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Clinical Outcomes as Basis for FDA Licensure Application—Lessons Learned
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Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
hospitalization burden overall & especially low rates of readmission (<15%) beyond the first 3 months post-CBT (Figure 2A). Conclusions: 2-year PFS in adult CBT recipients (median 51 years) after Cy/Flu/Thio/TBI is high overall (69%). Pts with 0-2 aaHCT-CI score do especially well (81%) with low hospitalization burden in the first 2 years post-CBT. As with all allograft types, new strategies to reduce CBT complications in pts with high aaHCT-CI are needed. Notably, however, given the very rapid graft availability & high PFS, dCBT should have a high priority in adult pts with low aaHCT-CI & high risk malignancies.
In summary, this retrospective analysis indicates that second transplant can be a viable option for treatment of relapse following HSCT offering long-term survival for some. The mortality rate remains high, with the most common cause of death being relapse. Novel therapeutic strategies are needed to further improve outcomes.
187 Outcomes of Second Transplants for Patients with Hematological Malignancies Who Relapse after First Transplant: A Retrospective Analysis of a Single Institution Experience Lauren Stafford 1, Jesse D. Troy 1, Timothy A. Driscoll 1, Kristin Page 1, Suhag Parikh 2, Vinod K. Prasad 1, Joanne Kurtzberg 1, Paul L. Martin 2. 1 Pediatric Blood and Marrow Transplant Division, Duke University Medical Center, Durham, NC; 2 Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, NC Introduction: Post-transplant relapse remains a major cause for failure after Hematopoietic Stem Cell Transplantation (HSCT) in pediatric patients with hematologic malignancies. Although the prognosis following relapse is grim, second transplant may offer the chance of cure and long term survival. To determine the long-term outcomes of this population, we reviewed the outcomes of pediatric patients who were treated at Duke University from 2000-present who received a second allogeneic HSCT due to relapse after first transplant. Methods: We conducted a retrospective review of 28 patients, ages .9-18 yr (median, 6 yr) at time of first transplant, who relapsed 1-30 (median 10.75) months following allogeneic HSCT. Diagnoses included AML (N = 14), ALL (N = 11) and MDS (N = 3). Graft sources for the first HSCT included unrelated umbilical cord blood (UCB, N = 14), matched siblings (MSD, N = 10) and matched unrelated donors (MUD, N = 4). Second transplant graft sources were mostly UCB (26) with one MUD and one MSD. All subjects received myeloablative conditioning (MAC). All received TBI as part of the first (n = 16) or second (n = 11) HSCT, one patient received TBI with both. Sixteen patients had active disease at the time of second transplant. Descriptive statistics, Kaplan-Meier (KM) estimates of survival and cox regression to identify predictors of survival were utilized. Results: The KM probability of 5-yr overall survival was 28.1% (95% CI: 11.29%, 44.97%) with a median follow-up of 5.5 years (range, 1.5-16yrs). Three of 8 survivors had disease (2 AML, 1 MDS) at the time of conditioning. The majority of survivors (N = 5) had a MSD graft for the first HSCT followed by UCB for second graft. Two survivors received UCB grafts for both transplants, with double UCBT for the second, and one had a MUD followed by double UCB transplant. Of the 8 survivors, 4 received TBI with the first transplant, 3 with the second, and one received a dose with both transplants. Of the 20 patients who did not survive, 12 died of relapse with an even division between those who received TBI with the first and second transplants. Eight of the patients who relapsed had active disease at the time of conditioning for second transplant. Additional causes of death were infection and organ failure. Time to death ranged from 1-18 mos (median 4.5 mos). Median time to relapse after first transplant was 8 months for both cohorts. The median interval between the 2 transplants was 12 months for the surviving patients and 15 months for the deceased patients. No outcome predictors were identified.
188 Clinical Outcomes as Basis for FDA Licensure Application—Lessons Learned Wouter Van’t Hof, Marcie Finney, Lisa Johnson, Sara Shields, Dawn Thut, Mary J. Laughlin. Cleveland Cord Blood Center, Cleveland, OH Clinical outcomes were reported to the Department of Health & Human Services Food & Drug Administration March 2016 as part of a biologic license application (BLA) for HPC, Cord Blood under the provisions of section 351(a) in the manufacture of biologic products under 21 CFR 600.12. The clinical outcomes for all patients sequentially receiving unrelated umbilical cord blood (HPC, cord blood) for allogeneic stem cell transplantation (alloSCT) during the time period 20092015 from this single public cord blood bank were included. Data reported included FDA mandated specifications including infused total nucleated count (TNC) > 2.5 × 10e7/kg and >4/6 HLA match at antigen level at HLA-A and -B and allele level at DRB1. CIBMTR clinical outcome data reported included n = 91 patients. Median age was 40 years (range 0-68) with 67% of patients >17 years of age. 74 patients were Caucasian (81%), 9 African-American (10%) and 5 Asian. The majority of patients had hematologic malignancies (n = 75; 83%) with 8% of patients undergoing alloSCT for inherited metabolic disorders, 5% immunodeficiency, 2% bone marrow failure, and 2% hemoglobinopathies. All patients received a single UCB graft with exception n = 2 patients. HLA match level was primarily 4/6 (n = 45; 49%), with HLA 5/6 match (n = 34; 37%) and HLA match 6/6 (n = 12; 13%) in this series. Primary graft failure defined as failure to achieve an absolute neutrophil count >500/ul by day 42 after HPC, Cord Blood infusion occurred in n = 2 patients. 7 patients (8%) experienced Infusion-Related Adverse Reactions. At median follow up 36 months n = 12 deaths have occurred. Causes of death included: disease recurrence in 4 patients (33%), organ failure in 2 patients (16%), graft failure in 2 patients (16%), and hemorrhage, pulmonary toxicity, infection and GVHD each occurring in n = 1 patient respectively.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
Conclusion: The risk benefit assessment of HPC, Cord for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on the characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells. These comparison data await the results of prospective randomized studies.
189 Promising Outcomes of Urgent Cord Blood Transplantation for Fulminant Aplastic Anemia in Adults Hisashi Yamamoto, Naoyuki Uchida, Kyosuke Yamaguchi, Mitsuhiro Yuasa, Kosei Kageyama, Aya Nishida, Kazuya Ishiwata, Shinsuke Takagi, Go Yamamoto, Yuki Asano-Mori, Koji Izutsu, Atsushi Wake, Shuichi Taniguchi. Department of Hematology, Toranomon Hospital, Tokyo, Japan Backgrounds: In patients with aplastic anemia (AA), absolute neutrophil count at diagnosis is one of the critical factors for selecting optimal treatment strategies. Fulminant aplastic anemia (FAA), defined as no neutrophils in the peripheral blood at diagnosis despite administration of G-CSF, has been known to be the most severe type of AA. Although patients diagnosed with FAA are at high risk for life-threatening infections, the optimal treatment has not been established. The aim of this study is to evaluate the efficacy of cord blood transplantation (CBT) for patients with FAA. Methods: We retrospectively reviewed 5 patients with FAA who underwent CBT at our institute from Aug 2007 to Sep 2015 consecutively. Results: Their median age was 52 years (range, 18-70). All patients met criteria of FAA and had no suitable HLAidentical related donor. Two patients developed bacterial sepsis before starting the conditioning regimen; one was successfully treated by controlled by antibiotics while another received granulocyte transfusion as well. The median duration from diagnosis to transplant was 32 (range, 20-74) days. All patients were conditioned with fludarabine, melphalan (80 mg/m2) and 4 Gy of TBI and were used TAC plus MMF for GVHD prophylaxis. ATG was not used in all patients. The median number of TNC and CD34+ cells were 2.16 (range, 1.74-4.39) × 107/kg and 1.00 (range, .39-1.52) × 105/ kg, respectively. All patients received single cord blood unit (CBU) with 2-mismatches (MM) in HLA-A, B, or DRB1 to the recipient (n = 3) and 1-MM (n = 2). Anti-HLA antibodies were screened before transplant to select proper CBU in 3 patients except for 2 patients who were transplanted before 2008. All but one patients achieved neutrophil and platelet engraftment. The median times to achieve neutrophil engraftment and platelet count >20 × 109/L were 15 (range, 10-18) days and 34 (range, 31-37) days, respectively. All patients who achieved engraftment had complete hematological recovery and became free from transfusion dependence, and they showed complete donor-type chimerism. One patient developed graft rejection and was later found to have antibody against mismatched HLA on CBU. The patient underwent a second CBT on day 33 after the first CBT, and obtained rapid engraftment. Among 4 evaluable patients who achieved primary engraftment, one developed grade II acute GVHD and the other one developed limited type of chronic GVHD. At the time of analysis, all 5 patients survived for a median of 54 (range, 12-105) months
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after transplant. All became free from immunosuppressant with high Karnofsky performance status (KPS) score with the median of 100% (range; 60-100%). Conclusion: This study showed that urgent CBT without ATGcontaining immunosuppressive therapy provides rapid engraftment and excellent survival rate with good KPS longterm in patients with FAA.
GRAFT PROCESSING
190 Cryopreservation of Autologous Peripheral Blood Stem Cells Using 10% DMSO Followed by Thaw and Wash Prior to Autologous Stem Cell Transplantation Ruthee-Lu Bayer 1, Laura Donahue 1, Vinita Gupta 1, Suhui He 2, Shreya Goyal 3, Jane Han 2, Wei Xu 2. 1 Hematology/ Oncology, Northwell Health, North Shore University Hospital, Lake Success, NY; 2 HPC Transplant Lab, Northwell Health, North Shore University Hospital, Manhasset, NY; 3 Medicine, North Shore University Hospital, Manhasset, NY Background and objectives: A number of published protocols evaluated the implications of post thaw washing of cryopreserved hematopoietic stem cells and showed favorable impact on DMSO related infusion reactions and minimal effect on hematopoietic recovery. However, this procedure has not been widely adopted due to concerns about potential stem cell loss. The aim of this study is to present an update on a single institution’s experience with cryopreservation of autologous PBSC using 10%DMSO and applying post thaw DMSO depletion. Materials and methods: Data were retrospectively collected on cryopreserved autologous PBSC products (HPC, Apheresis products) from 573 evaluable patients between 2004 and 2015. All products were cryopreserved in a rate controlled freezer for initial freezing, and then stored in liquid nitrogen freezers (temperature range −145 to −195 degree C). The frozen autologous PBSC product contains cryoprotectant mixture with 10% DMSO, 2% human albumin, and 33% plasma-lyte A. Thawing procedures were performed in a 37 degree C water bath. Washing procedures were performed by using COBE 2991 cell processor with cell processing set. DMSO concentration was reduced below .1% in the final product after three washes. All products underwent cell viability testing by Trypan Blue method. Results: Storage time ranged between one month and 7 years. The total ex-vivo handling time after removal from liquid nitrogen storage including the time frame for completion of each product’s thaw and wash was approximately 4 hours. Cell concentration range either in the cryopreserved product or thawed-washed product was between 20 × 10 6 /mL and 300 × 106/mL. Average MNC infusion dose was 7.89 × 108/kg and average CD34+ cell infusion dose was 10.83 × 106/kg. All products were sent for sterility testing. All culture results were negative. Percentage cell recovery was calculated. Mean recovery is 87%. Mean cell viability is 81.7% by Trypan Blue method. Mean ANC engraftment for 560 evaluable patients is 12.6 days. Mean platelet engraftment for 345 evaluable patients was 22.9 days. Mean final infusion volume is 329 ml (range 110-700 ml). There were no reported infusion reactions. Conclusion: Our data suggests that post thaw washing of cropreserved PBSC can be successfully performed without significantly jeopardizing hematopoietic recovery and with favorable impact on DMSO related toxicity.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
hospitalization burden overall & especially low rates of readmission (<15%) beyond the first 3 months post-CBT (Figure 2A). Conclusions: 2-year PFS in adult CBT recipients (median 51 years) after Cy/Flu/Thio/TBI is high overall (69%). Pts with 0-2 aaHCT-CI score do especially well (81%) with low hospitalization burden in the first 2 years post-CBT. As with all allograft types, new strategies to reduce CBT complications in pts with high aaHCT-CI are needed. Notably, however, given the very rapid graft availability & high PFS, dCBT should have a high priority in adult pts with low aaHCT-CI & high risk malignancies.
In summary, this retrospective analysis indicates that second transplant can be a viable option for treatment of relapse following HSCT offering long-term survival for some. The mortality rate remains high, with the most common cause of death being relapse. Novel therapeutic strategies are needed to further improve outcomes.
187 Outcomes of Second Transplants for Patients with Hematological Malignancies Who Relapse after First Transplant: A Retrospective Analysis of a Single Institution Experience Lauren Stafford 1, Jesse D. Troy 1, Timothy A. Driscoll 1, Kristin Page 1, Suhag Parikh 2, Vinod K. Prasad 1, Joanne Kurtzberg 1, Paul L. Martin 2. 1 Pediatric Blood and Marrow Transplant Division, Duke University Medical Center, Durham, NC; 2 Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, NC Introduction: Post-transplant relapse remains a major cause for failure after Hematopoietic Stem Cell Transplantation (HSCT) in pediatric patients with hematologic malignancies. Although the prognosis following relapse is grim, second transplant may offer the chance of cure and long term survival. To determine the long-term outcomes of this population, we reviewed the outcomes of pediatric patients who were treated at Duke University from 2000-present who received a second allogeneic HSCT due to relapse after first transplant. Methods: We conducted a retrospective review of 28 patients, ages .9-18 yr (median, 6 yr) at time of first transplant, who relapsed 1-30 (median 10.75) months following allogeneic HSCT. Diagnoses included AML (N = 14), ALL (N = 11) and MDS (N = 3). Graft sources for the first HSCT included unrelated umbilical cord blood (UCB, N = 14), matched siblings (MSD, N = 10) and matched unrelated donors (MUD, N = 4). Second transplant graft sources were mostly UCB (26) with one MUD and one MSD. All subjects received myeloablative conditioning (MAC). All received TBI as part of the first (n = 16) or second (n = 11) HSCT, one patient received TBI with both. Sixteen patients had active disease at the time of second transplant. Descriptive statistics, Kaplan-Meier (KM) estimates of survival and cox regression to identify predictors of survival were utilized. Results: The KM probability of 5-yr overall survival was 28.1% (95% CI: 11.29%, 44.97%) with a median follow-up of 5.5 years (range, 1.5-16yrs). Three of 8 survivors had disease (2 AML, 1 MDS) at the time of conditioning. The majority of survivors (N = 5) had a MSD graft for the first HSCT followed by UCB for second graft. Two survivors received UCB grafts for both transplants, with double UCBT for the second, and one had a MUD followed by double UCB transplant. Of the 8 survivors, 4 received TBI with the first transplant, 3 with the second, and one received a dose with both transplants. Of the 20 patients who did not survive, 12 died of relapse with an even division between those who received TBI with the first and second transplants. Eight of the patients who relapsed had active disease at the time of conditioning for second transplant. Additional causes of death were infection and organ failure. Time to death ranged from 1-18 mos (median 4.5 mos). Median time to relapse after first transplant was 8 months for both cohorts. The median interval between the 2 transplants was 12 months for the surviving patients and 15 months for the deceased patients. No outcome predictors were identified.
188 Clinical Outcomes as Basis for FDA Licensure Application—Lessons Learned Wouter Van’t Hof, Marcie Finney, Lisa Johnson, Sara Shields, Dawn Thut, Mary J. Laughlin. Cleveland Cord Blood Center, Cleveland, OH Clinical outcomes were reported to the Department of Health & Human Services Food & Drug Administration March 2016 as part of a biologic license application (BLA) for HPC, Cord Blood under the provisions of section 351(a) in the manufacture of biologic products under 21 CFR 600.12. The clinical outcomes for all patients sequentially receiving unrelated umbilical cord blood (HPC, cord blood) for allogeneic stem cell transplantation (alloSCT) during the time period 20092015 from this single public cord blood bank were included. Data reported included FDA mandated specifications including infused total nucleated count (TNC) > 2.5 × 10e7/kg and >4/6 HLA match at antigen level at HLA-A and -B and allele level at DRB1. CIBMTR clinical outcome data reported included n = 91 patients. Median age was 40 years (range 0-68) with 67% of patients >17 years of age. 74 patients were Caucasian (81%), 9 African-American (10%) and 5 Asian. The majority of patients had hematologic malignancies (n = 75; 83%) with 8% of patients undergoing alloSCT for inherited metabolic disorders, 5% immunodeficiency, 2% bone marrow failure, and 2% hemoglobinopathies. All patients received a single UCB graft with exception n = 2 patients. HLA match level was primarily 4/6 (n = 45; 49%), with HLA 5/6 match (n = 34; 37%) and HLA match 6/6 (n = 12; 13%) in this series. Primary graft failure defined as failure to achieve an absolute neutrophil count >500/ul by day 42 after HPC, Cord Blood infusion occurred in n = 2 patients. 7 patients (8%) experienced Infusion-Related Adverse Reactions. At median follow up 36 months n = 12 deaths have occurred. Causes of death included: disease recurrence in 4 patients (33%), organ failure in 2 patients (16%), graft failure in 2 patients (16%), and hemorrhage, pulmonary toxicity, infection and GVHD each occurring in n = 1 patient respectively.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
Conclusion: The risk benefit assessment of HPC, Cord for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on the characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells. These comparison data await the results of prospective randomized studies.
189 Promising Outcomes of Urgent Cord Blood Transplantation for Fulminant Aplastic Anemia in Adults Hisashi Yamamoto, Naoyuki Uchida, Kyosuke Yamaguchi, Mitsuhiro Yuasa, Kosei Kageyama, Aya Nishida, Kazuya Ishiwata, Shinsuke Takagi, Go Yamamoto, Yuki Asano-Mori, Koji Izutsu, Atsushi Wake, Shuichi Taniguchi. Department of Hematology, Toranomon Hospital, Tokyo, Japan Backgrounds: In patients with aplastic anemia (AA), absolute neutrophil count at diagnosis is one of the critical factors for selecting optimal treatment strategies. Fulminant aplastic anemia (FAA), defined as no neutrophils in the peripheral blood at diagnosis despite administration of G-CSF, has been known to be the most severe type of AA. Although patients diagnosed with FAA are at high risk for life-threatening infections, the optimal treatment has not been established. The aim of this study is to evaluate the efficacy of cord blood transplantation (CBT) for patients with FAA. Methods: We retrospectively reviewed 5 patients with FAA who underwent CBT at our institute from Aug 2007 to Sep 2015 consecutively. Results: Their median age was 52 years (range, 18-70). All patients met criteria of FAA and had no suitable HLAidentical related donor. Two patients developed bacterial sepsis before starting the conditioning regimen; one was successfully treated by controlled by antibiotics while another received granulocyte transfusion as well. The median duration from diagnosis to transplant was 32 (range, 20-74) days. All patients were conditioned with fludarabine, melphalan (80 mg/m2) and 4 Gy of TBI and were used TAC plus MMF for GVHD prophylaxis. ATG was not used in all patients. The median number of TNC and CD34+ cells were 2.16 (range, 1.74-4.39) × 107/kg and 1.00 (range, .39-1.52) × 105/ kg, respectively. All patients received single cord blood unit (CBU) with 2-mismatches (MM) in HLA-A, B, or DRB1 to the recipient (n = 3) and 1-MM (n = 2). Anti-HLA antibodies were screened before transplant to select proper CBU in 3 patients except for 2 patients who were transplanted before 2008. All but one patients achieved neutrophil and platelet engraftment. The median times to achieve neutrophil engraftment and platelet count >20 × 109/L were 15 (range, 10-18) days and 34 (range, 31-37) days, respectively. All patients who achieved engraftment had complete hematological recovery and became free from transfusion dependence, and they showed complete donor-type chimerism. One patient developed graft rejection and was later found to have antibody against mismatched HLA on CBU. The patient underwent a second CBT on day 33 after the first CBT, and obtained rapid engraftment. Among 4 evaluable patients who achieved primary engraftment, one developed grade II acute GVHD and the other one developed limited type of chronic GVHD. At the time of analysis, all 5 patients survived for a median of 54 (range, 12-105) months
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after transplant. All became free from immunosuppressant with high Karnofsky performance status (KPS) score with the median of 100% (range; 60-100%). Conclusion: This study showed that urgent CBT without ATGcontaining immunosuppressive therapy provides rapid engraftment and excellent survival rate with good KPS longterm in patients with FAA.
GRAFT PROCESSING
190 Cryopreservation of Autologous Peripheral Blood Stem Cells Using 10% DMSO Followed by Thaw and Wash Prior to Autologous Stem Cell Transplantation Ruthee-Lu Bayer 1, Laura Donahue 1, Vinita Gupta 1, Suhui He 2, Shreya Goyal 3, Jane Han 2, Wei Xu 2. 1 Hematology/ Oncology, Northwell Health, North Shore University Hospital, Lake Success, NY; 2 HPC Transplant Lab, Northwell Health, North Shore University Hospital, Manhasset, NY; 3 Medicine, North Shore University Hospital, Manhasset, NY Background and objectives: A number of published protocols evaluated the implications of post thaw washing of cryopreserved hematopoietic stem cells and showed favorable impact on DMSO related infusion reactions and minimal effect on hematopoietic recovery. However, this procedure has not been widely adopted due to concerns about potential stem cell loss. The aim of this study is to present an update on a single institution’s experience with cryopreservation of autologous PBSC using 10%DMSO and applying post thaw DMSO depletion. Materials and methods: Data were retrospectively collected on cryopreserved autologous PBSC products (HPC, Apheresis products) from 573 evaluable patients between 2004 and 2015. All products were cryopreserved in a rate controlled freezer for initial freezing, and then stored in liquid nitrogen freezers (temperature range −145 to −195 degree C). The frozen autologous PBSC product contains cryoprotectant mixture with 10% DMSO, 2% human albumin, and 33% plasma-lyte A. Thawing procedures were performed in a 37 degree C water bath. Washing procedures were performed by using COBE 2991 cell processor with cell processing set. DMSO concentration was reduced below .1% in the final product after three washes. All products underwent cell viability testing by Trypan Blue method. Results: Storage time ranged between one month and 7 years. The total ex-vivo handling time after removal from liquid nitrogen storage including the time frame for completion of each product’s thaw and wash was approximately 4 hours. Cell concentration range either in the cryopreserved product or thawed-washed product was between 20 × 10 6 /mL and 300 × 106/mL. Average MNC infusion dose was 7.89 × 108/kg and average CD34+ cell infusion dose was 10.83 × 106/kg. All products were sent for sterility testing. All culture results were negative. Percentage cell recovery was calculated. Mean recovery is 87%. Mean cell viability is 81.7% by Trypan Blue method. Mean ANC engraftment for 560 evaluable patients is 12.6 days. Mean platelet engraftment for 345 evaluable patients was 22.9 days. Mean final infusion volume is 329 ml (range 110-700 ml). There were no reported infusion reactions. Conclusion: Our data suggests that post thaw washing of cropreserved PBSC can be successfully performed without significantly jeopardizing hematopoietic recovery and with favorable impact on DMSO related toxicity.