Improved Survival of Patients Diagnosed with Severe (Grade 3-4) Acute GVHD or Severe NIH Grade Chronic GVHD in the Current Era Compared to Historic Controls

Severe (grade 3-4) acute GVHD (aGVHD) and NIH grade severe chronic GVHD (cGVHD) have historically been associated with poor survival. However, earlier diagnosis, improved treatment and supportive care, may result in an improvement in outcomes for patients recently diagnosed with severe GVHD compared to prior cohorts. Our institution has prospectively documented onset, grading and therapy of patients with GVHD using a single dedicated practitioner since 2005. We assessed 851 consecutive patients who received allografts at our center between 1/2005 and 12/ 2016 and identified 130 patients (15.3%) who developed severe aGVHD through Dec 2017 without prior relapse of malignancy. Characteristics were: median age 52.5, 51% male, race-81% white -17% black, diagnosis- AML 31% - MDS/MPD 20%- NHL/HL/CLL-23%, -ALL 11%, donor - MRD 21% - MUD 49% - haplo 30%, PBSC 78%, BM 17%, CBU 5%, preparative regimen MAC 44% - RIC/NST 56%, median time from BMT to onset of severe aGVHD was 49 days (7-376). Maximum grade = gd 3 (85%), gd 4 (15%), Median follow-up for survivors from date of onset was 59 months (23-155m). Survival estimates for the entire cohort from date of onset of grade 3-4 aGVHD at 1, 2 and 3 years were 62%, 49% and 47% respectively. Patients who developed severe aGVHD in 2016-2017 had significantly improved overall survival compared to patients who developed severe acute GVHD in prior years (2005-2015) -1 and 2 yr survival 86% & 79% vs 55% & 41% respectively, p=0.002 log-rank test, Fig 1). No significant differences were found between earlier cohorts. On multivariable analysis assessing the following variables: age, gender, race, diagnosis, donor type, cell source, regimen intensity, DRI, HCT-CI, CMV status, grade of aGVHD (3 vs 4), days from transplant to gd 3-4 aGVHD onset, year of development of severe acute GVHD (2016-2017 vs earlier) remained significant for survival (HR 0.36, p=0.018). Other significant variables were grade 4 vs 3 GVHD (HR 3.78, p<0.001) and DRI (high/very high vs low/intermediate, HR 1.84, p=0.011). For cGVHD we assessed 522 consecutive patients who underwent allografts between 4/2011 (start date of prospective documentation of NIH grade cGVHD )and 12/2016, and identified 146 (28%) patients who developed moderate to severe NIH grade chronic GVHD without prior relapse by Dec 2017 (85 severe, 61 moderate). Patient characteristics were: median age 53, 55% male, race-74% white -22% black, AML 40% - MDS/MPD 31%- NHL/HL/CLL-15%, -ALL 12% , donor - MRD 34% - MUD 40% - haplo 25%, graft- PBSC 82%, BM 18%, preparative regimen MAC 54% - RIC/NST 44%, median time from BMT to onset of moderate/severe cGVHD was 289 days (27-1364). Median follow-up for survivors from date of onset of moderate to severe GVHD was 48 months (19-94m). Estimated rates of survival from date of onset of moderate to severe cGVHD for the entire cohort at 1, 2 and 3 years were 82%, 73% and 71% respectively. For patients who developed severe cGVHD the corresponding survival estimates were 77%, 67% and 63%. No significant difference in post-onset survival was encountered when comparing patients developing moderate cGVHD in 2011-2013, 2014-2015 and 2016-2017. However, for severe cGVHD, 1 and 2 year estimated survival rates for the three cohorts were : 53% & 41%, 79% & 73% and 87% and 74% respectively (p=0.004 for 2011-2013 vs 2014-2015 but p=NS for 2014-2015 vs 2016-2017, Fig 2). On a multivariable analysis considering age, gender, race, diagnosis, donor type, graft source, regimen intensity, DRI, HCT-CI, and days from transplant to cGVHD onset, none of these variables was significantly associated with post-cGVHD survival. In the Cox model including year of onset of severe cGVHD, onset in recent years was linked to lower risk of mortality compared to onset in earlier years (onset 2014-2015 vs 2011-2013 - HR=0.34, p-0.012; onset 2016-2017 vs 2011-2013 - HR=0.28, p=0.006). These data suggest that survival of patients developing either severe aGVHD or severe NIH grade cGVHD has significantly improved in recent years compared to historical controls. More than two-thirds of such patients now survive two years from onset of severe GVHD. This must be taken into account when evaluating novel therapies for severe GVHD. Disclosures Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.

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Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Blood ◽

10.1182/blood-2019-127445 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 669-669 ◽

Cited By ~ 3

Author(s):

Haris Ali ◽

David Snyder ◽

Tracy Stiller ◽

Timothy Synold ◽

Saloomeh Mokhtari ◽

...

Keyword(s):

Pilot Study ◽

Median Time ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Cell Transplant ◽

Reduced Intensity Conditioning ◽

Grade 3 ◽

Reduced Intensity

Ruxolitinib (Rux), a potent JAK1/2 inhibitor, is the only FDA-approved drug for treatment of primary and secondary myelofibrosis (MF). Rux has been recently approved for treatment of steroid refractory acute graft-versus-host disease (GVHD), a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). In MF patients proceeding with transplant, Rux is typically discontinued pre-HCT. Given the therapeutic, immunologic, and anti-inflammatory properties of Rux, we hypothesized that continuous peri-HCT administration of the drug is safe and can result in better transplant outcomes in MF patients. Here, we are reporting outcomes of our single arm, single center pilot study (NCT02917096) investigating the safety and efficacy of Rux administration in patients with primary or secondary MF undergoing HCT with fludarabine (125 mg/m2) and melphalan (140 mg/m2) as reduced intensity conditioning and sirolimus/tacrolimus (target levels: 5-10ng/ml for both) as GVHD prophylaxis. This pilot study is being conducted in MF patients with the goal of extending the therapy to other hematologic malignancies. The primary objective was to identify the maximum tolerated dose and recommended phase II dose. Rux was given at 2 dose levels (DL) of 5 and 10 mg BID, starting from day -3 pre-HCT until day +30 post-HCT, then tapered off by day +33. DLs were chosen based on previous retrospective studies identifying the drug dose for treatment of GVHD. Primary endpoint was safety. Dose limiting toxicity (DLT) was defined as grade 4 neutropenia associated with fever, infection, or engraftment failure or any grade ≥3 non-hematologic toxicities over 45 days. Key secondary endpoints were grade 2-4 acute GVHD, engraftment, infection, overall survival (OS), progression-free survival (PFS), NRM, relapse and chronic GVHD. So far, we have enrolled 12 patients: 6 for DL1 arm and 6 for DL2. Median age at the time of HCT was 53 years (range: 25-66) for DL1 and 68 years (range: 56-72) for the DL2 arm. Detailed patient/transplant characteristics are listed in table 1. One-year OS, PFS and NRM for all patients were 80% (95%CI: 39-95), 68% (95%CI: 30-89) and 21% (95%CI: 3-50), respectively. All patients engrafted (n=12), with the median time to neutrophils engraftment of 19 days (range: 13-23) for DL1 and 16 days (range: 12-22) for the DL2 arm. Hematologic DLTs were not observed in patients at either dose level. At DL1, by day +60, grade ≥3 toxicities were cardiac (n=1), pulmonary (n=1) and gastrointestinal (n=1). Only one case of grade ≥3 pulmonary toxicity was observed in patients at DL2. After median follow-up time of 373 days (range: 365-744) in DL1 and 98 days (range: 30-379) for DL2, there were two deaths; one due to respiratory failure in DL1, and another due to acute GVHD at DL2. Median time of acute GVHD onset was 20 days (range: 19-35) in DL1 and 51 days (range: 26-76) in DL2. Grade III-IV acute GVHD was seen in only 1 out of 12 patients and grade 1 acute GVHD was seen in 4 patients. One patient in DL1 relapsed at 9 months and re-entered remission with post-HCT treatment. CMV infection was seen in only 1 patient at DL2. Pharmacokinetics (PK) studies were done for five patients at DL1 and all patients at DL2. PK was dose-proportional, in which doubling of the dose corresponded to the twice greater Cmax and AUC. The half-lives and oral clearances were not different between the two DLs. The Cmax and AUC were lower in our patients compared to a previously published report in healthy volunteers. Furthermore, the elimination half-life was similar to the published data, indicating that the lower drug exposures measured on the current trial is most likely due to decreased oral absorption. Lastly, GVHD biomarkers and inflammatory cytokines levels were not different between patients receiving Rux at DL1 and DL2. In conclusion, early results of this pilot study indicate that Rux administration at 10 mg BID in MF patients undergoing HCT is safe and feasible, with 100% engraftment and low rate of acute GVHD. We are currently accruing an expansion cohort of 6 patients at DL2. Results of our PK studies indicated a direct correlation between Cmax and AUC and that higher oral clearance compared to previous study is most likely due to poor GI absorption of the drug in HCT patients. More follow up is needed to see the impact of this combination on incidence of chronic GVHD. This regimen may also be useful for patients undergoing HCT for other hematologic malignancies. Disclosures Palmer: Gilead Sciences: Consultancy. Salhotra:Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Mei:Seattle Genetics, Inc.: Research Funding. Nakamura:Celgene: 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 ; Merck: Membership on an entity's Board of Directors or advisory committees; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

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Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽

10.1182/blood-2019-122762 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3320-3320

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Javier Bolanos-Meade ◽

Richard J. Jones

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Prospective Trial ◽

Stopping Rules ◽

High Dose ◽

Gvhd Prophylaxis ◽

Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

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Prophylactic Rituximab After Allogeneic Stem Cell Transplantation Prevents Steroid-Requiring Chronic Graft-Vs.Host Disease

Blood ◽

10.1182/blood.v116.21.214.214 ◽

2010 ◽

Vol 116 (21) ◽

pp. 214-214 ◽

Cited By ~ 1

Author(s):

Corey Cutler ◽

Lixian Sun ◽

Haesook Kim ◽

Stefanie Sarantopoulos ◽

Bhavjot Bindra ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

First Year ◽

Cell Recovery ◽

Systemic Corticosteroids ◽

Gvhd Prophylaxis ◽

Donor Type ◽

Grade 3

Abstract Abstract 214 There are no standard methods for the pharmacologic prevention of chronic GVHD (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Based on compelling biology implicating B cells in the pathophysiology of cGVHD and the utility of rituximab as therapy for established cGVHD, we performed a phase II trial of rituximab for the prevention of cGVHD after HSCT. Methods: 64 patients in remission without active GVHD received rituximab (375 mg/m2) at 3, 6, 9 and 12 months after HSCT. Related and unrelated donor recipients of 5/6 or 6/6 HLA-matched PBSCs were eligible. Prophylactic IVIG infusions were permitted at investigator discretion. Chronic GVHD severity was assessed by the requirement for systemic corticosteroids, with a historical rate of steroid-requiring cGVHD within 1 year of transplantation of approximately 60% at our institution. Results: 56 patients have been followed for at least 12 months from HSCT. One patient had a hypersensitivity reaction requiring treatment discontinuation and one patient was lost to follow-up, leaving 54 evaluable patients. The median patient age was 55 years (range 19 – 74); 25 were MRD recipients and 31 were URD recipients. 21 underwent myeloablative and 35 underwent reduced-intensity HSCT. Prior grade II-IV acute GVHD occurred in 6 patients (10.7%). Primary GVHD prophylaxis was sirolimus+tacrolimus (67.9%) or calcineurin inhibitor+methotrexate (32.1%), both without ATG. Overall, in the first year after HSCT there were 18 episodes of grade 3 toxicity and 8 episodes of grade IV toxicity without clear relationships to rituximab. There were 15 documented bacterial infections. Transient grade 3–4 neutropenia occurred in 11 subjects. 12 patients relapsed during the year after HSCT and 2 subjects died of non-relapse causes (pneumonitis and sepsis). The cumulative incidence of any cGVHD at 1 year from HSCT was 44.6%, however, the cumulative incidence of cGVHD requiring initiation of systemic corticosteroids was only 31.2%. When stratified by donor type, the incidence of all cGVHD and steroid-requiring cGVHD was 33.6 and 22.9% (MRD) and 52.3 and 37.0% (URD). Donor type, age, conditioning intensity, GVHD prophylaxis, donor gender or malignancy did not impact the incidence of cGVHD in a multivariable model. 8 additional patients required corticosteroids during the first post-transplant year for treatment of anorexia, pneumocystis pneumonia, pneumonitis or late acute GVHD. At 12 months, 50% of all patients had successfully discontinued all immunosuppressants and only 22.4% of all patients were on corticosteroids. Since anecdotally, myofascial and sclerodermatous cGVHD are treated effectively with rituximab, it is notable that only 1 patient had this subtype of cGVHD in contrast to the expected frequency of this manifestation of cGVHD in individuals not given rituximab. At 12 months from HSCT, relapse-free survival was 71.1% and overall survival was 88.6%. CD19+ B cells were very low during the first year post-HSCT, however patients without cGVHD demonstrated a trend toward enhanced B cell recovery at 6, 9 and 12 months from HSCT (6 months 0.58 vs. 0.28 × 106/L; 9 months 1.10 vs. 0.66 × 106/L; 12 months 1.09 vs. 0.76 × 106/L, all p=NS). Similarly, there was a trend for BAFF levels to be higher throughout the first year in patients without cGVHD (6 months 13.64 vs. 11.81; 9 months 12.30 vs. 9.57; 12 months 12.25 vs. 9.79, all p=NS). Among patients with cGVHD, there was a trend for BAFF levels to be higher in those who did not require systemic corticosteroids when compared to those that required steroids at 9 and 12 months (9 months 15.09 vs. 5.89 p=0.045; 12 months 11.86 vs. 7.14, p=0.25). 18 month B cell and BAFF data will be available at ASH. Conclusions. The use of rituximab at 3, 6, 9 and 12 months after allogeneic HSCT can reduce the rate of steroid-requiring cGVHD by up to 50% when compared with historical control data. The presence of enhanced B cell recovery, potentially related to higher BAFF levels found during the first year after HSCT, predicts freedom from cGVHD and a reduction in the severity of cGVHD among those affected. These data provide additional support for the hypothesis that B cells contribute to the development of cGVHD. A randomized trial should be performed to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

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Busulfan Fludarabine Vs. Busulfan Cyclophosphamide As a Preparative Regimen Prior to Allogeneic Hematopoietic Cell Transplantation – Systematic Review and Meta-analysis

Blood ◽

10.1182/blood.v124.21.3872.3872 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3872-3872

Author(s):

Sharon Ben Barouch ◽

Omri Cohen ◽

Liat Vidal ◽

Irit Avivi ◽

Ron Ram

Keyword(s):

Systematic Review ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Meta Analysis ◽

Chronic Gvhd ◽

All Cause Mortality ◽

Preparative Regimen ◽

Grade 3 ◽

Neutrophil Engraftment

Abstract Background: Both busulfan-cyclophosphamide (BuCy) and the reduced toxicity regimen busulfan-fludarabine (BuFlu) are considered myeloablative preparative regimens given prior to allogeneic hematopoietic cell transplantation (HCT). A comprehensive literature evaluation of BuFlu vs. BuCy is lacking and the question of the preferable regimen is still debatable. Objectives: We aimed to compare the efficacy and safety of BuFlu (intervention arm) vs. BuCy (comparable arm) as preparative regimens in patients given allografts. Methods: Systematic review and meta-analysis of all randomized controlled trials (RCTs) and non-randomized comparative trials of patients given BuFlu vs. BuCy as preparative regimens prior to allografts. Electronic search in the Cochrane Library, MEDLINE and conference proceedings was conducted up-to July 2014. Primary outcomes were all-cause mortality at 100 days and at the end of study. Secondary outcomes were time to neutrophil engraftment, primary & secondary rejection, risk for grade 3-4 mucositis, sinusoidal obstruction syndrome (SOS), microbiology documented infection, overall and grade 3-4 acute graft vs. host disease (GVHD), overall and extensive chronic GVHD, non-relapse mortality at 100 day and at the end of study, and relapse risk. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD). Results: Our search yielded 14 trials recruiting 1578 patients. Three trials were RCTs and 11 were either one arm intervention trials compared to historical controls or retrospective studies. There were no differences in all-cause mortality at 100 days and end of study ( RR 0.85; 95% CI 0.56-1.30, 9 trials and RR 0.77; 95% CI 0.59-1.02, 12 trials, respectively), Figure, with similar results in sensitivity analyses including only RCTs and only studies in which patients' age and status of disease at HCT were well matched. Both primary and secondary rejections were comparable between the two regimens. Time to neutrophil engraftment was 1-day longer in patients given the BuCy regimen (WMD 0.84; 95% CI 0.37-1.31, 6 trials). Both the risks for SOS and microbiology documented infections were lower in the BuFlu patients (RR 0.34; 95% CI 0.19-0.62, 8 trials and RR 0.79; 95% CI 0.64-0.97, 2 trials, respectively). Grade 3-4 mucositis was comparable between the two groups. There was a lower incidence of grade 2-4 acute GVHD in patients given FluBu (RR 0.67; 95% CI 0.46-0.99, 10 trials), however this was no longer true in sensitivity analysis including only RCTs. There were no differences between the two arms in grade 3-4 acute GVHD, overall and extensive chronic GVHD, non-relapse mortality at 100 days and at the end of study and relapse risk. Conclusions: While toxicity profile of BuFlu regimen is safer than the classic BuCy regimen, this does not translate into composite transplantation outcomes. Patients at higher risk for SOS may benefit from the BuFlu regimen; however additional RCTs are required to identify other subgroups of patients who will benefit from a tailored-preparative regimen approach. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

Blood ◽

10.1182/blood.v128.22.831.831 ◽

2016 ◽

Vol 128 (22) ◽

pp. 831-831 ◽

Cited By ~ 1

Author(s):

Yvette L. Kasamon ◽

Ephraim J. Fuchs ◽

Marianna Zahurak ◽

Gary L. Rosner ◽

Heather J. Symons ◽

...

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Stopping Rules ◽

High Dose ◽

Stopping Criteria ◽

Gvhd Prophylaxis ◽

Grade 3

Abstract Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. Disclosures No relevant conflicts of interest to declare.

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A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Celltransplantation for Patients with Primary or Secondary Myelofibrosis

Blood ◽

10.1182/blood-2021-146330 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 169-169

Author(s):

Gabriela Hobbs ◽

Haesook T. Kim ◽

AJ S. Bottoms ◽

Michael T. Byrne ◽

Mark A. Schroeder ◽

...

Keyword(s):

Phase Ii ◽

Cumulative Incidence ◽

Interim Analysis ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Free Survival ◽

Grade 3 ◽

Neutrophil Engraftment

Abstract Background: Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease. Methods: This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis. Results: This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD. As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing. Discussion: The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. Figure 1 Figure 1. Disclosures Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Will describe the use of ruxolitinib in the ongoing clinical trial.

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Low-Dose Methotrexate as Salvage Therapy for Refractory Graft-Versus-Host Disease (GVHD) after Reduced-Intensity Conditioning (RIC) for Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v106.11.1802.1802 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1802-1802

Author(s):

Mohamad Mohty ◽

Hugues de Lavallade ◽

Catherine Faucher ◽

Sabine Furst ◽

Jean El-Cheikh ◽

...

Keyword(s):

Side Effects ◽

Salvage Therapy ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Risk Population ◽

High Morbidity ◽

Dose Methotrexate ◽

Grade 3

Abstract Background. RIC regimens are increasingly used for allo-SCT. Although such regimens are associated with a relatively low early transplant-related mortality (TRM) in comparison to standard myeloablative allo-SCT, GVHD remains a matter of concern. Of note, corticosteroid-resistant GVHD is associated with high morbidity and mortality, and therapeutic options are limited for those patients. Furthermore, patients undergoing RIC allo-SCT are older than patients undergoing myeloablative allo-SCT, and are thus more exposed to the side effects and complications of long term corticosteroids (CS) administration. Low dose methotrexate (MTX) therapy is a well established modality for prophylaxis of GVHD after standard myeloablative allo-SCT. However, little is known about the role of this drug in the treatment of CS-resistant GVHD. Patients and Methods. The aim of this pilot single center study was to investigate the role and benefit of MTX in a curative setting after failure of CS treatment in 20 consecutive patients undergoing RIC allo-SCT. 20 patients experiencing severe GVHD received IV infusions of low dose MTX (5 mg/m2/infusion) at weekly intervals, for at least four weeks. Reasons for MTX administration were: refractory acute GVHD (after at least one week of 2 mg/Kg CS administration), CS-refractory chronic GVHD, chronic GVHD exacerbation after CS taper, or CS side effects and complications (CS-induced diabetes requiring insulin therapy, severe metabolic or psychiatric disorders). Responses to low dose MTX infusions were assessed one month after the last infusion in each involved organ. Results. 12 patients were treated for severe acute GVHD, while 8 patients received MTX for extensive chronic GVHD. Median age of patients was 51 (range, 22–60). Median time of administration of MTX was day +89 (range, 32–300) after allo-SCT. Of note, none of the patients received any other concomitant therapy for refractory GVHD. 13 patients responded to MTX administration (65 %) with 5 complete responses (25%). Among the 12 patients treated for acute GVHD, 7 responded (58%) of whom 5 CRs (42%). 3 patients did not respond and died from resistant GVHD. Interestingly, 5 patients from the group of grade 3–4 acute GVHD responded. Among the 8 patients treated for chronic GVHD, 6 were responders (75%). In addition, MTX allowed a significant reduction of CS daily dosage ranging from 25% to 80%, as assessed one month after the last administration of MTX. With a median follow-up of 287 days, no increase of CS therapy was necessary among these 6 MTX-responding patients. In the whole study population, toxicity of low dose MTX administration was low (transient and mild reversible cytopenia in 3 cases, 15%). Among the 20 patients, 14 are still alive (70%) with a median follow-up of 293 (range, 65–513) days. Overall, 2 patients died of progressive disease, while 4 patients died from refractory GVHD. Conclusions. In this study, the global response rate of severe GVHD to low dose MTX was impressively high (65%) if considered in terms of salvage therapy in this relatively elderly and high risk population. Low dose MTX appears to be a well-tolerated, inexpensive and likely steroid-sparing agent that is worthy of further investigation in prospective trials for treatment of refractory GVHD, but also as frontline therapy in combination with CS.

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Improved Post-Transplant Outcomes in Hematologic Malignancy Patients Undergoing Non-Myeloablative Hematopoietic Stem Cell Transplant (NMHSCT) Using a 400 cGy Total Body Irradiation (TBI) Dose with Fludarabine.

Blood ◽

10.1182/blood.v106.11.3674.3674 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3674-3674

Author(s):

Ronald M. Sobecks ◽

Karl S. Theil ◽

Lisa Rybicki ◽

Roger Macklis ◽

Brad Pohlman ◽

...

Keyword(s):

T Cell ◽

Median Time ◽

Graft Rejection ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Disease Relapse ◽

Post Transplant ◽

Transplant Outcomes ◽

Preparative Regimen

Abstract Fludarabine and TBI (200 cGy) is a common NMHSCT preparative regimen. However, this regimen resulted in a 14% graft rejection rate and 42% incidence of disease relapse at our institution. We hypothesized that escalation of the TBI dose to 400 cGy may improve post-transplant outcomes. From 12/10/03 to 4/19/05, 17 patients (pts) with hematologic malignancies underwent NMHSCT using a preparative regimen of fludarabine 30 mg/m2/d IV on days −5, −4 and −3 and TBI 200 cGy on days −1 and 0 (total dose 400 cGy). Immunosuppressant therapy consisted of cyclosporine and mycophenolate for matched sibling donor pts (n = 10) or Tacrolimus and mycophenolate for matched unrelated donor pts (MUD) (n = 7), which was started day −1 and discontinued day +56 in the absence of GVHD. Diagnoses included 4 NHL, 3 AML, 2 MDS, 2 myelofibrosis (MFB), 1 Hodgkin lymphoma (HL), 1 ALL, 1 multiple myeloma (MM), 1 CLL, 1 chronic myeloproliferative disorder (CMD) and 1 bilineal acute leukemia (BAL). Only 2 (12%) pts were in complete remission at the time of transplant (both AML). The median time from diagnosis to transplant was 11 months (range, 3–246 months). All transplants were performed as an outpatient, but 16 (94%) pts required hospitalization and the most common reason was for fever (9 pts– 56%). The median CD34+ and CD3+ cell doses infused were 4.92 x 106/kg and 4.44 x 108/kg, respectively. The median time to absolute neutrophil count recovery of ≥500/μL was 10 days (range, 8–13 days) while time to platelet recovery ≥20K/μL was 12 days (range, 11–16 days). T-cell (CD3+) chimerism was monitored by short tandem repeat analysis and complete donor chimerism (CDC) was defined as ≥ 95% donor DNA in CD3+ T-cells. CDC was achieved in 14 (82%) pts at a median of 28 days (range, 21–130 days), whereas, in our prior analysis with pts receiving 200 cGy TBI, 75% of pts achieved durable CDC at a median of 77 days (range, 14–310 days). Ten (59%) pts developed acute GVHD at a median of 61 days (range, 13–85 days) with 4 grade I, 4 grade II, 1 grade III, and 1 grade IV. Chronic GVHD developed in 5 (29%) pts at a median of 10 months (range, 3–13 months) and only 1 (6%) developed extensive chronic GVHD. Responses included 4 CR (1 NHL, 1 AML, 1 CLL, 1 MFB), 4 PR (2 NHL, 1 HL, 1 MM), 2 stable disease (1 CMD, 1 NHL), and 3 not evaluable (2 MDS, 1 MFB). Graft rejection occurred in only 1 AML patient with a MUD and HLA-B and -Cw disparities. Three (18%) pts (1 ALL, 1 AML, 1 BAL) had disease relapse at a median of 6 months post-transplant (range, 2–12 months). The Kaplan-Meier method reported a median relapse-free survival of 11.6 months. Seven pts died, 3 within 100 days of NMHSCT; estimated median survival was 12.7 months. Causes of death included 2 acute GVHD, 1 chronic GVHD, 1 relapse, 1 sepsis, 1 ARDS, 1 cardiac arrest. We conclude that escalation of the TBI dose to 400 cGy in combination with fludarabine for NMHSCT is an effective approach which when compared to the 200 cGy regimen has resutled in less graft rejection (6% vs. 14%, respectively) and a lower relapse rate (18% vs. 42%, respectively). The more rapid achievement of T-cell CDC may be responsible for these differences. Further investigation and follow-up with this regimen is warranted.

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Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Multiple Myeloma (MM): Long Term Follow-up in a Single Centre Series

Blood ◽

10.1182/blood.v112.11.4398.4398 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4398-4398

Author(s):

Malek Benakli ◽

Redhouane Ahmednacer ◽

Amina Talbi ◽

Farih Mehdid ◽

Rachida Belhadj ◽

...

Keyword(s):

Complete Remission ◽

Median Time ◽

Acute Gvhd ◽

Late Onset ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Peripheral Blood Stem Cells ◽

Heavily Pretreated ◽

Blood Stem Cells

Abstract Background: RIC allo-SCT has been proposed as a strategy for retaining the graft versus myeloma effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 15 patients (pts) with MM treated by RIC allo-SCT. Patients and methods: Between April 2001 and December 2007, 15 pts with MM underwent RIC allo-SCT with an HLA-identical sibling donor. Initially, 8 pts had MM with Ig G, one IgA, 2 light chains, 3 non-secretory and one undetermined. Three pts were stage II and 12 stages III. At time of allo-SCT, 6 pts were in complete remission and 9 in refractory/progressive disease (2 received prior autologous transplants). Median age was 48 years (range, 38–60) and the sex-ratio (M/F) 1,5. Median time from diagnosis to RIC allo-SCT was 18 (range, 6–76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 4,5.106/kg (range, 1.92–13). Results: Neutropenia occurred in all pts and the median duration of aplasia was 8 (range, 5–14) days. Only 3 pts (20 %) required red blood cells transfusions and 12 pts (80 %) needed platelets transfusions. Acute GVHD was observed in 6 cases (40 %) including 4 cases of grade II–IV. Eight pts (72 %) had chronic GVHD, of whom 5 with an extensive form. Three pts (20 %) had CMV reactivation at a median time 91 (range, 53–158) days after transplantation. Four pts (26 %) had late onset relapse at a median time of 826 (range, 248–1370) days. TRM was 33 % at one year after RIC allo-SCT. With a median follow-up of 50 (range 14–86) months, 5 pts (33 %) are still alive in complete remission with full donor chimerism. Ten pts (66 %) died (2 early severe infections, 3 acute GVHD, 3 after relapse, one myocardial infarction, and one public highway accident). Overall and progression-free survivals at 7 years are 37,5 % and 31,2 % respectively. Conclusion: This study suggests that RIC allo-SCT is a potential therapy for relapsed MM. However, TRM and relapse remain a matter of concern, likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Future protocols, should aim for better patient selection, focussing on those pts in first chemosensitive relapse.

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Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v126.23.5537.5537 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5537-5537

Author(s):

Colombe Saillard ◽

Raynier Devillier ◽

Sabine Furst ◽

Jérome Rey ◽

Angela Granata ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Donor Type ◽

The Impact ◽

Disease Free

Abstract Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for patients with myelodysplasia (MDS). However, because of age, MDS patients represent a challenging population for such an intensive treatment. Additionally, the low rate of HLA-identical donor has represented a major limitation in this strategy. Recently, reduced-intensity conditioning (RIC) regimens have made feasible Allo-HSCT in the elderly, although relapse rate might be increased. Additionally, the development of HSCT using alternative donors overcomes HLA-compatibility limitations. Graft-versus-host disease (GVHD) is a major post-transplant event, graft-versus-leukemia effect being counterbalanced by toxicity and impaired quality of life. The aim of this retrospective study was to report outcome of patients with MDS who underwent Allo-HSCT and to study the impact of GVHD. Methods Between 2003 and 2014, 100 consecutive patients presenting with MDS, or MDS-secondary AML, underwent Allo-HSCT in our institution. At diagnosis, 58 patients had ≥ 2 cytopenias. IPPS was low/intermediate-1 in 46% and intermediate-2/high in 54%, R-IPSS was very low/low in 25%, intermediate in 20% and high/very high in 55%. Cytogenetics, according to Disease Risk Index (DRI), was intermediate in 79% and adverse in 21%. Secondary MDS represented 27% of our cohort. Before Allo-HSCT, 42% received 5-Azacytidine, 27% intensive chemotherapy and 9% were transplanted upfront. At the time of Allo-HSCT, the median recipient age was 61 (19-71) years. Median time between diagnosis and Allo-HSCT was 12 months (1-131). After excluding patients transplanted upfront, 31 patients still had ≥5% blasts after treatment. Donors were HLA-matched in 70% (41% related, 29% unrelated), 30% were not HLA-matched (10% unrelated, 7% cord blood, 13% T-repleted haplo-HSCT). Stem cell source was peripheral blood stem cells in 90%. Twelve percent of patients received non-myeloablative (NMA) conditioning regimen, 75% RIC and 13% reduced-toxicity conditioning (RTC) regimens. Post-graft immunosuppression consisted in cyclosporine A (CSA) in 58%, CSA-Mycophenolate Mofetil (MMF) in 15%, CSA-Methotrexate in 14% and CSA-MMF-Cyclophosphamide for haplo-HSCT (13%). Results Median follow-up was 37 months (3-197). The incidence of 3-4 acute GVHD at day 100 was 7% (95% CI = 2-12). The incidence of severe chronic GVHD at 3 years was 19% (95% CI = 11-27). One and 3-year non-relapse mortality (NRM) were 23 and 29% respectively. The cumulative incidence of relapse (CIR) at 1 year and 3 years 24% and 33% respectively. One and 3-year progression-free survival (PFS) were 52% (95% CI = 43-63) and 37% (95% CI = 28-49). One and 3-year overall survival (OS) were 60% (95% CI = 51-71) and 48% (95% CI = 39-60). At one year, 51 patients were alive and disease-free, including 61% (n=31) without immunosuppression. At the end of follow-up, 39 patients were alive and disease-free, including 85% (n=33) without immunosuppression and 77% (n=30) GVHD-free. Time-dependent analysis of GVHD impact (Table 1), adjusted on age, donor-type, DRI and conditioning regimen, revealed that acute GVHD strongly impacts on OS (HR 3.8, 95% IC = 2-7, p<0.01), PFS (HR 3.1, 95% CI = 1.7-5.6, p<0.01) and NRM (HR 12, 95% CI = 5.2-28, p<0.01). Chronic GVHD was statistically significant on CIR (HR 0.16, 95% CI = 0.04-0.7, p=0.02) and NRM (HR 2.8, 95% CI = 1-8, p=0.05). Pre-transplant disease characteristics did not have any impact by univariate analysis. Multivariate analysis did not find any impact of age, donor type, DRI and conditioning regimen in terms of OS, PFS, NRM and CIR. Conclusion Our results suggest that GVHD highly influences outcome, regardless of MDS and Allo-HSCT characteristics. It should be quoted that a significant number of patients are alive, long-term survivors, disease-free and GVHD-free suggesting good quality of life. These results invite defining better strategies of GVHD prevention while retaining disease control magnifying the existing graft-versus-leukemia effect. Table 1. Time-dependent analysis of the impact of acute and chronic GVHD, adjusted on age (< or > 60), donor-type (HLA-matched or not matched), DRI and conditioning regimen (NMA, RIC or RTC). HR 95% CI p Acute GVHD OS PFS NRM CIR 3.8 3.1 12 0.4 2-7 1.7-5.6 5.2-28 0.09-1.7 <0.01 <0.01 <0.01 0.2 Chronic GVHD OS PFS NRM CIR 0.7 0.8 2.8 0.2 0.3-1.5 0.4-1.8 1.01-8 0.04-0.8 0.4 0.6 0.050.02 Disclosures Vey: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

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