Early Immune Reconstitution after Hematopoietic Stem Cell Transplantation for Adolescents and Adults with Sickle Cell Disease

Abstract Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p < 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p < 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.

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Pre-/Post-HSCT Imatinib Improves Survival of Childhood with BCR/ABL+ Acute and Chronic Leukemia

Blood ◽

10.1182/blood.v124.21.5248.5248 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5248-5248

Author(s):

Fuyu Pei ◽

Qi Li ◽

Wenfeng Xu ◽

Zhiyong Peng ◽

Xuedong Wu ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Myeloid Leukemia ◽

Myelogenous Leukemia ◽

Hematopoietic Stem ◽

Post Transplant ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source

Abstract Objective:To evaluate the effect of hematopoietic stem cell transplantation (HSCT) for children with leukemia in our center in recent years. Methods: We retrospectively analyzed data of 87 patients with leukemia underwent HSCT at a median age of 8 years from February 2006 to December 2013 in our center. The median follow-up time was 28 months (range, 2-96), the ratio of male to female patients was 59:28. Conditioning regimen included cyclophosphamide, fludarabine, busulfan with or without (w/o) thiotepa. Anti-thymocyte globulin and cytarabine were individually used for the patients with lymphoid leukemia and myeloid leukemia. GVHD prophylaxis included tacrolimus, mycophenolate mofetil w/o post-transplant cyclophosphamide. Median nucleated cells: 3.75 (1.16`7.56) × 107/Kg. Patients with BCR/ABL+ acute lymphoblastic leukemia (ALL) received imatinib before and after transplant over 6 months per each one. Twenty-six patients received transplant from sibling donors, 31 from haploidentical donor, 30 from unrelated donors; Status before transplant were grouped as CR1 (n= 57), CR 2 (n=13), CR 3 (n=1) and NR (n=16). Source of stem cells included PBSC in 40 cases, UCB in 3 cases, BM in 24 cases, BM+PBSC in 9 cases, and mixed stem cells (BM /PBSC+ UCB) in 11 cases. Results: The estimated 5-year overall survival (OS) was 56.8 ± 5.8% in total.Among them, OS was 54.3 ± 8.0% in 45 patients with ALL; 85.7 ± 13.2% in 8 patients with BCR/ABL+ALL; 48.6 ± 8.7% in 37 patients with BCR/ABL-ALL. 32.8 ± 15% in 29 patients with acute myeloid leukemia and 82.5 ± 11.3% in 13 patients with chronic myelogenous leukemia, respectively. Single factor analysis showed there was no significant difference for OS in comparison of BCR/ABL+ALL, BCR/ABL-ALL, AML and CML (P=0.057), but patients with BCR/ABL+ALL had higher OS compared to those with BCR/ABL-ALL (P=0.048) and to AML (P=0.040). In comparison of difference status before transplant, OS were 55.2 ± 11.6%, 54.9 ± 15.6%, 0,and 27.5 ± 11.6% in CR1, CR2, CR3 and NR, respectively (P=0.025). OS was higher in CR1 than NR (P=0.005). When comparing stem cell source, OS was 65.5 ± 8.5%, 0%, 41.7 ± 11.4%, 33.3 ± 15.7%, and 72 ± 17.8% in PBSC, unrelated CB (UCB), BM, BM+PBSC, and BM/PBSC+UCB transplants, respectively (P=0.003); PBSC transplant associated with higher OS than BM (P=0.049) and BM+PBSC (P=0.009); and BM/PBSC+UCB mixed transplant had highest OS (P=0.026). Multivariate analysis showed Risk factors for OS only remained stem cell source (P=0.046) and status before transplantation (P=0.048). the transplant types (P=0.023), and follow up time(P=0.017). Conclusion: Comparing with data reported in literature we have similar outcomesin total for childhood with leukemia. Use of imatinib pre-/post-transplant for patients with BCR/ABL+ALL conduces to the highest OS in current study. Stem cell sources and the status before transplant have a significant effect on OS. Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Blood ◽

10.1182/blood-2018-99-114841 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 970-970 ◽

Cited By ~ 2

Author(s):

Robert Chiesa ◽

Junfeng Wang ◽

Henric-Jan Blok ◽

Benedicte Neven ◽

Despina Moshous ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Engraftment Failure

Abstract Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

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Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors — a Retrospective Study By the EBMT Chronic Malignancies Working Party

Blood ◽

10.1182/blood-2018-99-114592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3465-3465

Author(s):

Aleksandar Radujkovic ◽

Henric-Jan Blok ◽

Arnon Nagler ◽

Francis Ayuketang Ayuk ◽

Jürgen Finke ◽

...

Keyword(s):

Stem Cell ◽

Prognostic Factors ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Blast Crisis ◽

Disease Status ◽

Advisory Committees ◽

Stem Cell Source ◽

Cell Source

Abstract Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

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Umbilical Cord Blood Transplantation after Graft Failure from a Previous Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2021-145287 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1785-1785

Author(s):

Fernanda Volt ◽

Annalisa Ruggeri ◽

Graziana Maria Scigliuolo ◽

Regis Peffault De Latour ◽

Marc Bierings ◽

...

Keyword(s):

Stem Cell ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Research Funding ◽

Malignant Diseases ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Support Research

Abstract Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). The incidence of GF after HCT using human leukocyte antigen (HLA) matched donors is lower than 5%; however, a higher incidence is observed when considering HLA mismatched donors or alternative donor sources and the use of reduced intensity conditioning (RIC) regimens. In the absence of autologous recovery, a second HCT is necessary to attempt preventing death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after a GF with different types of donor sources report a wide range of overall survival (OS) and transplant related mortality (TRM), however studies including a large number of patients receiving a second transplant with umbilical cord blood (UCB) are scarce. In this retrospective study, using registry data from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT), we report the outcomes of 247 umbilical cord blood transplants (UCBT) performed after GF following a previous HCT. Data were analyzed separately for patients with malignant (n=141) and non-malignant diseases (n=106). UCB was the most frequent stem cell source that resulted in GF (65.0% and 68.9%, for malignant and non-malignant diseases, respectively), and most of the reported GF occurred within 100 days after HCT (92.3% and 85.9%). The most frequent diagnosis in malignant diseases was acute leukemia (64.5%), mainly acute myeloid leukemia (AML). In non-malignant diseases, the diagnoses most often reported were inborn error of metabolism (IEM) (37.7%), followed by bone marrow failure syndrome (BMF) (34.0%) and primary immune deficiency (PID) (21.7%). In malignant and non-malignant diseases, we observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% CI 51.4- 67.9%) and 60.4% (95% CI 51.7- 70.6%), in a median time of 23 and 24 days, and a 3-year OS of 28.9% (95% CI 21.8- 37.3%) and 49.1% (95% CI 39.5- 58.8%). TRM at 100 days and at 3 years for malignant diseases was 39.9% (95%CI 32.5 - 49.1%), and 57.5% (95%CI 49.4 - 66.8%). In multivariate analyses, none of the characteristics were statistically significantly associated with engraftment or overall survival. Although survival for patients requiring a second transplant is not optimal, UCB remains a valid life-saving option for some patients with GF as it is an immediately available source of stem cells in severely ill patients. The most appropriate stem cell source for salvage transplants remains controversial, as it depends on multiple factors including center choice, donor availability, underlying disease and existing comorbidities. Disclosures Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

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Impact of COVID-19 Pandemic on Global Unrelated Stem Cell Donations in 2020 - Report from World Marrow Donor Association

Blood ◽

10.1182/blood-2021-150013 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3887-3887

Author(s):

Monique Jöris ◽

Stefanie Bernas ◽

Alexander H. Schmidt ◽

Jay Feinberg ◽

Nicoletta Sacchi ◽

...

Keyword(s):

Growth Rate ◽

Stem Cell ◽

Cord Blood ◽

Hematopoietic Stem Cell ◽

Research Funding ◽

Systems Science ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Cell Source ◽

Privately Held

Abstract Introduction: World Marrow Donor Association (WMDA) promotes global collaboration for the benefit of stem cell donors and transplant patients. WMDA activities include recording the number of unrelated hematopoietic stem cell (HSC) donations globally. Because the COVID-19 pandemic also has an impact on the treatment of patients with other diseases, we hypothesise that it also impacted the practice of unrelated hematopoietic stem cell transplantation (HSCT). We used the 2020 WMDA data to examine the trends in unrelated HSC donations during the COVID-19 pandemic globally, per continent and per country/region. Methods: Donor registries (DRs) and cord blood banks (CBBs) from 61 countries participated in the 2020 survey, compared to 59 countries in the 2019. Slight differences in participation between the data sets of 2019 and 2020 do not explain the trends we observe in HSC donations. Country/region-specific COVID-19 data on cases and deaths were obtained from the data repository operated by the Johns Hopkins University Center for Systems Science and Engineering(https://github.com/CSSEGISandData/COVID-19, accessed July 12, 2021); and population data were retrieved from the Worldometer website(https://www.worldometers.info/, accessed July 12, 2021). Results: HSC donations from unrelated donors (peripheral blood stem cells (PBSC) and bone marrow (BM)) decreased from 20,330 in 2019 to 19,623 in 2020 (-3.5%), compared to an average annual growth rate of 3.9% from 2015 to 2019 (figure 1). The 3.5% decrease is composed of a 29.0% decrease for BM and a 2.6% increase for PBSC, resulting in a drop in the BM share of unrelated HSC donations from 19.3% in 2019 to 14.2% in 2020. The number of cord blood unit (CBU) shipments globally decreased with 3.5% from 2,851 to 2,750. The percentage of national use of HSC products (PBSC and BM) increased from 51.2% to 53.5%. When considering the continent on which the patient is transplanted (table 1), the change rate of use of HSC donated products in 2020 vs. 2019 ranged from -28.0% in South America to +18.2% in Africa. In absolute numbers, the largest decrease of HSC donations occurred for patients in Asia (n=-485) followed by Europe (n=-205), and the largest increase occurred in North America (n=+88) followed by Oceania (n=+25). The share of HSC donations requiring intercontinental transport decreased from 24.6% in 2019 to 21.9% in 2020. In terms of the country/region of transplant (table 2), the largest percentage decrease occurred in Colombia (-90,5%) followed by Russia (-55,5%). In absolute numbers, the largest decrease occurred in Turkey (-147), with Japan following (-128, although Japan saw an increase of CBU use of +106). The highest growth rate was observed in Iran (+28,7%), followed by South Africa (+28,2%). In absolute figures, the greatest increase occurred in Italy (+67). The two countries receiving the largest HSC donation numbers showed no major changes versus the previous year: USA: +0.6% (although a decrease for CBU of -21,0% was observed) and Germany: -2.4%. We did not find any significant correlation between the numbers of COVID-19 cases or COVID-19-related deaths per 1 million inhabitants with the HSC donation numbers (Spearman's r=0.05 for cases and =0.08 for deaths). Discussion: The decline in the number of unrelated HSC donations in 2020 suggests an impact of the COVID-19 pandemic on HSC donation and unrelated HSCT. The significant decrease in BM collections and intercontinental/cross-border shipments can be explained by logistically complex processes, as well the increased risk to the donor of being exposed to an operative procedure. CBU as a stem cell source potentially circumvents these logistical complications. However, on a global scale our data does not show increased use of CBU suggesting that decisions to use CBU as a stem cell source did not change in the pandemic . We were unable to demonstrate a correlation between country/region-specific severity of the pandemic and HSC donation numbers. We suspect this is due to the data quality of reported number of COVID-19 cases and COVID-19-related deaths. Also, we did not gather monthly data and therefore could not specify pandemic waves. In conclusion, we would like to point out the fact that global exchanges of HSC products continued and only decreased slightly is an extraordinary achievement of DRs, CBBs and their donors and is a testament to the importance of international collaborations in the WMDA. Figure 1 Figure 1. Disclosures Devine: Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Be the Match: Current Employment. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

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Features of Herpesviruses (CMV, EBV, HHV6) Infections and Immune Reconstitution after Allogeneic Stem Cell Transplantation (allo-SCT) Using Alternative Donors: Comparison Between Matched Unrelated Donors (MUD) and Cord Blood (CB) as Stem Cell Source.

Blood ◽

10.1182/blood.v112.11.1148.1148 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1148-1148

Author(s):

Patrice Chevallier ◽

Thierry Guillaume ◽

Lucie Planche ◽

Imen Hebia-Fellah ◽

Celine Bressollette- Bodin ◽

...

Keyword(s):

Stem Cells ◽

Multivariate Analysis ◽

Risk Factor ◽

Stem Cell ◽

Immune Reconstitution ◽

Cmv Infection ◽

Post Transplant ◽

Stem Cell Source ◽

Increased Risk ◽

Cell Source

Abstract Features of herpesvirus infections (CMV, EBV, HHV6) and immune reconstitution after CB transplantation (CBT) has been little studied thus far. Here, we report a retrospective comparison between 15 consecutive adult CBT recipients (CBT group) and 40 patients who received allo-SCT using MUD (MUD group). The 2 groups had no significant differences in terms of gender, age, disease features, transplant characteristics (CB: meloablative conditioning 46% vs. MUD: 35%; P=NS). However, in vivo T-cell depletion was more frequently used in the MUD group (62.5% vs 6%, P=0.0002). As expected, median number of CD34+ stem cells infused was significantly lower in the CBT group (0.15 10*6/Kg vs 8.2 10*6/Kg, P<0.0001). Both groups were stringently monitored through CMV, EBV, and HHV6 DNA quantifications in the blood prior to allo-SCT, and then monthly up to 9 months after allo-SCT. An active infection was defined by the presence of at least one positive PCR during the follow-up period (detection limit at 2 Log/mL blood). Of note, both groups experienced similar incidences of acute grade 2–4 GVHD, chronic GVHD and disease relapses. Immune reconstitution (T4, T8, B and NK lymphocytes ) at 3, 6 and 9 months post transplant was investigated and compared between the two groups. In this cohort, 22, 29 and 29 patients experienced at least one positive PCR for CMV, EBV and HHV6 respectively, with the % of positive samples for CMV, EBV and HHV6 being 14%, 16% and 27% respectively. No correlation in term of incidence could be found between the 3 viruses. The incidence of CMV infection did not differ between the two groups, and the univariate analysis could not identify a significant risk factor for CMV infection. However, HHV6 positivity was significantly higher in the CBT group as compared to the MUD group (CBT: 80%; MUD: 42.5%; P <0.0001). HHV6 viral loads were also significantly higher in the CBT group (mean, 3.98±0.86 Log/mL, vs. 3.19±0.82 Log/ mL, P<0.0001). In multivariate analysis, the use of CB cells as stem cell source in combination with a myeloablative conditioning regimen appeared to be independent parameters associated with an increased risk of HHV6 infection (OR=5.4, 95%CI, 1.2- 23.0; P=0.02 and OR=3.5, 95%CI, 1.03–12.05, P= 0.04, respectively). Interestingly, the occurrence of HHV6 infection translated towards delayed engraftment (median time to neutrophils and platelets recovery: 37 vs 16 d.; P=0.03; and 98 vs. 12 d.; P=0.0001). In sharp contrast with HHV6, EBV infections were less frequent in the CBT group as compared to the MUD group (27% vs. 62%; P<0.0001). In multivariate analysis, the use of a MUD for allo-SCT, was the strongest risk factor associated with an increased EBV infection (OR=0.31, 95%CI, 0.07–1.37; P=0.04). At 3, 6 and 9 months post transplant, median B lymphocytes count in the CBT group was significantly higher (P=0.03; P=0.003; P=0.01) whereas median T8 lymphocytes count was significantly lower (P=0.05; P=0.01; P=0.09). We also noticed that median NK lymphocytes count in the CBT group was significantly higher at 3 months (P=0.0006) but this was not linked to HHV6 infections. Overall, these results show that after allo-SCT, the pattern of HHV6 and EBV infections is dependant on the source of stem cells. A specific relationship is suggested between HHV6 PCR positivity and the use of CB cells. In addition to a potential delayed engraftment, the clinical implications of the latter finding need to be refined and prospective screening and antiviral prophylaxis approaches are warranted in the context of CBT.

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HLA-Matched Related Hematopoietic Stem Cell Transplantation in Adolescents and Adults with Sickle Cell Disease: Comparison of Myeloablative Versus Non Myeloablative Approaches. Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire

Blood ◽

10.1182/blood-2021-147052 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 909-909

Author(s):

Nathalie Dhedin ◽

Florian Chevillon ◽

Martin Castelle ◽

Virginie Lavoipierre ◽

Jean-Hugues Dalle ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Conditioning Regimen ◽

Group Versus ◽

Hematopoietic Stem ◽

Post Transplant ◽

Donor Chimerism ◽

Adolescents And Adults ◽

The One

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) allowing a SCD-free survival over 95% among children with matched HLA-identical donor (Gluckman E. Blood, 2017; Bernaudin F. Haematologica, 2020). In adults, myeloablative HSCT is associated with more graft-versus host disease (GVHD) and higher toxicity (Cappelli B. Haematologica, 2019). More recent approaches using non myeloablative (NMA) conditioning regimen (3 gray (Gy) total body irradiation (TBI) plus alemtuzumab) followed by HLA-identical peripheral blood stem cells (PBSC) and post-transplant sirolimus appear safe in adults (Hsieh MM. JAMA, 2014), but incidence of graft failure might be higher than the one reported after myeloablative conditioning (MAC) (Alzahrani M. Br J Haematol, 2021). Here, we compare outcomes after MAC or NMA conditioning regimens in patients over 15 years old transplanted from a matched related donor (MRD). Patients and methods All consecutive patients transplanted for SCD from a MRD from January 2015 to October 2020 were eligible if they were over 15 years old and received a busulfan-based MAC conditioning regimen or a NMA conditioning regimen. Chimerism was studied by analyzing various polymorphisms after polymerase chain reaction (PCR) amplification of DNA obtained from whole blood cells. Rejection was defined as donor chimerism <5%. Event-free survival (EFS) was defined as the probability to be alive with blood donor chimerism over 20%. Results Thirty-four patients were included: 20 in the MAC and 14 in the NMA groups. Median age at transplant was 17 years (range 15-46) without difference between groups. Forty four percent of patients had a history of cerebral vasculopathy, 79% of recurrent vaso-occlusive crises and 76% of acute chest syndrome. ABO major incompatibility was present in 15% of patients. There was no difference in patient characteristics according to the conditioning regimen group except for pre-transplant cerebral vasculopathy, more frequently reported in the MAC group: 70% versus 6% in the NMA group (p<0.001). In the MAC group, conditioning regimen associated busulfan (12.8 mg/kg IV), cyclophosphamide (N=17) or fludarabine (N= 3) and anti-thymoglobulin (ATG, mostly 20mg/kg). Stem cell source was bone marrow and post-transplant immunosuppression combined cyclosporine and mycophenolate or methotrexate. In the NMA group, conditioning regimen associated 3Gy TBI and alemtuzumab (1mg/kg), followed by PBSC and post-transplant sirolimus. All patients engrafted and no secondary graft failure was observed. One MAC group patient died from GVHD. The 2-year overall and EFS were 95% (CI 95%: 85.9-100) in the MAC group (median follow-up of 39 months (range 8-63)) and 100% (CI 95%: 100-100) in the NMA group (median follow-up of 17 months (range 9-39)). Incidence of grade II-IV acute GVHD was 0% in the NMA group versus 20% in the MAC group (p=0.12). Incidence of chronic GVHD was 0% in the NMA group versus 25% in the MAC group (p=0.06). From the 27 patients with follow-up>12 months, 17/17 discontinued immunosuppressive therapy in the MAC group versus 8/10 in the NMA group. Hematopoietic recovery was faster in the NMA group with less platelet and red blood cell units transfused (Table). Throughout the follow-up, median donor chimerism was higher after MAC transplantation than after NMA transplantation: 98% (range 69-100) and 86 % (range 50-97) respectively at 1 year (p=0.017). Donor chimerism remained above 50% throughout the follow-up in all patients except 1 of the NMA group who displayed stable chimerism between 40 and 50%. All patients achieved HbS level close to the one of their donors. There was no difference between the 2 groups regarding occurrence of infections. MAC transplant was more often associated with hypertension, neurological complications, severe mucositis and need of enteral or parenteral nutrition. Moreover, duration of hospitalization was longer in MAC group: 54 days (range 39-192) versus 35 days in the NMA group (range 21-52) (p<0.001) (table). Conclusion In this series of adolescents and adults transplanted for SCD, the survival without SCD was excellent with a faster hematological recovery and a lower toxicity after NMA HSCT. Longer follow-up is required to confirm stable mixed donor chimerism and the cure of SCD after NMA approach. Figure 1 Figure 1. Disclosures Joseph: bluebird bio: Consultancy. Boissel: Servier: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Pondarré: ADDMEDICA: Honoraria.

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Long-Term Experience with Large Granular Lymphocytic Leukemia Evolving after Solid Organ and Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-130167 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1226-1226

Author(s):

Hassan Awada ◽

Reda Z. Mahfouz ◽

Jibran Durrani ◽

Ashwin Kishtagari ◽

Deepa Jagadeesh ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Viral Infections ◽

De Novo ◽

Post Transplantation ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Post Transplant ◽

Stat3 Mutations

T-cell large granular lymphocyte leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGLL mainly manifest in elderly and is associated with autoimmune diseases including rheumatoid arthritis (RA), B cell dyscrasias, non-hematologic cancers and immunodeficiency (e.g., hypogammaglobulinemia). LGL manifestations often resemble reactive immune processes leading to the dilemmas that LGLs act like CTL expansion during viral infections (for example EBV associated infectious mononucleosis). While studying a cohort of 246 adult patients with T-LGLL seen at Cleveland Clinic over the past 10 years, we encountered 15 cases of overt T-LGLL following transplantation of solid organs (SOT; n=8) and hematopoietic stem cell transplantation (HSCT; n=7). Although early studies reported on the occurrence of LGL post-transplant, these studies focused on the analysis of oligoclonality skewed reactive CTL responses rather than frank T-LGLL. We aimed to characterize post-transplantation T-LGLL in SOT and HSCT simultaneously and compare them to a control group of 231 de novo T-LGLL (cases with no history of SOT or HSCT). To characterize an unambiguous "WHO-defined T-LGLL" we applied stringent and uniform criteria. All cases were diagnosed if 3 out of 4 criteria were fulfilled, including: 1) LGL count >500/µL in blood for more than 6 months; 2) abnormal CTLs expressing CD3, CD8 and CD57 by flow cytometry; 3) preferential usage of a TCR Vβ family by flow cytometry; 4) TCR gene rearrangement by PCR. In addition, targeted deep sequencing for STAT3 mutations was performed and charts of bone marrow biopsies were reviewed to exclude other possible conditions. Diagnosis was made 0.2-27 yrs post-transplantation (median: 4 yrs). At the time of T-LGLL diagnosis, relative lymphocytosis (15-91%), T lymphocytosis (49-99%) and elevated absolute LGL counts (>500 /µL; 93%) were also seen. Post-transplantation T-LGLL were significantly younger than de novo T-LGLL, (median age: 48 vs. 61 yr; P<.0001). Sixty% of post-transplantation T-LGLL patients were males. Fifteen% of patients had more cytogenetic abnormalities compared to de novo T-LGLL, had a lower absolute LGL count (median: 4.5 vs. 8.5 k/µL) and had less frequent neutropenia, thrombocytopenia and anemia (27 vs. 43%, 33 vs. 35% and 20% vs. 55%; P=.01). TCR Vb analysis identified clonal expansion of ≥1 of the Vb proteins in 60% (n=9) of the patients; the remaining 40% (n=6) of the cases had either a clonal process involving a Vb protein not tested in the panel (20%; n=3) or no clear expansion (20%; n=3). Signs of rejection were observed in 20% (n=3/15) and GvHD in 13% (n=2/15) of the patients. Post-transplantation, 27% of cases presented with neutropenia (absolute neutrophil count <1.5 x109/L; n=4), 33% with thrombocytopenia (platelet count <150 x109/L; n=5) and 25% with anemia (hemoglobin <10 g/dL; n=3). T-LGLL evolved in 10 patients (67%; 10/15) despite IST including cyclosporine (n=5), tacrolimus (n=4), mycophenolate mofetil (n=5), cyclophosphamide (n=1), anti-thymocyte globulin (n=1), and corticosteroids (n=6). Lymphadenopathy and splenomegaly were seen in 13% (n=2) and 33% (n=5) of the patients. Other conditions observed were MGUS (20%; n=3) and RA (7%; n=1). Conventional cytogenetic showed normal karyotype in 89% (n=11, tested individuals 13/15). Somatic STAT3 mutations were identified in 2 patients. Sixty% of cases (n=9) were seropositive for EBV when tested at different time points after transplant. Similarly, 53% (n=8) were seropositive for CMV, of which, 5 were positive post-transplantation and 3 pre-/post-transplantation. The complexity of T-LGLL expansion post-transplantation might be due to several mechanisms including active viral infections, latent oncogenic viral reactivation and graft allo-antigenic stimulation. However, in our cohort graft rejection or GvHD was encountered in a few patients (2 allo-HSCT recipients). Autoimmune conditions were present in 50% of SOT recipients (n=4/ 8, including RA, ulcerative colitis, systemic lupus erythematosus). Some of our patients also had low immunoglobulin levels. Overt EBV (post-transplant lymphoproliferative disorder) and CMV reactivation was diagnosed in only 27% (4/15) of the patients. In sum we report the long term follow up of a cohort of T-LGLL and emphasize the expansion of T-LGLL post-transplant highlighting the difficulty in assigning one unique origin of LGLL. Disclosures Hill: Genentech: Consultancy, Research Funding; Takeda: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria. Majhail:Atara Bio: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Incyte: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

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Lower Hematopoietic Progenitor Cell Counts and Yields at Subsequent Donations Is Influenced By a Shorter Inter-Donation Interval between the First and Subsequent Mobilizations

Blood ◽

10.1182/blood-2019-123492 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1962-1962

Author(s):

Sandhya R. Panch ◽

Brent R. Logan ◽

Jennifer A. Sees ◽

Bipin N. Savani ◽

Nirali N. Shah ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Time Interval ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Peripheral Blood Cd34 ◽

Cell Counts ◽

Cd34 Cells

Introduction: Approximately 7% of unrelated hematopoietic stem cell (HSC) donors are asked to donate a subsequent time to the same or different recipient. In a recent large CIBMTR study of second time donors, Stroncek et al. incidentally found that second peripheral blood stem cell (PBSC) collections had lower total CD34+ cells, CD34+ cells per liter of whole blood processed, and CD34+ cells per kg donor weight. Based on smaller studies, the time between the two independent PBSC donations (inter-donation interval) as well as donor sex, race and baseline lymphocyte counts appear to influence CD34+ cell yields at subsequent donations. Our objective was to retrospectively evaluate factors contributory to CD34+ cell yields at subsequent PBSC donation amongst NMDP donors. Methods. The study population consisted of filgrastim (G-CSF) mobilized PBSC donors through the NMDP/CIBMTR between 2006 and 2017, with a subsequent donation of the same product. evaluated the impact of inter-donation interval, donor demographics (age, BMI, race, sex, G-CSF dose, year of procedure, need for central line) and changes in complete blood counts (CBC), on the CD34+ cell yields/liter (x106/L) of blood processed at second donation and pre-apheresis (Day 5) peripheral blood CD34+ cell counts/liter (x106/L) at second donation. Linear regression was used to model log cell yields as a function of donor and collection related variables, time between donations, and changes in baseline values from first to second donation. Stepwise model building, along with interactions among significant variables were assessed. The Pearson chi-square test or the Kruskal-Wallis test compared discrete variables or continuous variables, respectively. For multivariate analysis, a significance level of 0.01 was used due to the large number of variables considered. Results: Among 513 PBSC donors who subsequently donated a second PBSC product, clinically relevant decreases in values at the second donation were observed in pre-apheresis CD34+ cells (73.9 vs. 68.6; p=0.03), CD34+cells/L blood processed (32.2 vs. 30.1; p=0.06), and total final CD34+ cell count (x106) (608 vs. 556; p=0.02). Median time interval between first and second PBSC donations was 11.7 months (range: 0.3-128.1). Using the median pre-apheresis peripheral blood CD34+ cell counts from donation 1 as the cut-off for high versus low mobilizers, we found that individuals who were likely to be high or low mobilizers at first donation were also likely to be high or low mobilizers at second donation, respectively (Table 1). This was independent of the inter-donation interval. In multivariate analyses, those with an inter-donation interval of >12 months, demonstrated higher CD34+cells/L blood processed compared to donors donating within a year (mean ratio 1.15, p<0.0001). Change in donor BMI was also a predictor for PBSC yields. If donor BMI decreased at second donation, so did the CD34+cells/L blood processed (0.74, p <0.0001). An average G-CSF dose above 960mcg was also associated with an increase in CD34+cells/L blood processed compared to donors who received less than 960mcg (1.04, p=0.005). (Table 2A). Pre-apheresis peripheral blood CD34+ cells on Day 5 of second donation were also affected by the inter-donation interval, with higher cell counts associated with a longer time interval (>12 months) between donations (1.23, p<0.0001). Further, independent of the inter-donation interval, GCSF doses greater than 960mcg per day associated with higher pre-apheresis CD34+ cells at second donation (1.26, p<0.0001); as was a higher baseline WBC count (>6.9) (1.3, p<0.0001) (Table 2B). Conclusions: In this large retrospective study of second time unrelated PBSC donors, a longer inter-donation interval was confirmed to be associated with better PBSC mobilization and collection. Given hematopoietic stem cell cycling times of 9-12 months in humans, where possible, repeat donors may be chosen based on these intervals to optimize PBSC yields. Changes in BMI are also to be considered while recruiting repeat donors. Some of these parameters may be improved marginally by increasing G-CSF dose within permissible limits. In most instances, however, sub-optimal mobilizers at first donation appear to donate suboptimal numbers of HSC at their subsequent donation. Disclosures Pulsipher: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Bellicum: Consultancy; Amgen: Other: Lecture; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Honoraria. Shaw:Therakos: Other: Speaker Engagement.

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Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2019-129872 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4496-4496 ◽

Cited By ~ 1

Author(s):

Luke Eastburg ◽

David A. Russler-Germain ◽

Ramzi Abboud ◽

Peter Westervelt ◽

John F. DiPersio ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Early Mortality ◽

Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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