Myelodysplastic Syndrome

Key clinical point: Paroxysmal nocturnal hemoglobinuria (PNH) clones are highly prevalent in myelodysplastic syndrome (MDS). PNH positivity predicted higher response to immunosuppressive therapy (IST) and stem cell transplants along with a favorable impact on overall survival (OS).

Major finding: PNH clones were present in 20.3% of MDS cases. PNH-positive vs. PNH-negative patients showed significantly higher response to IST (84% vs. 44.7%; P = .01) and stem cell transplant (71% vs. 56.6%; P = .09). PNH positivity had a favorable impact on disease progression (P less than .01) and overall survival (P less than .0001).

Study details: Data come from a large single-center study involving 3,085 patients with suspected underlying myeloid disorders, cytopenia, or unexplained thrombosis who underwent a first-time PNH test. The cohort had 869 cases of MDS.

Disclosures: The authors did not declare any source of funding. The authors declared no competing interests.

Source: Fattizzo B et al. Leukemia. 2021 Mar 4. doi: 10.1038/s41375-021-01190-9.

Key clinical point: Paroxysmal nocturnal hemoglobinuria (PNH) clones are highly prevalent in myelodysplastic syndrome (MDS). PNH positivity predicted higher response to immunosuppressive therapy (IST) and stem cell transplants along with a favorable impact on overall survival (OS).

Major finding: PNH clones were present in 20.3% of MDS cases. PNH-positive vs. PNH-negative patients showed significantly higher response to IST (84% vs. 44.7%; P = .01) and stem cell transplant (71% vs. 56.6%; P = .09). PNH positivity had a favorable impact on disease progression (P less than .01) and overall survival (P less than .0001).

Study details: Data come from a large single-center study involving 3,085 patients with suspected underlying myeloid disorders, cytopenia, or unexplained thrombosis who underwent a first-time PNH test. The cohort had 869 cases of MDS.

Disclosures: The authors did not declare any source of funding. The authors declared no competing interests.

Source: Fattizzo B et al. Leukemia. 2021 Mar 4. doi: 10.1038/s41375-021-01190-9.

Key clinical point: Paroxysmal nocturnal hemoglobinuria (PNH) clones are highly prevalent in myelodysplastic syndrome (MDS). PNH positivity predicted higher response to immunosuppressive therapy (IST) and stem cell transplants along with a favorable impact on overall survival (OS).

Major finding: PNH clones were present in 20.3% of MDS cases. PNH-positive vs. PNH-negative patients showed significantly higher response to IST (84% vs. 44.7%; P = .01) and stem cell transplant (71% vs. 56.6%; P = .09). PNH positivity had a favorable impact on disease progression (P less than .01) and overall survival (P less than .0001).

Study details: Data come from a large single-center study involving 3,085 patients with suspected underlying myeloid disorders, cytopenia, or unexplained thrombosis who underwent a first-time PNH test. The cohort had 869 cases of MDS.

Disclosures: The authors did not declare any source of funding. The authors declared no competing interests.

Source: Fattizzo B et al. Leukemia. 2021 Mar 4. doi: 10.1038/s41375-021-01190-9.

Key clinical point: Findings confirm dismal outcomes after azacitidine (AZA) discontinuation in patients with myelodysplastic syndrome (MDS); however, outcomes were best in those who discontinued AZA while being in response to undergo planned hematopoietic stem cell transplantation (HSCT).

Major finding: At discontinuation, 20.3% of the patients were still responding to AZA, 35.4% had primary resistance, and 44.3% developed adaptive resistance. Long-term survival was significantly better in patients who discontinued AZA while in response vs. those with primary or adaptive resistance (P = .004) with best outcomes in patients who discontinued to undergo planned HSCT with the median survival not reached and a 5-year survival rate of 56% (P less than .001).

Study details: This retrospective study evaluated 414 patients with MDS consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche (FISiM) and treated with AZA.

Disclosures: FISiM received support from Celgene Corporation to carry on the analysis. Some of the authors declared receiving personal fees, grants, and/or honoraria from various pharmaceutical companies including Celgene/Bristol-Myers Squibb.

Source: Clavio M et al. Cancer. 2021 Mar 19. doi: 10.1002/cncr.33472.

Key clinical point: Findings confirm dismal outcomes after azacitidine (AZA) discontinuation in patients with myelodysplastic syndrome (MDS); however, outcomes were best in those who discontinued AZA while being in response to undergo planned hematopoietic stem cell transplantation (HSCT).

Major finding: At discontinuation, 20.3% of the patients were still responding to AZA, 35.4% had primary resistance, and 44.3% developed adaptive resistance. Long-term survival was significantly better in patients who discontinued AZA while in response vs. those with primary or adaptive resistance (P = .004) with best outcomes in patients who discontinued to undergo planned HSCT with the median survival not reached and a 5-year survival rate of 56% (P less than .001).

Study details: This retrospective study evaluated 414 patients with MDS consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche (FISiM) and treated with AZA.

Disclosures: FISiM received support from Celgene Corporation to carry on the analysis. Some of the authors declared receiving personal fees, grants, and/or honoraria from various pharmaceutical companies including Celgene/Bristol-Myers Squibb.

Source: Clavio M et al. Cancer. 2021 Mar 19. doi: 10.1002/cncr.33472.

Key clinical point: Findings confirm dismal outcomes after azacitidine (AZA) discontinuation in patients with myelodysplastic syndrome (MDS); however, outcomes were best in those who discontinued AZA while being in response to undergo planned hematopoietic stem cell transplantation (HSCT).

Major finding: At discontinuation, 20.3% of the patients were still responding to AZA, 35.4% had primary resistance, and 44.3% developed adaptive resistance. Long-term survival was significantly better in patients who discontinued AZA while in response vs. those with primary or adaptive resistance (P = .004) with best outcomes in patients who discontinued to undergo planned HSCT with the median survival not reached and a 5-year survival rate of 56% (P less than .001).

Study details: This retrospective study evaluated 414 patients with MDS consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche (FISiM) and treated with AZA.

Disclosures: FISiM received support from Celgene Corporation to carry on the analysis. Some of the authors declared receiving personal fees, grants, and/or honoraria from various pharmaceutical companies including Celgene/Bristol-Myers Squibb.

Source: Clavio M et al. Cancer. 2021 Mar 19. doi: 10.1002/cncr.33472.

Key clinical point: Among patients with a solid tumor, the use of poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) was associated with an increased incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in those receiving a PARPi early in their disease course.

Major finding: Use of PARPi was associated with an increased incidence of MDS/AML in the frontline setting (incidence rate ratio [IRR], 5.43; 95% confidence interval [CI], 1.51–19.60) but not in the recurrent setting.

Study details: Findings are from a meta-analysis of 14 phase 2 and 3 clinical trials that randomly allocated 5,739 patients with solid tumors to either PARPi or control therapy.

Disclosures: This study was supported by the National Institutes of Health, National Cancer Institute, and National Center for Advancing Translational Sciences. Some of the authors declared receiving research funding, grants, and/or personal fees from various pharmaceutical companies.

Source: Nitecki R et al. Gynecol Oncol. 2021 Mar 15. doi: 10.1016/j.ygyno.2021.03.011.

Key clinical point: Among patients with a solid tumor, the use of poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) was associated with an increased incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in those receiving a PARPi early in their disease course.

Major finding: Use of PARPi was associated with an increased incidence of MDS/AML in the frontline setting (incidence rate ratio [IRR], 5.43; 95% confidence interval [CI], 1.51–19.60) but not in the recurrent setting.

Study details: Findings are from a meta-analysis of 14 phase 2 and 3 clinical trials that randomly allocated 5,739 patients with solid tumors to either PARPi or control therapy.

Disclosures: This study was supported by the National Institutes of Health, National Cancer Institute, and National Center for Advancing Translational Sciences. Some of the authors declared receiving research funding, grants, and/or personal fees from various pharmaceutical companies.

Source: Nitecki R et al. Gynecol Oncol. 2021 Mar 15. doi: 10.1016/j.ygyno.2021.03.011.

Key clinical point: Among patients with a solid tumor, the use of poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) was associated with an increased incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in those receiving a PARPi early in their disease course.

Major finding: Use of PARPi was associated with an increased incidence of MDS/AML in the frontline setting (incidence rate ratio [IRR], 5.43; 95% confidence interval [CI], 1.51–19.60) but not in the recurrent setting.

Study details: Findings are from a meta-analysis of 14 phase 2 and 3 clinical trials that randomly allocated 5,739 patients with solid tumors to either PARPi or control therapy.

Disclosures: This study was supported by the National Institutes of Health, National Cancer Institute, and National Center for Advancing Translational Sciences. Some of the authors declared receiving research funding, grants, and/or personal fees from various pharmaceutical companies.

Source: Nitecki R et al. Gynecol Oncol. 2021 Mar 15. doi: 10.1016/j.ygyno.2021.03.011.

Key clinical point: Red blood cell transfusion independence (TI) among patients with myelodysplastic syndrome (MDS) was associated with longer overall survival and lower risk for acute myeloid leukemia (AML) progression.

Major finding: Risk of death was 61.8% (hazard ratio [HR], 0.382; 95% credible interval [CrI], 0.201-0.666) lower in patients with TI vs. transfusion dependence (TD) and 63.4% (HR, 0.366; 95% CrI, 0.217-0.553) lower in patients who acquired TI through treatment vs. those who did not. Patients with TD vs. TI showed a trend toward worse prognosis and higher risk for AML progression (HR, 0.754; 95% CrI, 0.311-1.811).

Study details: Findings are from a meta-analysis of pooled studies that estimated the effect of transfusion sensitivity on clinical outcomes in patients with MDS.

Disclosures: The study was supported by Bristol-Myers Squibb Company. D Tang reported being an employee and equity holder of Bristol-Myers Squibb. T Schroeder reported being a consultant for Celgene International, a Bristol-Myers Squibb Company. The other authors declared no conflicts of interest.

Source: Lemos MB et al. Eur J Haematol. 2021 Mar 14. doi: 10.1111/ejh.13619.

Key clinical point: Red blood cell transfusion independence (TI) among patients with myelodysplastic syndrome (MDS) was associated with longer overall survival and lower risk for acute myeloid leukemia (AML) progression.

Major finding: Risk of death was 61.8% (hazard ratio [HR], 0.382; 95% credible interval [CrI], 0.201-0.666) lower in patients with TI vs. transfusion dependence (TD) and 63.4% (HR, 0.366; 95% CrI, 0.217-0.553) lower in patients who acquired TI through treatment vs. those who did not. Patients with TD vs. TI showed a trend toward worse prognosis and higher risk for AML progression (HR, 0.754; 95% CrI, 0.311-1.811).

Study details: Findings are from a meta-analysis of pooled studies that estimated the effect of transfusion sensitivity on clinical outcomes in patients with MDS.

Disclosures: The study was supported by Bristol-Myers Squibb Company. D Tang reported being an employee and equity holder of Bristol-Myers Squibb. T Schroeder reported being a consultant for Celgene International, a Bristol-Myers Squibb Company. The other authors declared no conflicts of interest.

Source: Lemos MB et al. Eur J Haematol. 2021 Mar 14. doi: 10.1111/ejh.13619.

Key clinical point: Red blood cell transfusion independence (TI) among patients with myelodysplastic syndrome (MDS) was associated with longer overall survival and lower risk for acute myeloid leukemia (AML) progression.

Major finding: Risk of death was 61.8% (hazard ratio [HR], 0.382; 95% credible interval [CrI], 0.201-0.666) lower in patients with TI vs. transfusion dependence (TD) and 63.4% (HR, 0.366; 95% CrI, 0.217-0.553) lower in patients who acquired TI through treatment vs. those who did not. Patients with TD vs. TI showed a trend toward worse prognosis and higher risk for AML progression (HR, 0.754; 95% CrI, 0.311-1.811).

Study details: Findings are from a meta-analysis of pooled studies that estimated the effect of transfusion sensitivity on clinical outcomes in patients with MDS.

Disclosures: The study was supported by Bristol-Myers Squibb Company. D Tang reported being an employee and equity holder of Bristol-Myers Squibb. T Schroeder reported being a consultant for Celgene International, a Bristol-Myers Squibb Company. The other authors declared no conflicts of interest.

Source: Lemos MB et al. Eur J Haematol. 2021 Mar 14. doi: 10.1111/ejh.13619.

Key clinical point: Oral azacitidine (CC-486) was associated with a significantly higher red blood cell (RBC) transfusion independence (TI) rate in patients with low-risk myelodysplastic syndrome (MDS) and high-risk disease features. The rate of early death was higher in the CC-846 arm.

Major finding: A significantly higher proportion of patients achieved RBC TI for 56 consecutive days in CC-486 vs. placebo arms (30.8% vs. 11.1%; odds ratio, 3.6; P = .0002). Overall, the death rate was similar, but death within the first 56 days was higher with CC-486 vs. placebo (16 vs. 6), most related to infections in patients with significant pretreatment neutropenia.

Study details: Findings are from AZA-MDS-003, a phase 3 trial involving 216 patients with low-risk MDS and RBC transfusion-dependent anemia and thrombocytopenia who were randomly allocated to either CC-486 (n=107) or placebo (n=109) for 21 days/28-day cycle.

Disclosures: The study was supported by Celgene Corporation, a Bristol-Myers Squibb company. Some of the authors declared receiving research funding, honoraria, travel and accommodation expenses, consulting/advisory role, being an employee of and/or stock/other ownership interest in various pharmaceutical companies including Celgene.

Source: Garcia-Manero G et al. J Clin Oncol. 2021 Mar 25. doi: 10.1200/JCO.20.02619. 

Key clinical point: Oral azacitidine (CC-486) was associated with a significantly higher red blood cell (RBC) transfusion independence (TI) rate in patients with low-risk myelodysplastic syndrome (MDS) and high-risk disease features. The rate of early death was higher in the CC-846 arm.

Major finding: A significantly higher proportion of patients achieved RBC TI for 56 consecutive days in CC-486 vs. placebo arms (30.8% vs. 11.1%; odds ratio, 3.6; P = .0002). Overall, the death rate was similar, but death within the first 56 days was higher with CC-486 vs. placebo (16 vs. 6), most related to infections in patients with significant pretreatment neutropenia.

Study details: Findings are from AZA-MDS-003, a phase 3 trial involving 216 patients with low-risk MDS and RBC transfusion-dependent anemia and thrombocytopenia who were randomly allocated to either CC-486 (n=107) or placebo (n=109) for 21 days/28-day cycle.

Disclosures: The study was supported by Celgene Corporation, a Bristol-Myers Squibb company. Some of the authors declared receiving research funding, honoraria, travel and accommodation expenses, consulting/advisory role, being an employee of and/or stock/other ownership interest in various pharmaceutical companies including Celgene.

Source: Garcia-Manero G et al. J Clin Oncol. 2021 Mar 25. doi: 10.1200/JCO.20.02619. 

Key clinical point: Oral azacitidine (CC-486) was associated with a significantly higher red blood cell (RBC) transfusion independence (TI) rate in patients with low-risk myelodysplastic syndrome (MDS) and high-risk disease features. The rate of early death was higher in the CC-846 arm.

Major finding: A significantly higher proportion of patients achieved RBC TI for 56 consecutive days in CC-486 vs. placebo arms (30.8% vs. 11.1%; odds ratio, 3.6; P = .0002). Overall, the death rate was similar, but death within the first 56 days was higher with CC-486 vs. placebo (16 vs. 6), most related to infections in patients with significant pretreatment neutropenia.

Study details: Findings are from AZA-MDS-003, a phase 3 trial involving 216 patients with low-risk MDS and RBC transfusion-dependent anemia and thrombocytopenia who were randomly allocated to either CC-486 (n=107) or placebo (n=109) for 21 days/28-day cycle.

Disclosures: The study was supported by Celgene Corporation, a Bristol-Myers Squibb company. Some of the authors declared receiving research funding, honoraria, travel and accommodation expenses, consulting/advisory role, being an employee of and/or stock/other ownership interest in various pharmaceutical companies including Celgene.

Source: Garcia-Manero G et al. J Clin Oncol. 2021 Mar 25. doi: 10.1200/JCO.20.02619. 

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

Key clinical point: High fibrinogen-albumin ratio index (FARI) is associated with shorter overall survival (OS) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) treated with azacitidine.

Major finding: One-year OS was significantly shorter in patients with high (at or above 0.079) vs. low (less than 0.079) FARI (35.6% vs. 77.5%; P less than .001).

Study details: Findings are from a retrospective study of 99 patients with de novo MDS (n=86) and AML-MRC (n=13) treated with azacitidine between May 2011 and June 2019.

Disclosures: The authors did not report any source of funding. The authors declared no potential competing interests.

Source: Akimoto M et al. Ann Hematol. 2021 Feb 1. doi: 10.1007/s00277-021-04440-z.

Key clinical point: High fibrinogen-albumin ratio index (FARI) is associated with shorter overall survival (OS) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) treated with azacitidine.

Major finding: One-year OS was significantly shorter in patients with high (at or above 0.079) vs. low (less than 0.079) FARI (35.6% vs. 77.5%; P less than .001).

Study details: Findings are from a retrospective study of 99 patients with de novo MDS (n=86) and AML-MRC (n=13) treated with azacitidine between May 2011 and June 2019.

Disclosures: The authors did not report any source of funding. The authors declared no potential competing interests.

Source: Akimoto M et al. Ann Hematol. 2021 Feb 1. doi: 10.1007/s00277-021-04440-z.

Key clinical point: High fibrinogen-albumin ratio index (FARI) is associated with shorter overall survival (OS) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) treated with azacitidine.

Major finding: One-year OS was significantly shorter in patients with high (at or above 0.079) vs. low (less than 0.079) FARI (35.6% vs. 77.5%; P less than .001).

Study details: Findings are from a retrospective study of 99 patients with de novo MDS (n=86) and AML-MRC (n=13) treated with azacitidine between May 2011 and June 2019.

Disclosures: The authors did not report any source of funding. The authors declared no potential competing interests.

Source: Akimoto M et al. Ann Hematol. 2021 Feb 1. doi: 10.1007/s00277-021-04440-z.

Key clinical point: Reduced-dose decitabine (DAC) could have a better response than reduced-dose azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) with different prognostic risks.

Major finding: Overall response rate (ORR) was higher in the DAC (62.5%) than AZA (42.1%) group (P = .007). Incidences of neutropenia (P = .016) and infections (P = .032) were higher in the DAC vs. AZA group.

Study details: Findings are from a retrospective study of 158 patients with MDS with varied prognostic risks who were administered reduced-dose of AZA (n=38) or DAC (n=120). Included patients received these hypomethylating agents for the first time between May 2006 and February 2020 and could not tolerate the standard doses.

Disclosures: The study was funded by the National Science and Technology Major Project of China. The authors declared no competing interests.

Source: Hu N et al. Med Sci Monit. 2021 Jan 30. doi: 10.12659/MSM.928454.

Key clinical point: Reduced-dose decitabine (DAC) could have a better response than reduced-dose azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) with different prognostic risks.

Major finding: Overall response rate (ORR) was higher in the DAC (62.5%) than AZA (42.1%) group (P = .007). Incidences of neutropenia (P = .016) and infections (P = .032) were higher in the DAC vs. AZA group.

Study details: Findings are from a retrospective study of 158 patients with MDS with varied prognostic risks who were administered reduced-dose of AZA (n=38) or DAC (n=120). Included patients received these hypomethylating agents for the first time between May 2006 and February 2020 and could not tolerate the standard doses.

Disclosures: The study was funded by the National Science and Technology Major Project of China. The authors declared no competing interests.

Source: Hu N et al. Med Sci Monit. 2021 Jan 30. doi: 10.12659/MSM.928454.

Key clinical point: Reduced-dose decitabine (DAC) could have a better response than reduced-dose azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) with different prognostic risks.

Major finding: Overall response rate (ORR) was higher in the DAC (62.5%) than AZA (42.1%) group (P = .007). Incidences of neutropenia (P = .016) and infections (P = .032) were higher in the DAC vs. AZA group.

Study details: Findings are from a retrospective study of 158 patients with MDS with varied prognostic risks who were administered reduced-dose of AZA (n=38) or DAC (n=120). Included patients received these hypomethylating agents for the first time between May 2006 and February 2020 and could not tolerate the standard doses.

Disclosures: The study was funded by the National Science and Technology Major Project of China. The authors declared no competing interests.

Source: Hu N et al. Med Sci Monit. 2021 Jan 30. doi: 10.12659/MSM.928454.

Key clinical point: Daratumumab provided some clinical activity in patients with low- to intermediate-risk myelodysplastic syndromes (MDS), who relapsed or were refractory to erythropoiesis-stimulating agents (ESA) treatment. No new safety signals were identified.

Major finding: Eight-week transfusion independence (TI) was achieved by 6.1% (95% confidence interval, 0.7%-20.2%) of patients. Time to 8-week TI was 4–5 weeks after the first daratumumab infusion. Daratumumab-related adverse events were reported by 54.5% of patients, of whom 3 patients experienced 4 serious adverse events. Infusion-related reaction was observed, but none led to treatment discontinuation.

Study details: Findings are from a phase 2, randomized, open-label study involving 34 patients with low- or intermediate-1-risk MDS, who were transfusion dependent and who relapsed or were refractory to ESA treatment. Patients received either daratumumab (n=33) or talacotuzumab (n=1); however, recruitment to talacotuzumab arm was closed after the occurrence of a serious adverse event in the first patient.

Disclosures: This study was supported by Janssen Research & Development. The lead author reported receiving research support from Johnson & Johnson. Some of the coinvestigators reported owning stocks, being an employee, serving on an advisory board, receiving support, and consulting for various pharmaceutical companies including Janssen Research & Development. Six of the coinvestigators declared no potential competing interests.

Source: Garcia‐Manero G et al. Am J Hematol. 2021 Jan 15. doi: 10.1002/ajh.26095.

Key clinical point: Daratumumab provided some clinical activity in patients with low- to intermediate-risk myelodysplastic syndromes (MDS), who relapsed or were refractory to erythropoiesis-stimulating agents (ESA) treatment. No new safety signals were identified.

Major finding: Eight-week transfusion independence (TI) was achieved by 6.1% (95% confidence interval, 0.7%-20.2%) of patients. Time to 8-week TI was 4–5 weeks after the first daratumumab infusion. Daratumumab-related adverse events were reported by 54.5% of patients, of whom 3 patients experienced 4 serious adverse events. Infusion-related reaction was observed, but none led to treatment discontinuation.

Study details: Findings are from a phase 2, randomized, open-label study involving 34 patients with low- or intermediate-1-risk MDS, who were transfusion dependent and who relapsed or were refractory to ESA treatment. Patients received either daratumumab (n=33) or talacotuzumab (n=1); however, recruitment to talacotuzumab arm was closed after the occurrence of a serious adverse event in the first patient.

Disclosures: This study was supported by Janssen Research & Development. The lead author reported receiving research support from Johnson & Johnson. Some of the coinvestigators reported owning stocks, being an employee, serving on an advisory board, receiving support, and consulting for various pharmaceutical companies including Janssen Research & Development. Six of the coinvestigators declared no potential competing interests.

Source: Garcia‐Manero G et al. Am J Hematol. 2021 Jan 15. doi: 10.1002/ajh.26095.

Key clinical point: Daratumumab provided some clinical activity in patients with low- to intermediate-risk myelodysplastic syndromes (MDS), who relapsed or were refractory to erythropoiesis-stimulating agents (ESA) treatment. No new safety signals were identified.

Major finding: Eight-week transfusion independence (TI) was achieved by 6.1% (95% confidence interval, 0.7%-20.2%) of patients. Time to 8-week TI was 4–5 weeks after the first daratumumab infusion. Daratumumab-related adverse events were reported by 54.5% of patients, of whom 3 patients experienced 4 serious adverse events. Infusion-related reaction was observed, but none led to treatment discontinuation.

Study details: Findings are from a phase 2, randomized, open-label study involving 34 patients with low- or intermediate-1-risk MDS, who were transfusion dependent and who relapsed or were refractory to ESA treatment. Patients received either daratumumab (n=33) or talacotuzumab (n=1); however, recruitment to talacotuzumab arm was closed after the occurrence of a serious adverse event in the first patient.

Disclosures: This study was supported by Janssen Research & Development. The lead author reported receiving research support from Johnson & Johnson. Some of the coinvestigators reported owning stocks, being an employee, serving on an advisory board, receiving support, and consulting for various pharmaceutical companies including Janssen Research & Development. Six of the coinvestigators declared no potential competing interests.

Source: Garcia‐Manero G et al. Am J Hematol. 2021 Jan 15. doi: 10.1002/ajh.26095.