
All SCD patients had sickle cell crises after antithymocyte globulin. Other toxicities included sirolimus-induced diabetes in 1 patient, worsening of Meniere’s disease in 1 patient, and BK cystitis in 1 patient.
Two patients developed grade 2 acute GVHD, and 1 developed grade 3 acute GVHD. Three patients had chronic GVHD, 2 mild and 1 moderate.
However, all cases of GVHD resolved. And, of the 8 engrafted patients with more than 1 year of follow-up, 6 are off systemic immunosuppression.
SALT LAKE CITY—Cure of severe hemoglobinopathies is now possible for most patients, according to a speaker at the 2018 BMT Tandem Meetings.
Results of a small study suggest that nonmyeloablative haploidentical bone marrow transplant (minihaplo-BMT), when used with 400 cGy total body irradiation and post-transplant cyclophosphamide, can cure sickle cell disease (SCD) and beta-thalassemia while conferring limited toxicity.
“This is our second study showing that you can certainly get rid of these conditions using haploidentical donors and, also, that you can cure these conditions with a nonmyeloablative regimen,” said Javier Bolaños-Meade, MD, of Johns Hopkins University in Baltimore, Maryland.
“What we saw [in the current study] is that increasing the total body irradiation from 200 cGy to 400 cGy can overcome the very high rate of graft failure we observed in our prior study.”
However, the results also suggest that major ABO incompatible donors should be avoided.
Dr Bolaños-Meade presented these findings as a late-breaking abstract (LBA3) at this year’s BMT Tandem Meetings.
He began the presentation by pointing out that allogeneic BMT is the only potential cure for SCD and beta-thalassemia. Unfortunately, most of these patients have been excluded from transplant due to a lack of matched donors, concerns over graft-vs-host disease (GVHD), and/or compromised end organ function precluding them from myeloablative conditioning.
With a prior study, Dr Bolaños-Meade and his colleagues found that minihaplo-BMT with post-transplant cyclophosphamide expanded the donor pool and was well tolerated in patients with SCD. However, the rate of secondary graft failure was high, at 43%.
“We hypothesized that increasing the amount of radiation that was given to these patients, making the regimen absolutely more intensive, will help us to overcome this rate of graft failure and retain the tolerability of the regimen,” Dr Bolaños-Meade said.
He and his colleagues tested this theory in 12 patients with SCD and 5 with beta-thalassemia.
The SCD patients had a median age of 26 (range, 6-31), and most (n=8) were female. Ten were African-American, and 2 were of Arab descent.
All SCD patients had at least 2 hospital admissions in the last 2 years, 5 had osteonecrosis, 3 were transfusion-dependent, 2 had a history of acute chest syndrome, and 1 patient had changes in brain magnetic resonance imaging.
The thalassemia patients had a median age of 7 (range, 6-16). Four were female, and all 5 were of Arab descent. All patients were transfusion-dependent from infancy.
Treatment
All patients received antithymocyte globulin (rabbit) at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, fludarabine at 30 mg/m2 on days -6 to -2, cyclophosphamide at 14.5 mg/kg on days -6 and -5, and total body irradiation at 400 cGy on day -1.
Patients received unmanipulated bone marrow that was collected and infused on day 0. Donors included 1 aunt, 4 brothers, 3 sisters, 5 mothers, and 4 fathers. There were 2 major ABO incompatible pairs, 5 minor ABO incompatible pairs, and 10 ABO compatible pairs.
For GVHD prophylaxis, patients received 50 mg/kg/day of cyclophosphamide on days 3 and 4, sirolimus (levels of 5-10 ng/dl) from days 5 to 365, and mycophenolate mofetil at 1 g every 8 hours from days 5 to 35.
Efficacy
All 17 patients are still alive at a median follow-up of 15 months (range, 3-34).
“Of all the patients transplanted, we only observed 1 graft failure,” Dr Bolaños-Meade said. “This is in sharp contrast to the 40% graft failure in our prior study.”
Thirteen patients achieved full donor chimerism, and 3 had mixed chimerism.
Four of the 5 beta-thalassemia patients achieved full donor chimerism, and 1 had mixed chimerism. All 5 patients became transfusion-independent.
Eleven of the 12 SCD patients engrafted, and 9 achieved full donor chimerism.
All but one of the engrafted SCD patients became transfusion-independent. The exception was a mixed chimeric patient who had a major ABO mismatched donor. The patient remains transfusion-dependent more than 30 months after BMT.
“This is the main problem we have seen in all our sickle cell and hemoglobinopathy experiences,” Dr Bolaños-Meade said. “If you have a major ABO incompatibility, and there’s mixed chimerism, you’re asking for trouble.”
Toxicity
All SCD patients had sickle cell crises after antithymocyte globulin. Other toxicities included sirolimus-induced diabetes in 1 patient, worsening of Meniere’s disease in 1 patient, and BK cystitis in 1 patient.
Two patients developed grade 2 acute GVHD, and 1 developed grade 3 acute GVHD. Three patients had chronic GVHD, 2 mild and 1 moderate.
However, all cases of GVHD resolved. And, of the 8 engrafted patients with more than 1 year of follow-up, 6 are off systemic immunosuppression.
High objective response rate, OS seen with ATA129 in PTLD
SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.
The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Study participants included those with or without underlying immune deficiency with Epstein-Barr virus (EBV)–positive PTLD, EBV-positive lymphoma, EBV-positive hemophagocytic lymphohistiocytosis, or EBV viremia, and they had to have measurable disease. All had adequate organ function and performance status. The overall median age of the cohort was 41 years, and among the transplant recipients the median age was 24.5 years. They received a median of 5 weeks of therapy (2.1 months among post-HCT patients and 12.9 months among post-SOT patients), she said.
Patients in the trial underwent the adoptive T cell therapy with partially human leukocyte antigen (HLA)–matched ATA129 that shared at least 2 of 10 HLA alleles at high resolution, including at least 1 through which ATA129 exerted cytotoxicity, or “HLA restriction,” Dr. Prockop said, noting that the product was licensed and obtained breakthrough designation in February 2015.
The ATA129 dose was 1.6-2 million T cells/kg infused on days 1, 8, and 15 of every 35-day cycle. Those without toxicity were eligible to receive additional cycles, and patients with progressive disease after one cycle were allowed to switch to an ATA129 product with a different HLA restriction, she noted.
Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.
“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”
PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.
Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.
SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.
Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.
“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.
The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.
“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.
Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.
SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.
SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.
The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Study participants included those with or without underlying immune deficiency with Epstein-Barr virus (EBV)–positive PTLD, EBV-positive lymphoma, EBV-positive hemophagocytic lymphohistiocytosis, or EBV viremia, and they had to have measurable disease. All had adequate organ function and performance status. The overall median age of the cohort was 41 years, and among the transplant recipients the median age was 24.5 years. They received a median of 5 weeks of therapy (2.1 months among post-HCT patients and 12.9 months among post-SOT patients), she said.
Patients in the trial underwent the adoptive T cell therapy with partially human leukocyte antigen (HLA)–matched ATA129 that shared at least 2 of 10 HLA alleles at high resolution, including at least 1 through which ATA129 exerted cytotoxicity, or “HLA restriction,” Dr. Prockop said, noting that the product was licensed and obtained breakthrough designation in February 2015.
The ATA129 dose was 1.6-2 million T cells/kg infused on days 1, 8, and 15 of every 35-day cycle. Those without toxicity were eligible to receive additional cycles, and patients with progressive disease after one cycle were allowed to switch to an ATA129 product with a different HLA restriction, she noted.
Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.
“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”
PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.
Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.
SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.
Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.
“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.
The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.
“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.
Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.
SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.
SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.
The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Study participants included those with or without underlying immune deficiency with Epstein-Barr virus (EBV)–positive PTLD, EBV-positive lymphoma, EBV-positive hemophagocytic lymphohistiocytosis, or EBV viremia, and they had to have measurable disease. All had adequate organ function and performance status. The overall median age of the cohort was 41 years, and among the transplant recipients the median age was 24.5 years. They received a median of 5 weeks of therapy (2.1 months among post-HCT patients and 12.9 months among post-SOT patients), she said.
Patients in the trial underwent the adoptive T cell therapy with partially human leukocyte antigen (HLA)–matched ATA129 that shared at least 2 of 10 HLA alleles at high resolution, including at least 1 through which ATA129 exerted cytotoxicity, or “HLA restriction,” Dr. Prockop said, noting that the product was licensed and obtained breakthrough designation in February 2015.
The ATA129 dose was 1.6-2 million T cells/kg infused on days 1, 8, and 15 of every 35-day cycle. Those without toxicity were eligible to receive additional cycles, and patients with progressive disease after one cycle were allowed to switch to an ATA129 product with a different HLA restriction, she noted.
Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.
“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”
PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.
Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.
SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.
Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.
“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.
The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.
“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.
Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.
SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Overall 1-year survival was 90.3%.
Study details: Interim results in 23 patients from a multicenter study.
Disclosures: Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.
Source: Prockop S et al. BMT Tandem Meetings Abstract 21.
Regimen deemed ‘safe and feasible’ in MM
SALT LAKE CITY—A novel transplant regimen is “safe and feasible” for patients with multiple myeloma (MM), according to a presentation at the 2018 BMT Tandem Meetings.
Researchers conducted a phase 1 trial investigating the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard autologous hematopoietic stem cell transplant (ASCT) and lenalidomide maintenance in MM patients.
The regimen was considered well tolerated, as most adverse events (AEs) were grade 1 or 2.
The complete response (CR) rate was 40% at both 90 days and 1 year after ASCT.
Keren Osman, MD, of Mount Sinai Health System in New York, New York, reported these results as abstract 26.* This is an investigator-sponsored study, conducted in collaboration with Bristol Myers Squibb, the company marketing elotuzumab.
Dr Osman noted that elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7. The drug directly activates natural killer (NK) cells through the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on MM cells and facilitates interaction with NK cells to mediate the killing of MM cells through antibody-dependent cellular cytotoxicity.
“The hypothesis behind this phase 1 study was that . . ., in the peri-transplant period, if we add elotuzumab, we will succeed in promoting NK-mediated elimination of residual multiple myeloma cells as well as promote transition from innate to adaptive immune responses against multiple myeloma-associated antigens,” Dr Osman said.
She and her colleagues tested this hypothesis in 15 MM patients. They had a median age of 59 (range, 49-70), and 60% of them were male.
Forty percent of patients had stage I disease, 27% had stage II, and 20% had stage III. All patients had an ECOG status of 0 (47%) or 1 (53%).
The patients had a median of 174 days since diagnosis (range, 98-393).
All patients had received 1 to 2 prior lines of therapy. They all had bortezomib as part of their induction therapy, and 67% of them had received lenalidomide.
Seventy-three percent of patients had any cytogenetic abnormality, and 47% had high-risk cytogenetics.
Treatment
Patients underwent leukopheresis for PBMC collection, followed by standard peripheral blood stem cell mobilization and harvest.
They received standard melphalan conditioning on day -1 and autologous stem cell rescue on day 0. Autologous PBMCs were reinfused on day 3 after stem cell infusion.
Elotuzumab was given at 20 mg/kg intravenously on day 4. The drug was given every 28 days up to cycle 12.
Lenalidomide maintenance was given at 10 mg orally on days 1 to 21 of every 28-day cycle, starting with cycle 4 of elotuzumab (90 days post-ASCT). Maintenance could continue beyond cycle 12 at the investigators’ discretion.
Thirteen patients completed a year of treatment. One patient withdrew from the study due to early progression. The other patient withdrew due to personal choice and had a very good partial response (VGPR) at withdrawal.
Safety
“The majority of the adverse events, including infusion reactions attributable to elotuzumab, were grade 2 or lower,” Dr Osman noted. “And there were no AEs related to PBMC administration.”
One patient had a delay in hematopoietic reconstitution, which resulted in hospitalization exceeding 21 days.
One patient had grade 3 hypertension, which was attributed to elotuzumab and resolved with supportive care.
Eight patients had grade 3 lymphopenia, which was associated with elotuzumab, during the maintenance phase. Patients received prophylactic antibiotics, and there were no opportunistic infections.
Efficacy
At screening (after induction but before ASCT), 13 patients (87%) had a VGPR, and 2 (13%) had a partial response (PR).
At 90 days post-ASCT, 2 patients (13%) had a stringent CR, and 4 (27%) had a CR. Six patients (40%) had a VGPR, and 2 (13%) had a PR. One patient (7%) had progressed.
“In this very high-risk PR/VGPR population, stem cell transplant with elotuzumab and PBMC infusion resulted in a CR rate of 40%—with 13% of patients achieving stringent CR—by day 90,” Dr Osman noted. “And maintenance elotuzumab plus lenalidomide promoted further conversion to 33% stringent CR by 1 year.”
At 1 year, 5 patients (33%) had a stringent CR, and 1 (7%) had a CR. Six patients (40%) had a VGPR, and 1 (7%) had a PR. Two patients (13%) had progressed.
So the 1-year progression-free survival rate was 86% (13/15).
“In conclusion, we see that elotuzumab and PBMC administration with standard autologous stem cell transplant and lenalidomide maintenance for consolidation therapy in multiple myeloma is certainly both safe and feasible,” Dr Osman said. “We’re planning a phase 2 study.”
*Information in the abstract differs from the presentation.
SALT LAKE CITY—A novel transplant regimen is “safe and feasible” for patients with multiple myeloma (MM), according to a presentation at the 2018 BMT Tandem Meetings.
Researchers conducted a phase 1 trial investigating the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard autologous hematopoietic stem cell transplant (ASCT) and lenalidomide maintenance in MM patients.
The regimen was considered well tolerated, as most adverse events (AEs) were grade 1 or 2.
The complete response (CR) rate was 40% at both 90 days and 1 year after ASCT.
Keren Osman, MD, of Mount Sinai Health System in New York, New York, reported these results as abstract 26.* This is an investigator-sponsored study, conducted in collaboration with Bristol Myers Squibb, the company marketing elotuzumab.
Dr Osman noted that elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7. The drug directly activates natural killer (NK) cells through the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on MM cells and facilitates interaction with NK cells to mediate the killing of MM cells through antibody-dependent cellular cytotoxicity.
“The hypothesis behind this phase 1 study was that . . ., in the peri-transplant period, if we add elotuzumab, we will succeed in promoting NK-mediated elimination of residual multiple myeloma cells as well as promote transition from innate to adaptive immune responses against multiple myeloma-associated antigens,” Dr Osman said.
She and her colleagues tested this hypothesis in 15 MM patients. They had a median age of 59 (range, 49-70), and 60% of them were male.
Forty percent of patients had stage I disease, 27% had stage II, and 20% had stage III. All patients had an ECOG status of 0 (47%) or 1 (53%).
The patients had a median of 174 days since diagnosis (range, 98-393).
All patients had received 1 to 2 prior lines of therapy. They all had bortezomib as part of their induction therapy, and 67% of them had received lenalidomide.
Seventy-three percent of patients had any cytogenetic abnormality, and 47% had high-risk cytogenetics.
Treatment
Patients underwent leukopheresis for PBMC collection, followed by standard peripheral blood stem cell mobilization and harvest.
They received standard melphalan conditioning on day -1 and autologous stem cell rescue on day 0. Autologous PBMCs were reinfused on day 3 after stem cell infusion.
Elotuzumab was given at 20 mg/kg intravenously on day 4. The drug was given every 28 days up to cycle 12.
Lenalidomide maintenance was given at 10 mg orally on days 1 to 21 of every 28-day cycle, starting with cycle 4 of elotuzumab (90 days post-ASCT). Maintenance could continue beyond cycle 12 at the investigators’ discretion.
Thirteen patients completed a year of treatment. One patient withdrew from the study due to early progression. The other patient withdrew due to personal choice and had a very good partial response (VGPR) at withdrawal.
Safety
“The majority of the adverse events, including infusion reactions attributable to elotuzumab, were grade 2 or lower,” Dr Osman noted. “And there were no AEs related to PBMC administration.”
One patient had a delay in hematopoietic reconstitution, which resulted in hospitalization exceeding 21 days.
One patient had grade 3 hypertension, which was attributed to elotuzumab and resolved with supportive care.
Eight patients had grade 3 lymphopenia, which was associated with elotuzumab, during the maintenance phase. Patients received prophylactic antibiotics, and there were no opportunistic infections.
Efficacy
At screening (after induction but before ASCT), 13 patients (87%) had a VGPR, and 2 (13%) had a partial response (PR).
At 90 days post-ASCT, 2 patients (13%) had a stringent CR, and 4 (27%) had a CR. Six patients (40%) had a VGPR, and 2 (13%) had a PR. One patient (7%) had progressed.
“In this very high-risk PR/VGPR population, stem cell transplant with elotuzumab and PBMC infusion resulted in a CR rate of 40%—with 13% of patients achieving stringent CR—by day 90,” Dr Osman noted. “And maintenance elotuzumab plus lenalidomide promoted further conversion to 33% stringent CR by 1 year.”
At 1 year, 5 patients (33%) had a stringent CR, and 1 (7%) had a CR. Six patients (40%) had a VGPR, and 1 (7%) had a PR. Two patients (13%) had progressed.
So the 1-year progression-free survival rate was 86% (13/15).
“In conclusion, we see that elotuzumab and PBMC administration with standard autologous stem cell transplant and lenalidomide maintenance for consolidation therapy in multiple myeloma is certainly both safe and feasible,” Dr Osman said. “We’re planning a phase 2 study.”
*Information in the abstract differs from the presentation.
SALT LAKE CITY—A novel transplant regimen is “safe and feasible” for patients with multiple myeloma (MM), according to a presentation at the 2018 BMT Tandem Meetings.
Researchers conducted a phase 1 trial investigating the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard autologous hematopoietic stem cell transplant (ASCT) and lenalidomide maintenance in MM patients.
The regimen was considered well tolerated, as most adverse events (AEs) were grade 1 or 2.
The complete response (CR) rate was 40% at both 90 days and 1 year after ASCT.
Keren Osman, MD, of Mount Sinai Health System in New York, New York, reported these results as abstract 26.* This is an investigator-sponsored study, conducted in collaboration with Bristol Myers Squibb, the company marketing elotuzumab.
Dr Osman noted that elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7. The drug directly activates natural killer (NK) cells through the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on MM cells and facilitates interaction with NK cells to mediate the killing of MM cells through antibody-dependent cellular cytotoxicity.
“The hypothesis behind this phase 1 study was that . . ., in the peri-transplant period, if we add elotuzumab, we will succeed in promoting NK-mediated elimination of residual multiple myeloma cells as well as promote transition from innate to adaptive immune responses against multiple myeloma-associated antigens,” Dr Osman said.
She and her colleagues tested this hypothesis in 15 MM patients. They had a median age of 59 (range, 49-70), and 60% of them were male.
Forty percent of patients had stage I disease, 27% had stage II, and 20% had stage III. All patients had an ECOG status of 0 (47%) or 1 (53%).
The patients had a median of 174 days since diagnosis (range, 98-393).
All patients had received 1 to 2 prior lines of therapy. They all had bortezomib as part of their induction therapy, and 67% of them had received lenalidomide.
Seventy-three percent of patients had any cytogenetic abnormality, and 47% had high-risk cytogenetics.
Treatment
Patients underwent leukopheresis for PBMC collection, followed by standard peripheral blood stem cell mobilization and harvest.
They received standard melphalan conditioning on day -1 and autologous stem cell rescue on day 0. Autologous PBMCs were reinfused on day 3 after stem cell infusion.
Elotuzumab was given at 20 mg/kg intravenously on day 4. The drug was given every 28 days up to cycle 12.
Lenalidomide maintenance was given at 10 mg orally on days 1 to 21 of every 28-day cycle, starting with cycle 4 of elotuzumab (90 days post-ASCT). Maintenance could continue beyond cycle 12 at the investigators’ discretion.
Thirteen patients completed a year of treatment. One patient withdrew from the study due to early progression. The other patient withdrew due to personal choice and had a very good partial response (VGPR) at withdrawal.
Safety
“The majority of the adverse events, including infusion reactions attributable to elotuzumab, were grade 2 or lower,” Dr Osman noted. “And there were no AEs related to PBMC administration.”
One patient had a delay in hematopoietic reconstitution, which resulted in hospitalization exceeding 21 days.
One patient had grade 3 hypertension, which was attributed to elotuzumab and resolved with supportive care.
Eight patients had grade 3 lymphopenia, which was associated with elotuzumab, during the maintenance phase. Patients received prophylactic antibiotics, and there were no opportunistic infections.
Efficacy
At screening (after induction but before ASCT), 13 patients (87%) had a VGPR, and 2 (13%) had a partial response (PR).
At 90 days post-ASCT, 2 patients (13%) had a stringent CR, and 4 (27%) had a CR. Six patients (40%) had a VGPR, and 2 (13%) had a PR. One patient (7%) had progressed.
“In this very high-risk PR/VGPR population, stem cell transplant with elotuzumab and PBMC infusion resulted in a CR rate of 40%—with 13% of patients achieving stringent CR—by day 90,” Dr Osman noted. “And maintenance elotuzumab plus lenalidomide promoted further conversion to 33% stringent CR by 1 year.”
At 1 year, 5 patients (33%) had a stringent CR, and 1 (7%) had a CR. Six patients (40%) had a VGPR, and 1 (7%) had a PR. Two patients (13%) had progressed.
So the 1-year progression-free survival rate was 86% (13/15).
“In conclusion, we see that elotuzumab and PBMC administration with standard autologous stem cell transplant and lenalidomide maintenance for consolidation therapy in multiple myeloma is certainly both safe and feasible,” Dr Osman said. “We’re planning a phase 2 study.”
*Information in the abstract differs from the presentation.
‘Remarkable’ survival seen with pretransplant JAK inhibitor
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.
The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“So this is pretty exciting for us,” she added, explaining that allogeneic HCT, which is currently indicated only for patients with intermediate-2– or high-risk disease on the Dynamic International Prognostic Scoring System (DIPSS), remains the only curative treatment option for patients with myelofibrosis.
“Transplant outcomes have been associated with DIPSS and DIPSS+ risk scores,” she said, adding that a study demonstrating that association showed a 54% survival rate at 3 years in patients with intermediate-2–risk disease. “Then JAK-2 inhibitors came down the pipe, and they are also indicated for patients with DIPSS intermediate-2– and high-risk disease. They’ve been shown to decrease spleen size, increase quality of life scores, decrease cytokine levels, and improve constitutional symptoms.”
Posttransplant benefits of pre-HCT JAK inhibitor therapy could include improved graft function because of decreased spleen size and cytokines, potentially decreased severe graft-versus-host disease (GVHD), and decreased nonrelapse mortality.
“Our hypothesis was that the use of JAK inhibitors before transplant in patients with myelofibrosis – by decreasing inflammation, improving constitutional symptoms, and reducing splenomegaly – would result in a decreased DIPSS score” and improved posttransplant survival, Dr. Salit said.
Study participants were patients aged 18 years and older (median of 53 years) with primary or secondary myelofibrosis (14 each). About two-thirds of the study participants were men. Prior to JAK inhibitor therapy, 2 patients were low risk, 10 patients were intermediate-1 risk, and 16 patients were intermediate-2 risk according to the DIPSS.
They were given ruxolitinib (Jakafi) for at least 8 weeks prior to HCT (median of 7 months, but up to 3 years), and the treatment was tapered over 1-2 weeks through day 2 or 3 of conditioning chemotherapy, depending on the conditioning regimen. Conditioning regimens were determined by the physician based on donor type.
“After the ruxolitinib, we had 6 patients who were intermediate-1 and 21 who were intermediate-2, so in that way they failed to meet that hypothesis,” Dr. Salit said. This happened because the patients became anemic, so they gained points on their DIPSS scores for declining constitutional symptoms.
Of the 28 participants, 23 received myeloablative HCT, and 5 received reduced-intensity HCT.
“We had a mixture of related, unrelated, and cord blood recipients,” she noted.
At a median follow-up of just over 1 year, and at up to 3 years in some patients, no cases of cytokine release syndrome have occurred with the overlap of ruxolitinib and conditioning chemotherapy, and there have been no graft failures. All patients, including cord blood recipients, engrafted. The median time to engraftment was 19 days, but the range went as high as 35 days. “The 35 was one of our cord blood recipients,” she noted.
Median time to platelet engraftment was 20 days, and median CD3 and CD33 chimerism at day 80 were 88% and 100%, respectively.
Acute grades II-IV GVHD occurred in 70% of patients, but just 15% of these cases were grades III or IV, she said.
Chronic GVHD occurred in 35% of patients, including two severe cases. Two patients relapsed, including one at 6 months with marrow blast and one at 2 years with myeloid sarcoma. Two treatment-related deaths occurred, including one each at days 54 and 81.
The strategy of overlapping a JAK inhibitor with conditioning chemotherapy was safe, and “better in that we haven’t seen any cytokine release syndrome,” she concluded, adding that no graft failures occurred and grades III-IV acute and severe chronic GVHD were encouragingly infrequent.
Future studies should look at the optimal amount of time for JAK inhibitor therapy prior to transplant and whether it’s safe to continue JAK inhibitors through transplant, she said.
“Some of the work in Germany has shown that JAK inhibitors are safe to include up to day 28 through transplant, and that’s something that we’re looking to explore,” she noted.
Dr. Salit reported having no financial disclosures. This study was sponsored by the Fred Hutchinson Cancer Research Center.
SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The 2-year overall survival rate was 89%.
Study details: Findings in 28 patients from an ongoing prospective phase 2 study.
Disclosures: Dr. Salit reported having no financial disclosures. The study was sponsored by the Fred Hutchinson Cancer Research Center in Seattle.
Source: Salit R et al. BMT Tandem Meetings, Abstract 17.