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A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation
S190
Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. CD34+-selected pts received no planned immunosuppression. EASIX scores (LDH x creatinine/platelet count) were calculated continuously until 1-year post-HCT. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A 1-unit increase in log2 EASIX is associated with a doubling of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM. Results: 360 pts (71%) received a CD34+-selected and 149 (29%) an unmodified allo-HCT. HLA matched donors were used in 435 (86%) and mismatched in 74 (14%) pts. HCT-CI was 0 in 24% of pts, 1-2 in 32%, and 3 in 44%. Median age was 56 (range 19-78) and 59% were males. Most unmodified allo-HCTs were done for nonHodgkin lymphoma (69%), and most CD34+-selected allo-HCTs were done for acute leukemia (61%). Among all patients, EASIX scores increased rapidly, peaked at day +8, then declined until day +40. Thereafter, scores decreased but remained above pre-HCT baseline for the first year (Figure 1a). In unmodified pts, EASIX scores appeared higher over time than in CD34+-selected pts, whose scores rapidly decreased by 2 months post-HCT (Figure 1b). EASIX’s ability to discriminate NRM in the subsequent 180 days was similar when analyzed as a categorical variable at landmark timepoints and as change from pre-HCT. EASIX discrimination of NRM was highest between day +180 to +210 (concordance index=0.85) (Figure 2). At this landmark, pts with log EASIX >2 died of infection (14%), GVHD (29%), relapse (33%), and other causes (25%) in the subsequent 180 days. Mean EASIX scores at this landmark were higher in men (mean log2 +0.52) and in pts who developed grade 2-4 GVHD by day +180 (+0.81), lower in pts who received matched unrelated versus mismatched donors (-0.81, all P<0.01), and did not differ based on disease. After day +30, pts who did not die of NRM had consistently lower EASIX scores compared to pts who died of NRM in the subsequent 180 days (Figure 3). Conclusion: EASIX scores are dynamic and variably concordant with NRM when analyzed longitudinally post-HCT, and patterns differ between allo-HCT platforms. Compared to preHCT evaluation, dynamic EASIX scores may better predict risk of NRM over time as pts acquire additional endothelial injury and toxicities along the allo-HCT journey.
280 A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation Omer Jamy MD1, Racquel Innis-Shelton MD2, Susan Bal M.D.3, Donna Salzman MD4, Luciano J. Costa MD, PhD4, Antonio di Stasi MD5, Lawrence Lamb PhD2, Shin Mineishi MD6, Ayman Saad MD4. 1 University of Alabama at Birmingham Hospital, Birmingham, AL; 2 Medicine, University of Alabama at Birmingham, Birmingham, AL; 3 University of Alabama at Birmingham, Birmingham, AL; 4 Bone Marrow Transplantation and Cell Therapy Program; Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham Hospital, Birmingham, AL; 5 Stem Cell Transplantation and Cellular Therapy, University of Alabama at Birmingham, Birmingham, AL; 6 Blood and Marrow Transplantation Program, Penn State Hershey Medical Center, Hershey, PA Background: The optimal regimen for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. Post-transplant cyclophosphamide (PT-Cy)
mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. We investigated the benefit of PT-Cy in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial of PT-Cy for GVHD prophylaxis following MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 to +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. Results: There were 39 patients enrolled in the study. The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). The most commonly used conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV. The incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of these were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. Conclusion: The use of one dose of PT-Cy in combination with MMF and tacrolimus is effective in preventing acute severe GVHD in myeloablative PBSC MUD HSCT recipients. We observe modest control over chronic GVHD with this regimen which may be explained by giving one dose of PT-Cy only. We report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD and may play a vital role in mismatched unrelated donor transplants as well.
Figure 1. Overall Survival.
Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. CD34+-selected pts received no planned immunosuppression. EASIX scores (LDH x creatinine/platelet count) were calculated continuously until 1-year post-HCT. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A 1-unit increase in log2 EASIX is associated with a doubling of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM. Results: 360 pts (71%) received a CD34+-selected and 149 (29%) an unmodified allo-HCT. HLA matched donors were used in 435 (86%) and mismatched in 74 (14%) pts. HCT-CI was 0 in 24% of pts, 1-2 in 32%, and 3 in 44%. Median age was 56 (range 19-78) and 59% were males. Most unmodified allo-HCTs were done for nonHodgkin lymphoma (69%), and most CD34+-selected allo-HCTs were done for acute leukemia (61%). Among all patients, EASIX scores increased rapidly, peaked at day +8, then declined until day +40. Thereafter, scores decreased but remained above pre-HCT baseline for the first year (Figure 1a). In unmodified pts, EASIX scores appeared higher over time than in CD34+-selected pts, whose scores rapidly decreased by 2 months post-HCT (Figure 1b). EASIX’s ability to discriminate NRM in the subsequent 180 days was similar when analyzed as a categorical variable at landmark timepoints and as change from pre-HCT. EASIX discrimination of NRM was highest between day +180 to +210 (concordance index=0.85) (Figure 2). At this landmark, pts with log EASIX >2 died of infection (14%), GVHD (29%), relapse (33%), and other causes (25%) in the subsequent 180 days. Mean EASIX scores at this landmark were higher in men (mean log2 +0.52) and in pts who developed grade 2-4 GVHD by day +180 (+0.81), lower in pts who received matched unrelated versus mismatched donors (-0.81, all P<0.01), and did not differ based on disease. After day +30, pts who did not die of NRM had consistently lower EASIX scores compared to pts who died of NRM in the subsequent 180 days (Figure 3). Conclusion: EASIX scores are dynamic and variably concordant with NRM when analyzed longitudinally post-HCT, and patterns differ between allo-HCT platforms. Compared to preHCT evaluation, dynamic EASIX scores may better predict risk of NRM over time as pts acquire additional endothelial injury and toxicities along the allo-HCT journey.
280 A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation Omer Jamy MD1, Racquel Innis-Shelton MD2, Susan Bal M.D.3, Donna Salzman MD4, Luciano J. Costa MD, PhD4, Antonio di Stasi MD5, Lawrence Lamb PhD2, Shin Mineishi MD6, Ayman Saad MD4. 1 University of Alabama at Birmingham Hospital, Birmingham, AL; 2 Medicine, University of Alabama at Birmingham, Birmingham, AL; 3 University of Alabama at Birmingham, Birmingham, AL; 4 Bone Marrow Transplantation and Cell Therapy Program; Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham Hospital, Birmingham, AL; 5 Stem Cell Transplantation and Cellular Therapy, University of Alabama at Birmingham, Birmingham, AL; 6 Blood and Marrow Transplantation Program, Penn State Hershey Medical Center, Hershey, PA Background: The optimal regimen for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. Post-transplant cyclophosphamide (PT-Cy)
mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. We investigated the benefit of PT-Cy in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial of PT-Cy for GVHD prophylaxis following MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 to +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. Results: There were 39 patients enrolled in the study. The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). The most commonly used conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV. The incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of these were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. Conclusion: The use of one dose of PT-Cy in combination with MMF and tacrolimus is effective in preventing acute severe GVHD in myeloablative PBSC MUD HSCT recipients. We observe modest control over chronic GVHD with this regimen which may be explained by giving one dose of PT-Cy only. We report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD and may play a vital role in mismatched unrelated donor transplants as well.
Figure 1. Overall Survival.