No Influence of Peripheral Blood CD34+ and CD3+ Graft Cell Counts on Outcomes after Reduced-Intensity Conditioning Transplantation Using Post-Transplant Cyclophosphamide

Abstract Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Reduced Severe aGVHD and Improved Survival Using Post Transplant Cyclophosphamide/Tacrolimus/Methotrexate Graft Versus Host Disease Prophylaxis in AML Patients Receiving Myeloablative Fractionated Busulfan Conditioning Regimen

Blood ◽

10.1182/blood-2019-125996 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3296-3296

Author(s):

Uday Popat ◽

Rima M. Saliba ◽

Rohtesh S. Mehta ◽

Amanda L. Olson ◽

Julianne Chen ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Similar Proportion ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods: Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P<0.001) and platelet engraftment by 9 days (22 vs 13 days; P<0.001) in the PTCy cohort. Full donor chimerism at day 30 was noted in 79% vs 28% in the PTCy and Tac/Mtx cohorts respectively, (P<0.001). Conclusion: As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Pfizer: Honoraria; Amgen: Research Funding; Jazz: Consultancy. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Qazilbash:Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

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Low Incidence of Chronic Graft-Versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Using Matched Related or Unrelated Donors: Phase II Study Interim Analysis

Blood ◽

10.1182/blood-2021-147569 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1811-1811

Author(s):

Najla H El Jurdi ◽

Daniel O'Leary ◽

Fiona He ◽

Todd E. DeFor ◽

Armin Rashidi ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Preparative Regimen

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

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Influence of Donor Type (sibling vs matched-unrelated donor vs haplo-identical donor vs cord blood) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies

Blood ◽

10.1182/blood-2018-99-112369 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3451-3451

Author(s):

Louise Bouard ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Alice Garnier ◽

Amandine Le Bourgeois ◽

...

Keyword(s):

Stem Cells ◽

Cord Blood ◽

Board Of Directors ◽

Peripheral Blood ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Donor Type ◽

Reduced Intensity

Abstract Background: Recently, we have reported the good results of a clofarabine-based reduced-intensity conditioning (RIC) regimen for peripheral blood stem cell (PBSC) allografts, using either matched (Le Bourgeois, ASH 2017) or haploidentical (haplo) donors (Chevallier, ASH 2017). However, the influence of donor type in this setting is unknown. Patients and Methods: We conducted a retrospective study including all adults (≥18 yo) allografted in our department with a clofarabine-based RIC regimen for a myeloid malignancy. All types of donors were accepted, and patients received allogeneic peripheral blood stem cells (PBSC) or cord blood (CB) transplants. The aim of this study was to assess whether or not the donor type (sibling, matched unrelated (MUD), haplo or CB) impacted outcomes. Results: Between October 2009 and February 2018, 122 patients met the inclusion criteria. Donors were sibling in 36 cases, "MUD" in 55 (including one 9/10 mismatched donor), haplo in 27 and CB in 4. The sibling+MUD patients received a CloB2A1/A2 RIC regimen consisting of clofarabine 30 mg/m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). Haplo and CB recipients were conditioned by a Baltimore-like RIC regimen and a Minneapolis-like regimen, respectively, where fludarabine were replaced by clofarabine. All patients received cyclosporine (CsA) + mycophenolate mofetyl as GVHD prophylaxis, except sibling recipients who were given CsA alone. Haplo recipients received also 2 days of post-transplant cyclophosphamide. All non-CB patients received PBSC as source of graft. The median age of the whole cohort was 61,5 years old (range: 18-73) and the median follow-up 31 months (range: 4,5-106). All patients engrafted except 1 CB patient and 1 haplo recipient who died of infection before engraftment. All CB cases died at 1, 8, 9 and 11,5 months post-transplant, respectively (infection n=1, relapse n=2, chronic GVHD n=1). As a consequence, we thereafter compared outcomes only between the three other donor groups. There were no significant differences between sibling, MUD or haplo recipient groups in terms of gender, median age, type of disease, ELN 2010 classification for AML, status at transplant (complete remission vs active), disease risk index, donor/recipient CMV status or median graft quantity of CD34+ stem cells. The only differences were the partition of ABO compatibility, less frequent in the MUD group (42% vs sibling 69% vs haplo 67%, p=0,02) and a history of previous allograft (haplo n=7, sibling n=0, MUD n=6, p=0,005). Neutrophils (>0,5 Giga/L) and platelets (50 Giga/L) recoveries were significantly delayed in the haplo-group (19 days, vs sibling 15 vs MUD 15, p=0.0003; and 31 days vs 11 vs 12, p<0.0001). Acute grade 2-4 or 3-4 graft versus host disease (GVHD) incidences were similar between the three groups at 50% and 22% for sibling, 34,5% and 14,5% for MUD and 48% and 11% for haplo (p=0,18 for grade 2-4 and p=0,45 for grade 3-4) as well as moderate+severe chronic GVHD incidences (sibling 14%, MUD 16%, haplo 15% p=0,94). Follow-ups were similar at 34.2 (6-74), 33.7 (4.5-106) and 21.4 (7-53) months respectively for sibling, MUD or haplo donors. This was associated with similar 2-year overall survivals (OS) at 64,7% (50-83), 73,9% (62-87) and 60,2% (43-83) respectively (p=0.4) and 2-year disease-free survivals (DFS) at 57,7% (43-76), 70,9% (59-84) and 53,6% (37-77) respectively (p=0.1). Two-year GVHD-relapse free survival (GRFS) was also similar at respectively 37,9% (24-57), 54,3% (41-70) and 38,9% (23-63) (p=0.2) as well as 2-year non-relapse mortality (NRM) at 14%, 11% and 18,5% (p=0,63). When considering only AML patients, again similar 2-year survivals were observed between the three groups. OS was 71.4% (54-93) for sibling (n=21), 75.1% (62-90) for MUD (n=40) and 66.6% (46-95) for haplo (n=15, p=0.65) and DFS respectively 66,6% (49-90), 70,8% (57-87) and 66,6% (46-95 p=0.47). The same was observed for GRFS at 38% (22-65), 56% (41-75) and 40% (21-74, p=0.14) and NRM at 14%, 7,5% and 7%, p=0.34). In multivariate analysis, donor type remained independent of outcomes in this series. Conclusion: These data confirm that since no difference was observed in terms of outcomes, haplodonors represent a valid alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack a matched sibling donor. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽

10.1182/blood.v110.11.3046.3046 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3046-3046 ◽

Cited By ~ 1

Author(s):

Vincent T. Ho ◽

Haesook Kim ◽

Shuli Li ◽

Corey Cutler ◽

John Koreth ◽

...

Keyword(s):

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Historical Cohort ◽

Post Transplant ◽

Donor Chimerism ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Reduced Intensity

Abstract We have previously shown that the combination of tacrolimus and sirolimus (TAC/SIR) without methotrexate (MTX) is a safe and effective regimen for GVHD prophylaxis after myeloablative SCT. However, TAC/SIR has not been investigated in the RIC setting. We hereby report a prospective phase II trial testing TAC/SIR as GVHD prophylaxis after RIC SCT from matched related donors (MRD). All patients received fludarabine (FLU) 30 mg/m2 IV and intravenous busulfan (BU) 0.8 mg/kg IV daily × 4 days (day -5 thru day -2) as conditioning, followed by transplantation of filgrastim mobilized peripheral blood stem cells. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Tacrolimus and sirolimus were started on day-3, and doses were adjusted to maintain target serum trough levels 5–10 ng/ml and 3–12 ng/ml, respectively. Twenty-six patients have been transplanted, with a median age of 52 years (range 29–64 yrs). Diagnoses include NHL (8), AML (6), HD (5), CLL/SLL (3), CML (2), MDS (1), MM (1). Median CD34+ cells infused was 8.06 × 106 cells/kg (range: 2.96–38.0 × 106 cells/kg). All patients had sustained hematologic engraftment. Only 4 (15%) patients developed neutropenia below ANC 500, and 6 (23%) had platelet counts below 20K. One patient had late graft failure at 7 months post transplant. Grade II-IV acute GVHD incidence was 20%, with grade III-IV incidence of 12%. No hepatic VOD or thrombotic microangiopathy was observed. Day +100 transplant related mortality (TRM) was 0%. The cumulative incidences of TRM and relapse at 1 year were 4% and 38%, respectively. The cumulative incidence of chronic GVHD at 1 year was 74%. A high level (>90%) of donor-derived hematopoiesis was achieved in 68% by 1 month post transplant. Median donor chimerism at between day 20–50 post transplant was 93.5% (range 32%-99%), and 94% (range 22%-100%) at day 85–115. With a median follow-up of 13.5 months among survivors (range 5.5–19 months), progression-free survival (PFS) and overall survival (OS) at 1 year were 58% and 79%, respectively. Compared to a historical cohort of 47 MRD transplant recipients treated with the same FLU/BU conditioning regimen and using TAC/SIR ± mini-MTX (5 mg/m2 IV day +1,3,6) as GVHD prophylaxis, there was no statistical difference between TAC/SIR vs. TAC/SIR/MTX in the incidence of grade II-IV acute GVHD (20% vs 11%, p= 0.48), cumulative incidence of relapse at year (38% vs. 57%, p= 0.25), 1-yr PFS (58% vs. 41%, p= 0.33), or 1-yr OS (79% vs. 73%, p= 0.79). These results demonstrate that omission of mini-MTX is permissible, and that the combination of TAC/SIR alone as GVHD prophylaxis following reduced intensity conditioning with FLU/BU is associated with low rates of acute GVHD, TRM, and high levels of donor chimerism after MRD SCT.

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Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽

10.1182/blood-2019-130338 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5742-5742

Author(s):

Han Bi Lee ◽

Jae-Ho Yoon ◽

Gi June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27

Blood ◽

10.1182/blood.v118.21.3025.3025 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3025-3025

Author(s):

Jose Antonio Perez-Simón ◽

Teresa Caballero-Velazquez ◽

Cristina Encinas ◽

Cristina Castilla-Llorente ◽

Rodrigo Martino ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Conditioning Regimen ◽

Disease Status ◽

Allogeneic Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Abstract 3025 Introduction: Although allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for MM, it is associated to a high morbility and mortality. Moreover, relapses are common after allo-RIC. Accordingly, new strategies are required to reduce both the risk of relapse and the toxicity of the procedure. As we have previously demonstrated, Bz induces a selective depletion of alloreactive T-cells and has immunomodulatory properties which might be of potential benefit for GVHD control. The primary end point of this study was to evaluate the efficacy of allo-RIC in terms of response when Bz was added as part of a reduced intensity conditioning prior to allo-SCT. Secondary end points included incidence of GVHD and analysis of the toxicity of the procedure when Bz is also administered post-infussion as part of the GVHD prophylaxis. Method: Prior to allo-RIC, patients received two cycles of Bz plus dexamethasone. Conditioning consisted of fludarabine (30 mg/m2 intravenously on days -9 to -5) and melphalan (70 mg/m2 intravenously on days -4, -3) plus Bz 1, 3mg/m2 on day - 11 and -2. GVHD prophylaxis included cyclosporine (CsA) and methotrexate for the first 9 patients and CsA plus MTX and Bz on days +3 and +7 for the remaining 7 patients. From day +50 post allo-RIC 7 cycles of Bz (+1, +8, +15) were administered, the first two cycles every 28 days and the rest every 56. Results: 16 patients from the Twenty-one initially enrolled, were evaluable. All 16 patients had received at least 2 lines of therapy including autologous-SCT. Disease status was CR or nCR in 4 patients, 9 had PR and the remaining 3 patients had relapsed / progressive disease. 15 patients maintained or improved status at transplant including all × patients with active disease at transplant. Eight patients (50%) relapsed, four with extramedullary involvement. No patient developed grade 4 aGVHD.Grades 2–3 aGVHD occurred in 6 patients (37%). Interestingly, two out of the nine (29%) patients who received Bz on days +3 and 7 developed grades 2–3 acute GVHD as compared to four of the nine (44%) who did not receive it. In terms of toxicity, one patient did not achieve platelet engraftment and 2 patients developed peripheral neuropathy requiring treatment withdrawal. 8 patients died, four of them due to relapse (MRT: 25%). With a median follow-up of 457 days overall survival was 46%. Conclusions: The current trial is the first evaluating the efficacy and safety of Bz as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Regarding the efficacy of the procedure all but one patient improved disease status post-alloRIC although relapse rate was still high in this heavily pretreated population. In addition, Bz post-alloSCT is well tolerated and may decrease the incidence of GVHD. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties. Off Label Use: This study evaluates the efficacy of Bortezomib as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Blood ◽

10.1182/blood.v124.21.1206.1206 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1206-1206

Author(s):

Olivia Laverick ◽

Amy Publicover ◽

Laura Jardine ◽

Kile Green ◽

Alan Potter ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Reduced Intensity Conditioning ◽

T Cell Depletion ◽

Gvhd Prophylaxis ◽

Full Intensity ◽

Conditioning Intensity ◽

Reduced Intensity

Abstract Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion. Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence. Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08). Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. Disclosures No relevant conflicts of interest to declare.

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A Prospective Phase 2 Study Testing High Dose Post-Transplant Cyclophosphamide As Sole Ghvd Prophylaxis after Matched Allotransplant Using Baltimore-Based Reduced-Intensity Conditioning Regimens and PBSC As Source of Graft

Blood ◽

10.1182/blood-2021-149534 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1812-1812

Author(s):

Patrice Chevallier ◽

Amandine Le Bourgeois ◽

Alice Garnier ◽

Pierre Peterlin ◽

Yannick Le Bris ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

High Dose ◽

Phase 2 ◽

Reduced Intensity Conditioning ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Phase 2 Study ◽

High Incidence ◽

Grade 3

Abstract Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults. Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767. Results: The results of the first 27 first patients (males n=17 and female n=10; median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17. Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached. Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported here may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing. Disclosures Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.

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Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Blood ◽

10.1182/blood-2021-151187 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2881-2881

Author(s):

Benjamin Bouchacourt ◽

Valerio Maisano ◽

Ana Benzaquen ◽

Angela Granata ◽

Sabine Furst ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Advisory Committees ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade Ii

Abstract Background: Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD. Patients and Methods: This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery. Results: 241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01). Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802). By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS. Conclusion: In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. Figure 1 Figure 1. Disclosures Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

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Myeloablative Versus Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia in Patients with Prior Myelodysplastic Syndrome/ Myeloproliferative Disorders: An ALWP of EBMT Study

Blood ◽

10.1182/blood.v130.suppl_1.907.907 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 907-907

Author(s):

Bipin N. Savani ◽

Ariane Boumendil ◽

Myriam Labopin ◽

Jürgen Finke ◽

Matthias Stelljes ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Gvhd ◽

Myeloproliferative Disorders ◽

Registry Study ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Secondary Acute Myeloid Leukemia ◽

Reduced Intensity

Abstract Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy. We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 [42.4%]) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62). Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p<0.001). Most patients received peripheral blood stem cell grafts (n=731 [90.3%]; MAC 85.6% vs RIC 93.4%, p<0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%). A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% [31-42] vs. RIC 45% [40-49], p=0.029) and 25% (95% CI, 22-28%, MAC 25% [20-30] vs. RIC 25% [21-29], p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% [38-50] vs. RIC 38% [33-43], p=0.041) and 34% (95% CI, 31-38; MAC 38% [33-45] vs. RIC 31% [27-36], p=0.032), respectively (Figure 1). In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 [1.16-2.55]; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 [1.02-1.84], p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes. In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI. Figure 1 Figure 1. Disclosures Savani: Jazz Pharmaceuticals: Speakers Bureau. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid: Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Speakers Bureau.

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