Optimal Outcomes after Second Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Recurrence Following Graft Failure/Rejection of the First Graft

Abstract Introduction. Graft failure/rejection (GF/R) is a significant complication following HCT in non- malignant diseases. The risk of GF/R in patients with thalassemia is particularly high as a consequence of alloimmunization related to transfusion exposures and hyperproliferative marrow. Although the GF/R rate after myeloablative HLA-matched sibling transplants for thalassemia has been reduced, its incidence still remains high following alternative donor transplantation. Typically, GF/R after HCT for thalassemia is accompanied by autologous hematopoietic recovery, but occasionally patients develop GF with prolonged marrow aplasia. Given great variability in conditioning regimens and outcomes after second HCT for GF/R, it is important to develop a uniform treatment approach to patients receiving second transplantation for GF/R with autologous recovery. Methods. We report on 21 consecutive patients with median age of 9 years (range, 4-24 years) with thalassemia who underwent a second HCT for GF/R with autologous recovery. Ten patients had primary and 11 patients secondary GF/R following the first BMT. Median time to second transplant was 41 months (range, 8- 204). Treatment protocol consisted of preconditioning cytoreduction/immunosuppression with hydroxyurea (30 mg/kg/day) and azathioprine (3 mg/kg/day) from day −45 pre-transplant, and fludarabine (30 mg/m2/day) from day −16 through day −12. Conditioning regimen included oral or intravenous (i.v.) busulfan, thiotepa 10 mg/kg/day, cyclophosphamide 200 mg/kg total dose, and thymoglobulin 12.5-10 mg/kg total dose. Cyclosporine, methylprednisolone and methotrexate were given for GVHD prophylaxis. All but 4 patients received second HCT from the same donor. Thirteen patients received bone marrow (BM), and 8 patients PBSC. One patient was in class 1, 7 patients in class 2, and 13 patients in class 3 of risk. Most patients had moderately severe iron overload with median serum ferritin of 2692 ng/ml (range, 500-10126 ng/ml). The median liver fibrosis score 1 (range 0-5). Results. All but 1 patient achieved sustained engraftment with a 5 year overall and disease-free survival (DFS) of 85% (95% CI, 59-95%). DFS was 92% (95% CI, 54-99%) in patients receiving BM and 75% (95% CI, 32-93%) in those given PBSC, although the difference was not statistically significant (p=0.27) (Figure 1). One patient had primary GF with the cumulative incidence of 5% (95% CI, 0-13%). The incidence of grade 2-4 acute GVHD was 50% (95% CI, 0-75%) in the PBSC and 8 % (95% CI, 0-24%) in the BM group (p=0.025). Respective incidences of moderate to severe chronic GVHD were 43% (95% CI, 0-70%) and 0% (p=0.012). The high incidence of both acute and chronic GVHD after PBSC transplantation prompted us to abandon its use for second transplantation since 2006. At the time of survival analysis, 18 patients were alive, with median follow-up duration of 10 years (range, 1.2-12.8 years). At present all patients are off immunosuppressive medication. There were 3 deaths due to pneumonia, postsplenectomy sepsis and rejection with cerebral bleeding. The most frequently observed toxicities were grade 2 elevations in AST and ALT, followed by grade 2 oral mucositis. Few patients experienced grade 3 liver and gut toxicities. None of the patients developed liver VOD. Three patients had pneumonia, and 4 patients developed grade 2-3 late onset BK virus -related hemorrhagic cystitis. None of the patients developed lymphoproliferative disorder. Conclusions. We demonstrate the excellent DFS in patients with thalassemia treated with second transplantation for GF/R following the first graft. Importantly, the intensified treatment protocol was not associated with increased nonhematological toxicity, even though most patients suffer from pre-existing organ damage due to iron overload and/or hepatitis. This study clearly showed that the same donor could be successfully used for second transplantation in these patients. Due to significantly high incidence of both acute and chronic GVHD after PBSC, bone marrow graft is preferred source for second transplantation in patients with thalassemia. Disclosures No relevant conflicts of interest to declare.

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Transplant Outcomes in High-Risk (Class 3) Patients with Thalassemia Treated with a Modified Protocol Are Equivalent to Low/Intermediate-Risk (Class 1/Class 2) Patients

Blood ◽

10.1182/blood.v126.23.620.620 ◽

2015 ◽

Vol 126 (23) ◽

pp. 620-620 ◽

Cited By ~ 2

Author(s):

Javid Gaziev ◽

Gioia De Angelis ◽

Antonella Isgro ◽

Pietro Sodani ◽

Marco Marziali ◽

...

Keyword(s):

Iron Overload ◽

Total Dose ◽

Graft Failure ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Free Survival ◽

Risk Class ◽

Transfusion Independence ◽

Class 1

Abstract Introduction. Bone marrow transplantation (BMT) for class 3 patients with thalassemia is challenging due to high rates of graft rejection and transplant-related mortality. Since the first studies of BMT in the late 1980s, a number of conditioning regimens have been designed to improve outcomes, but with suboptimal results. Here we report the outcome of transplantation in class 3 patients using a modified protocol. Methods. Between July 2004 and May 2015, 68 consecutive patients of 5-16.6 years of age with class 3 thalassemia received their first BMT from HLA-identical sibling donors. Of these patients, 26 were prepared for transplantation with the original protocol (Protocol 26) and 42 patients (since February 2007) with the modified protocol. The original protocol started with a preconditioning phase during which patients received hydroxyurea (30 mg/kg/day) and azathioprine (3 mg/kg/day) from day −45 pre-transplant, and fludarabine (20 mg/m2/day) from day −16 through day −12. Conditioning regimen included oral or intravenous (i.v.) busulfan and cyclophosphamide 160 mg/kg total dose. The modified protocol started with the same preconditioning phase except with 30 mg/m2/day of fludarabine. The conditioning regimen comprised i.v. Bu, thiotepa 10 mg/kg/day, and cyclophosphamide 160 mg/kg total dose. We compared the outcomes between these two groups.The two groups showed similar patient demographics. Patients in both groups had moderately severe iron overload, as evidenced by high median serum ferritin and liver iron concentrations. The median liver fibrosis score in the original and modified protocol-treated patients was 2 (range, 1-4) and 1 (range 1-5) (p=0.22), respectively. Results. At day 0, the degree of cytoreduction (lymphopenia, neuthropenia and thrombocytopenia) achieved by the modified protocol was significantly higher than the original protocol. Overall, 22 (84.6%) original protocol-treated patients and all 42 modified protocol-treated patients showed sustained engraftment. Platelet and neutrophil engraftment kinetics were similar between groups. All patients with sustained engraftment achieved RBC transfusion independence, with a median time to transfusion independence of 19 days (range, 0-88) with original protocol and 20 days (range, 0-85) with modified protocol. Among original protocol-treated patients, two experienced primary graft failure and two experienced secondary graft failure. No modified protocol-treated patients exhibited graft failure. Competing-risk analysis showed a significantly higher cumulative incidence of graft failure with original protocol (15%) compared to modified protocol (0%) (p=0.010). At the time of survival analysis, 22 original protocol -treated patients (85%) and 39 modified protocol-treated patients (93%) were alive, with median follow-up durations of 8.8 years (range, 8.2-10.8 years) and 3.5 years (range, 0.4-8 years), respectively. The 5-year probabilities of thalassemia-free survival were 93% with modified protocol and 73% with original protocol (p=0.032). The respective probabilities of overall survival were 93% and 85% (p=0.37). The incidence of grade 2-4 acute GVHD was 46% in the original and 24% in the modified group (p=0.066). Respective incidences of chronic GVHD were 12% and 5%. At present all patients are off immunosuppressive medication. There were 4 deaths in the original group and 3 deaths in the modified group. The most frequently observed toxicities were grade 2 elevations in AST and ALT, followed by grade 2 oral mucositis and diarrhea with similar rates in both groups. Few patients experienced grade 3 liver and gut toxicities in either groups with similar rates. There was no difference in the rate of infectious complications between the two groups. One patient in each group developed moderate hepatic VOD, both of which resolved with supportive care Conclusions. Modified treatment protocol effectively and safely prevented graft failure/rejection and significantly improved thalassemia-free survival of class 3 patients. Importantly, the treatment intensification was not associated with increased nonhematological toxicity, even though these patients suffer from pre-existing organ damage due to iron overload and/or hepatitis. Modified protocol makes allogeneic BMT accessible to all class 3 younger patients with results equal to class 1 or class 2 patients with thalassemia. Disclosures No relevant conflicts of interest to declare.

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Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽

10.1182/blood-2020-142397 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-47

Author(s):

Josu de la Fuente ◽

Dirk-Jan Eikema ◽

Paul Bosman ◽

Robert F Wynn ◽

Miguel Díaz ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Response To Treatment ◽

Variable Response ◽

Advisory Committees ◽

Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Long-Term Outcome After Matched Allogeneic Hematopoietic Stem Cell Transplantation for Fanconi Anemia On Behalf of the FA Committee of the Severe Aplastic Anemia Working Party (SAA WP) and the Pediatric Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v118.21.325.325 ◽

2011 ◽

Vol 118 (21) ◽

pp. 325-325

Author(s):

Régis Peffault de Latour ◽

Raphael Porcher ◽

Jean-Hugues Dalle ◽

Mahmoud Aljurf ◽

Elisabeth T Korthof ◽

...

Keyword(s):

Risk Factors ◽

Stem Cells ◽

Bone Marrow ◽

Clonal Evolution ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Working Party ◽

Secondary Malignancies ◽

Hematopoietic Stem

Abstract Abstract 325 Background: Fanconi anemia (FA) is a rare, genetically and phenotypically heterogeneous inherited disorder. The natural history of FA is characterized by progressive bone marrow failure (BMF) and an increased risk for development of malignancies. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is considered the treatment of choice for FA patients with BMF or clonal evolution (acute myeloid leukemia or MDS). Most deaths related to HSCT occur within the first year after HSCT. Risk factors for the development of malignancies after HSCT are still incompletely defined in patients with FA. Our objectives were to evaluate risk factors for late mortality and secondary malignancies in 1-year survivors in the largest cohort of FA patients post-HSCT ever studied, so far. Patients and methods: Patients with FA reported to the European Blood and Marrow Transplant (EBMT) Group alive 1 year after a matched allogeneic HSCT were reviewed. Donor and recipient were matched if HLA A and B were identical at the generic level and HLA DRB1 at the allelic level. Cord blood as source of stem cells was excluded because of a few number of FA patients with very long-term follow-up (FU). Data was analyzed using proportional hazards and proportional cause-specific hazards models. Results: Between May 1972 and January 2009, 789 patients with FA who underwent first SCT were reported to the EBMT registry. 509 patients were alive 1 year post-HSCT and were included in the present study. 273 patients were male. Median age at HSCT was 9 years (range, 10 months to 44 years). The majority (77%) of patients had received stem cells from a related donor and bone marrow (80%) was the main source of stem cells. Irradiation was used as part of the conditioning regimen in 27% of the cohort, while fludarabine-based regimen was used in 29%. T-cell depletion (ex vivo and in vivo) was used in 41%. In January 2010, 15% (n=74) of the patients had died. Median age at death was 19 years. With a median FU of 6 years (1 to 28 years), the probability for survival after HSCT was 49% at 20 years (95%CI 38–65). The main causes of death were secondary malignancies in 52% of cases and treatment related mortality in 21%. Solid tumor represented 89% of the secondary malignancies. Cumulative incidence of death and secondary cancer are presented in Figure 1. A worse survival was observed in patients transplanted before year 2000 (Hazard ratio - HR: 2.24; 95%CI 1.06–4.71; p=0.034), in those transplanted because of clonal evolution (acute myeloid leukemia or MDS) (HR: 3.88; 95%CI 2.03–7.41; p<0.0001), in patients older than 10 years at SCT (HR: 2.00; 95%CI 1.26–3.18; p<0.004), and in patients transplanted more than a year after FA diagnosis (HR: 1.98; 95%CI 1.10–3.54; p=0.02). Without taking into account transplant period, HSCT after the age of 10 (HR 1.88 [1.17 to 3.03], P=0.009), clonal evolution before HSCT (HR 3.31 [1.72 to 6.39], P=0.0004) and previous chronic GVHD (HR 2.72 [1.65 to 4.46], P<0.0001) were associated with decreased survival. After adjustment for these factors, patients transplanted before 2000 still showed a worse survival (HR 2.09 [0.99 to 4.41], P=0.052). Using occurrence of a secondary malignancy as a time-dependent covariate, the hazard of death after this event was extremely high (HR 17.3 [9.70 to 30.7], P<0.0001). Independent risk factors for secondary malignancies included HSCT after the age of 10 (HR 2.89 [1.53 to 5.45], P=0.001), peripheral blood as source of stem cells (HR 3.06 [1.18 to 5.45], P=0.001) and previous chronic GVHD (HR 2.89 [1.53 to 5.45], P=0.001). Irradiation in the conditioning regimen and donor type (related versus unrelated) did not correlate with outcomes (both late survival and secondary malignancies). Conclusion: We found improved outcomes for patients with FA post-HSCT in recent years (>2000). However, long-term survival in FA patients after HSCT is still mainly affected by secondary malignancies (89% of solid tumors). Patients should be transplanted before the age of 10 with bone marrow as source of stem cells to try to avoid this complication. Moreover, chronic GvHD still emerges as a major cause for both secondary malignancies and mortality. Clearly improved method for prevention, early diagnosis and treatment of this complication are urgently needed. This study also highlights the need for very long-term FU for FA patients after HSCT. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

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Allogeneic Hematopoietic Cell Transplantation for Acute Myelogenous Leukemia in Remission - a Prospective Comparison of Three Different Donor Groups; Matched Sibling, Matched Unrelated, and Haploidentical Family Donors

Blood ◽

10.1182/blood.v126.23.4379.4379 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4379-4379 ◽

Cited By ~ 1

Author(s):

Kyoo-Hyung Lee ◽

Je-Hwan Lee ◽

Jung-Hee Lee ◽

Dae-Young Kim ◽

Han-Seung Park ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Acute Myelogenous Leukemia ◽

Graft Failure ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Myelogenous Leukemia ◽

Acute Myelogenous ◽

Matched Sibling

Abstract Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial. Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate. Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1. Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P* Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69) Sex, male/female 37/44 44/46 29/28 0.824 CR1/CR2 76/5 82/8 47/10 0.098 Chromosome risk,low**/intermediate/high/high-monosomal 6/57/10/5 4/65/16/3 2/40/7/5 0.751 Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58) Donor age, yrup to 2526-45over 45 44136 29610 19326 0.000 Donor sex, male/female 46/35 76/14 36/21 0.000 Donor relation, parents/sibling/offspring 7/24/26 HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3) Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7) *by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy. The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47). Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P Cumulative incidence ( 95% confidence interval)* AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 ANC>500/uL median days (range) 100% 13 (9-20) 99%12 (10-45) 98% 12 (6-22) 0.049 Platelet>20,000/uL median days (range) 99% (86-100%) 14 (0-83) 97% (88-99%) 13 (0-77) 96% (83-99%) 14 (0-106) 0.352 Grades 2-4 acute graft-versus-host disease (GVHD) 12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 4-year survival** Event-free (EFS) 63% 69% 54% 0.381 Overall (OS) 62% 74% 64% 0.077 *compared by Gray's method; **compared by log-rank test Our study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered. Disclosures No relevant conflicts of interest to declare.

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Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Flurabine Improves Transplant Outcomes in Older MDS Patients

Blood ◽

10.1182/blood-2019-121970 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 253-253

Author(s):

Betul Oran ◽

Kwang Woo Ahn ◽

Caitrin Fretham ◽

Mithun Vinod Shah ◽

Ryotaro Nakamura ◽

...

Keyword(s):

Total Dose ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Sensitivity Analyses ◽

Unrelated Donor ◽

Advisory Committees ◽

Hematopoietic Stem

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative therapy in eligible patients with myelodysplastic syndromes (MDS). Reduced-intensity conditioning (RIC) regimens that have been developed to extend HSCT to older patients resulted in encouraging outcomes. However, several retrospective studies have raised concerns about disease control when RIC is used in MDS and the ideal conditioning regimen has not yet been found. In this study, we aimed to compare two most commonly used RIC regimens; intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel). Study population: Through the CIBMTR, after excluding patients with ex-vivo T cell depletion, we identified 1045 MDS patients aged ≥ 60 years and underwent first HSCT with matched related or matched (8/8) unrelated donor (MRD and MUD) using RIC between 2007-2016. RIC was defined via CIBMTR criteria as a regimen that incorporated an IV busulfan (BU) total dose ≤ 7.2 mg/kg or low-dose melphalan (MEL) total dose ≤ 150 mg/m2. By that, we identified 697 MDS patients who received FluBu (BU 6.4 mg/kg: 87%, BU 3.2 mg/kg: 13%) and 448 receiving FluMel (MEL 140 mg/m2: 80%, MEL 100 mg/m2: 20%). Results: The two groups, FluBu and FluMel, were comparable for disease and transplant related characteristics except the more frequent use of ATG or Campath in FluBu group (39% vs. 31%). The median age was 67 in both groups, and 26% and 19% of FluBu and FluMel groups were aged ³70, respectively. Hematopoietic comorbidity index (HCT-CI) was ³3 in 61% and 59% of FluBu and FluMel groups and MDS risk score by CIBMTR at HCT was high/very high in 34% in both groups. FluMel was associated with a reduced relapse incidence (RI) after HSCT compared with FluBu as presented in Table 1 and Table 2. Adjusted RI at 1-year was 43% with FluBu and 25% with FluMel (p=<0.0001). On the other hand, transplant related mortality (TRM) was higher with FluMel compared with FluBu (27% vs. 15%, p=<0.0001). The difference persisted at 2- and 3-years after HSCT as presented in the figure. Since the magnitude of improvement in RI was greater with FluMel than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 41% at 1-year, p=0.030, and 38% vs 28% at 3-years, p=0.0030). These outcome differences remained significant when sensitivity analyses were performed excluding patients who received RIC with either BU 3.2 mg/kg or Mel 100 mg/m2. FluMel, did not lead to higher incidence of severe grade 3-4 aGvHD (HR=1.2, 95%CI, 0.9-1.6, p=0.3) or chronic GvHD (HR=0.9, 95%CI=0.7-1.06, p=0.2). However, grade 2-4 aGVHD was observed more often with FluMel than FluBu (HR=1.3, 95%CI, 1.1-1.6, p=0.006). This led to inferior outcomes of GRFS within the first 2 months with FluMel (HR=1.9, HR=1.4-2.6, p<0.001) but superior outcomes of GRFS beyond 2 months with FluMel compared with FluBu (HR=0.7, 95%CI=0.6-0.8, p<0.001). Conclusion: Our results suggest that between the two most commonly used RIC regimens in older MDS patients, FluMel was associated with superior DFS and overall survival compared with FluBu due to reduced RI despite higher TRM. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Nakamura:Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Scott:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding.

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High Engraftment Rate after Second Stem Cell Transplantation for Thalassemia: A Prospective Study.

Blood ◽

10.1182/blood.v110.11.1107.1107 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1107-1107

Author(s):

Javid Gaziev ◽

Guido Lucarelli ◽

Pietro Sodani ◽

Paola Polchi ◽

Katia Paciaroni ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Second Transplantation ◽

Increased Risk ◽

Preparative Regimen

Abstract Unlike hematological malignancies patients with thalassemia have an increased risk of graft failure or rejection occurring in up to 15% of patients after myeloablative stem cell transplantation from HLA identical related donors. Patients who reject their grafts and have a return of thalassemic hematopoiesis could benefit from second transplantation with the prospect of cure. Our previous experiences of second SCT using BUCY conditioning regimen alone or in combination with antilymphocyte globulin or total lymphoid irradiation showed a higher graft failure rates (43% to 69%). In 2003 we devised a new preparative regimen in an attempt to improve engraftment rate after second transplantation for thalassemia. The treatment protocol (Protocol 26.1) consisted of pre-conditioning immunosuppression-cytoreduction with hydroxiurea 30 mg/kg/day, azathioprine 3 mg/kg/day (day -45 to -12) and fludarabine 30 mg/m2/day (day -17 to -13) and conditioning regimen with BU 14/16 TT10 CY200 ATG (Thymoglobulin)12,5/10. Thirteen patients with median age of 9 years (range, 4–20 years) were given a second SCT according to this protocol. The median time between the first and second transplant was 29 months (range, 8–204 months). As a stem cell source 4 patients received bone marrow and 9 patients unmanipulated peripheral blood stem cells (PBSC). All but two patients received stem cells from the same donor. Twelve out of 13 patients (92%) had sustained full donor engraftment. One patient had early graft failure and died from cerebral bleeding due to refractory thrombocytopenia despite an autologous back-up. Other two patients died from acute or chronic GvHD -related complications. The probability of survival, thalassemia-free survival, transplant related mortality and rejection were 76%, 76%, 18% and 8% respectively with a median follow-up of 26 months (range, 8–47 months). Four patients developed grade II–III and 1 patient grade IV acute GvHD responsive to steroids and 3 patients had extensive chronic GvHD. Both acute and chronic GvHD occurred in patients who received PBSC. The incidence of CMV and EBV reactivation was 62% and 38% respectively. None of these patients developed EBV related lymphoproliferative disorders. Six patients had BK virus- related hemorragic cystitis (2 moderate, 2 severe and 2 mild cystitis). In conclusion, the high engraftment rate observed in this study suggests that this new preparative regimen is effective curative treatment for second transplant in patients with thalassemia. Disclosure: No relevant conflicts of interest to declare.

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Donor-Type Aplasia After Bone Marrow Transplantation in Children with Aplastic Anemia: A Nationwide Retrospective Study

Blood ◽

10.1182/blood.v120.21.959.959 ◽

2012 ◽

Vol 120 (21) ◽

pp. 959-959 ◽

Cited By ~ 8

Author(s):

Nao Yoshida ◽

Hiroshi Yagasaki ◽

Hiromasa Yabe ◽

Akira Kikuchi ◽

Ryoji Kobayashi ◽

...

Keyword(s):

Bone Marrow ◽

Graft Failure ◽

Dose Group ◽

Independent Risk Factor ◽

Conditioning Regimen ◽

Japanese Children ◽

Full Dose ◽

High Incidence ◽

Half Dose ◽

Donor Type

Abstract Abstract 959 Survival after bone marrow transplantation (BMT) in children with aplastic anemia (AA) has improved markedly over the last 3 decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after BMT (donor-type aplasia), especially in the recent years. Since the 2000s, fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with AA. The present study therefore evaluated whether patient and transplantation characteristics (especially the FLU regimen) could associate with donor-type aplasia in a large population of children with AA. To identify the risk factors for donor-type aplasia, we reviewed the clinical data of 660 patients (< 20 years) with AA who received BMT from 1980 to 2010 and whose records were available in the Japan Society for Hematopoietic Cell Transplantation Registry. The influence of potential risk factors on donor-type aplasia was assessed according to patient and transplantation characteristics, including the conditioning regimen. The median age at transplantation was 11 years, and 238 patients received immunosuppressive therapy (IST) before BMT. The median interval between diagnosis and BMT was 9 months. Regarding transplantation, 419 patients received BMT from related donors, whereas 241 received BMT from unrelated donors. Totally, 220 patients received a regimen that included FLU. Primary graft failure was observed in 25 patients. Of the 635 patients who achieved primary engraftment, 46 developed secondary graft failure or relapse: 11 were of the recipient-type and 35 were of the donor-type. The cumulative incidence of donor-type aplasia was 5.7%, and the 10-year overall survival of patients who presented with donor-type aplasia was 87%. Notably, the incidence of donor-type aplasia was significantly higher in FLU regimen group than in non-FLU regimen group (11.6% vs. 2.7%; P < 0.0001), and multivariate analysis confirmed that the FLU regimen was an independent risk factor for donor-type aplasia. Low infused cells (≤ 3×108/kg) (P = 0.008) and IST before BMT (P = 0.04) were also associated with a high incidence of donor-type aplasia. Age at BMT, gender, etiology, severity, interval between diagnosis and BMT, transfusion times, donor type (related or unrelated), human leukocyte antigen disparity, acute or chronic graft versus host disease (GVHD), GVHD prophylaxis, and viral reactivation or infection did not influence the incidence of donor-type aplasia in multivariate analysis. When FLU was introduced in the regimen for Japanese children with AA, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity; the conventional dose of CY was 200 mg/kg before the introduction of FLU. Therefore, we investigated the impact of the dose reduction of CY in the FLU regimen group. In patients receiving the FLU regimen, the incidence of donor-type aplasia in the CY half-dose group (n = 175) was 14%, whereas donor-type aplasia was not observed in the CY full-dose group (n = 35) (P = 0.04). In contrast, the addition of antithymocyte globulin or irradiation did not influence the incidence of donor-type aplasia in the FLU regimen group. Of note, the incidence of heart failure as a result of CY administration was higher in the CY full-dose group (5.7%) than in the CY half-dose group (0.6%), although this difference was not statistically significant. In conclusion, the FLU regimen was identified as an independent risk factor for donor-type aplasia in children with AA, which could possibly be ascribed to the CY dose reduction. However, the high incidence of heart failure associated with the regimen including a full dose of CY is an important issue that needs to be resolved. To develop optimal treatment, the conditioning regimen for children with AA needs to be reconsidered. Disclosures: No relevant conflicts of interest to declare.

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Alternative Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe

Blood ◽

10.1182/blood-2018-99-111129 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4645-4645 ◽

Cited By ~ 2

Author(s):

Barbara Cappelli ◽

Graziana Maria Scigliuolo ◽

Fernanda Volt ◽

Selim Corbacioglu ◽

Josu de la Fuente ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Alternative Donor

Abstract Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children (<16 years) in both groups (23/40 and 19/24, respectively). Before HSCT, 68% of overall pts were treated with hydroxyurea and 62% received more than 20 red blood cell (RBC) units. RBC alloimmunization occurred in 14% of transfused pts. In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli: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; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

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Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Severe Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Blood ◽

10.1182/blood-2020-141771 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Adetola A. Kassim ◽

Josu de la Fuente ◽

Ali Debsan Alahmari ◽

Michael J. Eckrich ◽

Rabi Hanna ◽

...

Keyword(s):

Bone Marrow ◽

Sickle Cell ◽

Graft Rejection ◽

Research Funding ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Stopping Rules ◽

Global Learning ◽

Learning Collaborative

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to > 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants. Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules. Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as <5% donor myeloid chimerism or < 5% donor cells by whole blood chimerism by day +42 posttransplant. Secondary graft rejection was defined <5% donor myeloid chimerism or < 5% donor cells by whole blood chimerism with prior documentation of > 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD. Results: We enrolled 41 consecutive participants from 8/14/2014 - 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were <18 years of age. Donors included siblings (14/41, 34%), parents (27/41, 61%), and 88% (36/41) had sickle cell trait. Median TNC dose was 5.8 x 108 /kg (4.2, 8.0), and median CD34+ and CD3+ cell doses were 3.9 x 106/kg (2.6, 6.1) and 32.3 x 108/kg (27.1, 50.8), respectively. A total of 93% of participants engrafted. Median times to neutrophil (> 500/mcL) and platelet (>50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants <18 years of age, and all had autologous reconstitution (Table). Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (< 18 years), and all older participants (> 18 years) engrafted. The trial will add new stopping rules by age strata (<18, > or = to 18 years) and will modify the conditioning regimen in pediatric stratum. Disclosures Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

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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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