Incidence Of Extensive Chronic Graft-versus-host Disease Research Articles

Treosulfan is a safe and effective alternative to busulfan for conditioning in adult allogeneic HSCT patients: Data from a single center.

Type of conditioning regimen impacts the outcome of patients who undergo allogeneic HSCT since graft versus host disease (GVHD), infections, regimen related toxicities (RRT) are important causes of post-transplant mortality. Despite the RRT profile of busulfan, it is frequently used worldwide. Treosulfan has advantages in terms of dose of administration, lower incidence of sinusoidal obstruction syndrome and lower neurotoxicity. We retrospectively investigated outcomes of patients who underwent allogeneic HSCT with treosulfan or busulfan based conditioning regimens in our institution. Treosulfan was administered to 94 patients while 85 patients received busulfan. Our outcomes were RRT, chronic and acute GVHD, relapse related mortality (RRM), non-relapse mortality, and fungal infection. The clinical follow up data, regarding the primary and secondary endpoints of our study, of the patients who received treosulfan or busulfan based conditioning regimens were statistically analyzed. The median follow-up was 14 months for the treosulfan group while it was 11 months for the busulfan group (p = 0.16). RRT was 11.7% and 7.1% for treosulfan and busulfan respectively. The incidence of extensive chronic GVHD was less frequent in the treosulfan group compared to the busulfan group (15.7% vs. 32.1%) (p < 0.001). The incidence of acute GVHD (Grade 3 or higher) was 32.2% in the treosulfan group while it was 31.6% in the busulfan group. The RRM was 17% in the treosulfan group while it was 34% in the busulfan group. The non-relapse mortality was 35.5% and 29.4% in the treosulfan group and in the busulfan group respectively (p = 0.962). Treosulfan, with a lower RRM, lower chronic GVHD incidence and with a similar RRT profile appears to be a safe alternative to busulfan.

Impact of Early Anti-Cytomegalovirus Therapy on the Incidence of Chronic Graft-Versus-Host Disease

Introduction: Cytomegalovirus (CMV) infections are associated with poor outcomes in recipients of allogeneic hematopoietic stem cell transplants (HSCTs). Therefore, preventive therapy or preemptive treatment have been developed. Ganciclovir (GCV) and foscarnet (FCN) are essential intravenous anti-CMV agents. A previous regional multicenter study revealed a significantly lower risk of chronic graft-versus-host disease (GVHD) in patients who received preemptive FCN therapy. To validate this observation and to investigate the mechanism or target, we executed a comprehensive nationwide study. Patients and Methods: We defined the early anti-CMV therapy as administration within 180 days after transplantation without evidence of target therapy for CMV infections. We retrospectively analyzed patients who received FCN or GCV as early anti-CMV therapy, and who are not received any anti-CMV agents (no anti-CMV) between June 2005 and December 2019. We excluded patients who received FCN, GCV, valganciclovir, or letermovir as prophylactic therapy; those who began anti-CMV therapy before the day of transplantation; those who received both FCN and GCV; those who underwent T cell-depleting treatment. Results: A total of 19536 adults with hematological malignancies who received their first allogeneic HSCT were included. We compared patients who received FCN (n = 1555) or GCV (n = 7335) as early anti-CMV therapy, and no anti-CMV recipients (n = 10646). FCN or GCV recipients showed higher incidence of acute GVHD than no anti-CMV recipients. The cumulative incidence of acute GVHD 200 days after transplantation were 46% (95% confidence interval [CI], 41%-51%), 47% (95% CI, 45%-50%), and 26% (95% CI, 25%-28%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001). The cumulative incidence of chronic GVHD three years after transplantation were 28% (95% CI, 26%-31%), 37% (95% CI, 36%-38%), and 29% (95% CI, 28%-30%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001). The cumulative incidence of extensive chronic GVHD three years after transplantation were 17% (95% CI, 15%-19%), 22% (95% CI, 22%-23%), and 16% (95% CI, 15%-26%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001) (Figure A). In multivariate analyses adjusted for acute GVHD or other important variables, the risks of extensive chronic GVHD among GCV recipients was higher than FCN recipients (hazard ratio [HR], 1.17; 95% CI, 1.01-1.34; P = 0.031), whereas no-anti CMV recipients and FCN did not showed statistically significance. In further investigations, we performed stratified analyses and revealed that the incidence of extensive chronic GVHD was significantly lower among the FCN recipients than among the GCV recipients only in stratifications that involved male recipients of female donor HSCT (according to sex compatibility). Comparing with GCV, the incidence of extensive chronic GVHD was significantly reduced among male recipients of female donor HSCTs who were taking FCN (HR, 1.63; 95% CI, 1.19-2.23; P = 0.002), but FCN did not affect the incidence of extensive chronic GVHD for other sex compatibility-based stratifications (HR, 1.05; 95% CI, 0.90-1.23; P = 0.51). Among male recipients of female donor transplants, the incidence of extensive chronic GVHD three years after transplantation were 13% (95% CI, 10%-17%), 27% (95% CI, 25%-29%), and 20% (95% CI, 18%-21%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001; Figure B). FCN and no anti-CMV recipients showed similar risk of extensive chronic GVHD (HR, 1.22; 95% CI, 0.89-1.66; P = 0.21). The incidence of extensive chronic GVHD was significantly reduced among FCN recipients who received HSCT from female donors, regardless of stem cell source, GVHD prophylaxis, or previous acute GVHD incidence, in male recipients. Conclusions: In this study, patients requiring early anti-CMV therapy were at a high risk of chronic GVHD, primary due to their increased incidence of acute GVHD. Remarkably, FCN could potentially mitigate the incidence of chronic GVHD for them. Especially, FCN would be beneficial for male recipients of female donor transplants who are typically at high risk for chronic GVHD. These findings pave the way towards a deeper understanding of the mechanism underlying chronic GVHD and overcome the unmet needs of allogeneic HSCT recipients.

Addition of Inotuzumab Ozogamicin to the Conditioning Regimen of Allogeneic Stem Cell Transplantation (allo-SCT) for Relapsed CD22 (+) Lymphoid Malignancies: Long-Term Survival Results

Background: Inotuzumab ozogamicin (InO) is a humanized antibody-drug conjugate that targets CD22+ B-cells. InO demonstrated antitumor activity and manageable toxicity in phase 1/2 trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) as a single agent and in combination with rituximab. In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014). Herein we report long-term survival outcomes. Methods: InO was infused intravenously (iv) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2. Bendamustine 130 mg/m 2 iv daily on days -5 to -3 together with 30 mg/m 2 iv of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m 2 iv on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis. Results: The study included 26 patients. Median age was 59 (range, 26-70) years. Disease types: CLL [n=11 (27%) ; 64% with TP53 mutations (either alone, or with other mutations such as BTK, CDH2, ZMYM3); 22% with complex cytogenetics; 75% with unmutated IGHV; mantle cell lymphoma ( MCL) [n=8 (31%); 83% had Ki 67 &amp;gt;30%; 25% TP53 mutation; and 25% blastoid histology]; Follicularlymphoma (n=5, 19%), and diffuse large b cell ( DLBCL[n= 2; (8%)]. Median # prior treatments was 2.5 (range, 1-6). Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1). At study entry, 18 (69%) patients were in CR, 7 (27%) in PR, and 1 (4%) had SD. Eleven (42%) received their transplants from matched sibling donors (MSDs) and 15 (58%) from matched unrelated donors (MUDs). The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of InO were 4, 2 and 20 patients, respectively. No DLT was observed. Forty-two percent of patients never experienced severe neutropenia and 77% never experienced platelet counts &amp;lt; 20K x 10 9/L. Only 1 patient developed veno-occlusive disease, confounded by the simultaneous manisfestation of hyper-acute GVHD related to prior nivolumab pre-alloSCT. Treatment-related mortality (TRM) at 2-years was 12%. With a median follow-up of 48.7 months (range, 3.6-82.8), the 5-year overall survival (OS) and progression-free survival rates (PFS) were 84% and 80%, respectively. Seven of 8 (87.5%) patients with PR/SD at study entry converted to CR after allo-SCT. There was no significant difference in OS or PFS by histology subtype. Patients who received a transplant from MSDs had OS and PFS rates of 100% v 79% ( P = .060) and 64% ( P = .032) for those who received MUDs, respectively (Figure 1). We compared results of this trial to a group of patients (n=56) with relapsed lymphoid malignancies who received allo-SCT at our center in a preceding prospective trial using BFR conditioning without InO and the same GVHD prophylaxis (clinicaltrials.gov #NCT00880815) which was previously published. There was no statistically significant difference in patients, disease (including histology, disease status pre-transplant) or transplant characteristics between the 2 groups. We found no statistically significant differences in engraftment times, incidence and grades of liver toxicity, TRM, risk of acute grade II-IV or III-IV GVHD. However, the study group containing InO had a higher incidence of extensive chronic GVHD (mainly de novo) than the control group (50% vs 25%, P = .019), respectively. There was a trend in patients with NHL to have a better 5-year OS (93% vs 68%) and 5-year PFS (93% vs 58%, Figure 2) in the study group vs the control groups. We did not observe such a trend in patients with CLL (5-year PFS 62% vs 59%): this could be related to small #patients, level of expression of CD22, more adverse mutations in the study group. Conclusions: Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.

IPSS-Molecular but Not Individual Mutations Predicts Outcomes of Patients with Myelodysplastic Syndrome (MDS) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT): A Mayo Clinic Cohort

The decision to offer Allo-HCT in MDS relies on prognostic scoring models which include clonal cytogenetic (CG) abnormalities, blood counts (cytopenias), and % of marrow blasts (i.e. revised international prognostic scoring system, IPSS-R). Recently, an updated clinical-molecular prognostic model combining genomic profiling with hematologic and CG parameters, namely IPSS-Molecular (IPSS-M), showed better prognostic discrimination across all clinical endpoints and re-stratified almost one-half of patients (pts) vs. IPSS-R. Hence, we evaluated the impact of IPSS-M, CG risk group and individual mutations on Allo-HCT outcomes. The analysis included 191 consecutive MDS pts undergoing Allo-HCT who had available next generation sequencing (NGS) analysis performed at Mayo Clinic (at diagnosis (Dx, n=164 or prior to Allo-HCT, n=162) between 11/2015 and 1/2022. Median age at Allo-HCT was 64 (18-75) yrs, and 112 (58.6%) were male. At Dx, 126 (77%) pts had at least one pathogenic genetic alteration, including (>5% incidence) ASXL1 (28.0%), TP53 (18.9%), TET2 (14.6%), SRSF2(12.2%), U2FA1 (12.2%), DNMT3A (8.5%), BCOR (7.9%), RUNX1 (6.7%), and SF3B1 5.5%; a similar mutational pattern was present at Allo-HCT: ASXL1 (28%),TET2 (15.2%) U2AF1 (13.4%), TP53 (12.2%), SRSF2 (11%), RUNX1(9.8%), DNMT3A (7.3%), SETBP1 (7.3%), SF3B1 (6.7%), BCOR (6.7%), STAG2 (5.5%), and JAK2 (5.5%). Most pts (156, 81.7%) received at least 1 line of therapy, and 45 (23.6%) had >5% marrow blasts at Allo-HCT. The majority (134, 70%) received reduced intensity conditioning. Graft versus host disease (GVHD) prophylaxis consisted of methotrexate/tacrolimus in 138 (77.5%) and post-transplant cyclophosphamide in 40 (22.5%). HCT comorbidity index was >3 in 113 (59%). IPSS-M risk group was calculated and reclassified from IPSS-R into very low (1, 0.6%), low (24, 14.7%), moderate low (34, 20.9%), moderate high (41, 25.2%), high (29, 17.8%), very high (34, 20.9%), mainly for IPSS-R intermediate and high-risk groups (Fig. 1). Median F/U after Allo-HCT was 18.8 (0.4-76.8) months. The 100-day and 1-year non-relapse mortality (NRM) were 7.9% and 18.1%, respectively. The 2-year incidence of death and relapse were 40.1% (95% confidence intervals (CI) 33.5-48%) and 21.6% (95%CI 16.4-28.4%), respectively. Cumulative incidences of grade III-IV acute GVHD was 10% and 1-year cumulative incidence of extensive chronic GVHD was 12%. In multivariable analysis, IPSS-M predicted mortality [Hazard ratio (HR) (per 1 risk category) 1.21, 95%CI 1.00-1.47, p=0.049] and relapse (HR=1.47, 95%CI 1.13-1.92, p=0.004), but not NRM (HR 0.95, 95%CI 0.74-1.22). The 1-year mortality rates for very low/low, moderate-low, moderate-high, high/very high risks were 21%, 24%, 32%, and 37%, respectively (Fig. 1). Individual mutations had minimal independent association with outcome in the multivariable model. For mortality, only ASXL1 at Dx (HR 0.48, 95%CI 0.26-0.91, p=0.024) and SF3B1 at Allo-HCT (HR 2.51, 95%CI= 1.06-5.96, p=0.037) were significant. TP53 at Dx had a borderline association (HR 0.46, 95% CI= 0.942.69, p=0.086). Also, there was no significant association of individual mutation with relapse (including TP53 at Allo-HCT, HR 1.77, p=0.085). Only SF3B1 at Allo-HCT correlated with NRM (HR 3.16, 95%CI= 1.22-8.17, p=0.018). Conversely, CG risk group remained strongly associated with mortality (p=0.007) and relapse (p=0.003), particularly poor/very poor (P/VP) risk CG (Mortality: HR 2.46, 95%CI 1.44-4.19, p=0.001; Relapse: HR 3.46, 95%CI 1.70-7.05, p=0.0006). There was no association of CG risk with NRM. We demonstrate value of IPSS-M risk stratification in predicting outcomes after Allo-HCT for MDS, re-stratifying pts into more discrete prognostic groups that predict mortality and relapse risk. Hence, IPSS-M could inform post allo-HCT decision including future maintenance strategies to prevent relapse in high/very high IPSS-M. CG risk group (esp. P/VP risk), a core component of IPSS-M, independently contributes to outcome prediction both within the model and individually. Disease risk does not predict NRM, and individual mutations have limited association with outcome, suggesting allo-HCT may mitigate the poor prognostic impact of high-risk oncogenic mutations present at Dx, including TP53 and ASXL1. An updated analysis on mutational complexity will be shown at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Conditioning Regimen Intensity and Donor Choice Do Not Impact Outcomes of Patients (pts) with Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) in First Complete Remission (CR1): An EBMT Analysis

Allo-HCT is a curative treatment for fit pts with intermediate and adverse risk AML who achieve CR1. The presence of minimal residual disease (MRD) before allo-HCT has been shown to increase risk of relapse and decrease survival. Here, we describe outcomes of pts with AML who received allo-HCT in CR1 and the impact of MRD before allo-HCT on outcomes. We identified 1032 pts with AML who received allo-HCT in CR1 between 2015 and 2020 from the EBMT registry. The median age was 53.6 (range, 18.1-82.5) years and 526 (51%) were male. Most (94%) pts had de novo AML. FLT3-ITD and NPM1 mutations were detected in 46% and 44% of pts, respectively and high-risk cytogenetics were present in 20%. >1 course of induction therapy was required by 18% of pts to achieve CR1 and 39% were MRD positive at time of allo-HCT. The median time from diagnosis to allo-HCT was 4.9 months. Of pts with FTL3-wild type (FLT3-wt) disease, 33% were MRD negative and 22% were MRD positive at time of allo-HCT. In pts with FTL3-ITD mutation, 29% were MRD negative and 17% were MRD positive at time of allo-HCT. Donor type was matched sibling donor (MSD) in 29% of pts (n=297), matched unrelated donor (MUD) in 47% (n=481), mismatched unrelated donor (MMUD 9/10) in 8% (n=88), or haploidentical donor (haplo) in 16% (n=166). HCT-specific comorbidity index (HCT-CI) was >3 in 22% of pts (n=190). Myeloablative conditioning (MAC) was administered to 45% of pts (n=470), while reduced intensity conditioning (RIC) was used in 55% (n=562). The most common conditioning regimen was fludarabine/busulfan in MSD (n=148, 50%), MUD (n=272, 57%) and MMUD (n=38, 43%) recipients, while thiotepa/fludarabine/busulfan was the most used in haplo-HCT (n=99, 60%). Total body irradiation (TBI) was given to only 8% of pts (n=84), mainly in haplo-HCT (n=29). Most (n=1002, 98%) pts received calcineurin inhibitors (CNI), tacrolimus or cyclosporine A, for graft-versus-host disease (GVHD) prophylaxis in addition to mycophenolate mofetil (43%) or methotrexate (38%). Post-transplant cyclophosphamide was used in 18% (n=191) of pts, with 71% (n=136) having received haplo-HCT, and anti-thymocyte globulin was given to 67% (n=689). The median follow-up was 24 months. At day 60, the cumulative incidence of neutrophil engraftment was 99%. The cumulative incidence of grade III-IV acute GVHD (aGVHD) was 9% at day 180. At 2 years, the cumulative incidence of extensive chronic GVHD (cGVHD) was 17%. At 2 years, relapse incidence (RI), NRM, overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were 26%, 13%, 69%, 61%, and 48%, respectively. The main cause of death was primary disease in 55% of pts (n=157). Other causes of NRM were infections in 16% (n=45), and GVHD in 17% (n=47). In the multivariate analysis, compared to MSD, the use of MUD increased NRM (hazard ratio (HR) 1.86, p=0.02), GRFS (HR 1.28, p=0.039), aGVHD (HR 2.17, p<0.0001), and cGVHD (HR 1.36, p=0.044). The use of MMUD was associated with worse OS (HR 1.6, p=0.042) and higher risk of aGVHD (HR 2.11, p=0.003). Haplo-HCT was associated with higher incidence of aGVHD (HR 1.69, p=0.021) but lower risk of cGHVD (HR 0.63, p=0.033). Older age, lower performance status (PS), requiring >1 induction to achieve CR1, and FLT3-MRD positivity before allo-HCT were associated with worse LFS. Factors associated with lower OS were MMUD 9/10, older age, poor PS, >1 induction to achieve CR1, adverse cytogenetics, and FLT3-MRD positivity before transplant. In vivo TCD was associated with improved GRFS and lower risk of acute and cGVHD without increase of relapse. The use of RIC compared with MAC did not affect relapse, NRM or any other outcome. In conclusion, in pts with AML transplanted in CR1, those requiring >1 induction or with persistent FLT3-MRD positivity at time of allo-HCT had lower OS. Strategies to improve induction therapy, possibly through the addition of targeted agents, aiming to improve CR rates and deepening responses could potentially improve OS after allo-HCT. The use of RIC was associated with similar outcomes compared to MAC. This finding is particularly important for older pts or those with high HCT-CI scores unlikely to tolerate MAC. Survival after MSD allo-HCT is comparable to MUD and haplo, a finding that is in accordance with previous results for haplo and MUD as valid alternative donors in the absence of MSD. The use of MMUD was associated with lower OS compared to MSD and should be used as a last resort donor in this setting.

Outcomes with Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Background: Graft versus Host Disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplant (HSCT). In this condition, the donated stem cells attack the recipient cells, leading to life-threatening consequences. One of the methods of preventing GVHD is by using post-transplantation cyclophosphamide (PTCy). PTCy has proven to have minimum toxicities to the body and, at the same time, has a high success rate in mitigating the rate of rejection and reducing the incidence of GVHD by acting as a potent immunosuppressant on both B and T cell lymphocytes in the host and donor's cells. This systematic review and meta-analysis was conducted to observe the effect of using PTCy for GVHD prophylaxis after HSCT. Methodology: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane Library, and ClinicalTrials.gov through September 2021. We used MeSH terms and keywords for "Cyclophosphamide" AND "stem cell transplantation" AND "GVHD." No filters or publication time limits were applied to the search. A total of 17 studies were included after the screening of 1145 records and excluding duplicates, reviews, and non-relevant articles. Quality evaluation was done using the NIH quality assessment tool, and inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al.R programming language) and proportions with 95% confidence intervals (CI) were computed. Results: A total of 5649 patients from 17 studies were included in this meta-analysis. (Table 1) The median age of patients was 49 (18-80) years, and 24.8% (1402/5649) were males. The median duration of follow-up was 23 (1-158.4) months. The donor type was haploidentical 70% (3258/4650), matched unrelated donor (MUD) 16% (761/4650), matched related donor (MRD) 13% (580/4650), and mismatched unrelated donor (MMUR) 1% (49/4650). The conditioning was myeloablative (MAC) in 53% (1461/2734) and reduced intensity (RIC) in 47% (1273/2734) of the patients. The pooled median overall survival (OS) reported at two years was 59% (95%CI 0.53-0.64, I 2 =66%, p=0.02, n=2843) while the pooled relapse rate (RR) was 29% (95%CI 0.11-0.51, I 2 =92%, p <0.01, n=303). The pooled incidence of acute GvHD grade II-IV and grade III-IV was 26% (95%CI 0.19-0.35, I 2 =80%, p <0.01, n=859) and 12% (95%CI 0.04-0.32, I 2 =94%, p<0.01, n=562), respectively. The pooled incidence of chronic GVHD was 17% (95%CI 0.11-0.26, I 2 =90%, p<0.01, n=819) with pooled incidence of extensive chronic GVHD of 9% (95%CI 0.05-0.19, I 2 =83%, p<0.01, n=697) as reported by seven included studies. The pooled incidence for non-relapse mortality (NRM) was 16% (95%CI 0.09-0.24, I 2 =83%, p< 0.01, n=769). Conclusion: Post-transplant Cyclophosphamide is an effective treatment option for graft versus host disease prophylaxis after allogeneic hematopoietic stem cell transplantation with an acceptable toxicity profile. However, further randomized trials are needed to consolidate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparing Single Cord Blood Transplantation and Matched Related Donor Transplantation in Non-Remission Acute Myeloid Leukemia

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for refractory and relapsed acute myeloid leukemia (R/R AML) in non-remission status. Although human leukocyte antigen (HLA)-matched relatives are the preferred donors for R/R AML patients in non-remission status, their 2-year overall survival following HLA-matched related donor transplantation (MRDT) has only been reported to be 25% due to a high relapse rate of over 50%. Alternatively, cord blood transplantation (CBT) is a donor transplantation procedure that has similar advantages to MRDT in terms of rapid availability, making it possible for urgent HSCT. Moreover, CBT can induce a more potent graft-versus-leukemia (GVL) effect in AML patients under various conditions as compared to other donors. Therefore, this study aimed to investigate the impact of CBT as compared to MRDT using the Transplant Registry Unified Management Program 2 in Japan.MethodThis study included 2451 adult patients with non-remission AML who received CBT (1738 patients) or MRDT (713 patients), including bone marrow transplantation and peripheral blood transplantation, for their first HSCT between January 2009 and December 2018. The primary endpoint was set as 5-year progression-free survival (PFS), and secondary endpoints were set as 5-year overall survival (OS), 5-year cumulative incidence of relapse, 5-year cumulative incidence of non-relapse mortality (NRM), 100-day cumulative incidence of neutrophil engraftment, 1-year cumulative incidence of platelet engraftment, 1-year cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD), and 5-year cumulative incidence of extensive chronic GVHD. The impact of CBT compared to MRDT was then evaluated using propensity score (PS)-matching analysis. In PS calculation, covariates that may influence the selection of the donor and outcomes were selected clinically, and they included the following: age, sex, karyotype risk, disease status, presence of blasts in the peripheral blood, HCT-CI, intensity of conditioning regimen, acute graft versus host disease (GVHD) prophylaxis, and years of HSCT.ResultA total of 2451 patients, comprising 1738 who received CBT and 713 who received MRDT, were enrolled and analyzed. The median age was 55 years (interquartile range, 43-63 years), and 1484 patients (61%) were male. Differences in the clinical characteristics between the two groups were noted. Specifically, the CBT group had older patients, more patients with relapse, blasts in peripheral blood, a higher hematopoietic cell transplant comorbidity index, and had more patients who received reduced-intensity conditioning regimen, tacrolimus-based acute graft-versus-host disease prophylaxis, and transplanted recently. After PS matching, we selected 918 patients among the 2451 patients receiving CBT or MRD, and the patient characteristics were well balanced between the groups.Regarding the primary endpoint, the 5-year PFS was 25.2% (95% CI: 21.1%-25.5%) in the CBT group vs. 18.1% (95% CI: 14.5%-22.0%) in the MRDT group (P=0.009) in the PS-matched cohort (Figure 1). The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.69-1.00, P=0.045).Regarding secondary endpoints, CBT group compared to MRDT group had similar 5-year OS (28.4% in CBT group vs 21.7% in MRDT group, P=0.152), lower 5-year cumulative incidence of relapse (49.3% s 62.8%, P<0.001), higher cumulative incidence of 5-year NRM (25.5% vs 19.1% P=0.0158), lower 100 days neutrophil engraftment (49.5% vs 93.5%, P<0.001), lower one-year platelet engraftment (62.6% vs 79.1%, P<0.001), similar one-year cumulative incidence of grade II-IV acute GVHD (35.5% vs 30.5%, P=0.092), and lower 5-year cumulative incidence of extensive chronic GVHD (8.6% vs 18.5%, P<0.001) in the PS-matched cohort.ConclusionIn this population, CBT was associated with a better 5-year PFS as compared to MRDT after allogeneic HSCT. [Display omitted] DisclosuresKondo: MSD Pharmaceutical: Honoraria; Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Kanda: NextGeM Inc: Patents & Royalties; Ono Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Amgen Astellas BioPharma: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria. Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

Haploidentical transplantation is feasible and associated with reasonable outcomes despite major infective complications–A single center experience from India

Haploidentical stem cell transplantation (SCT) using post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis is a reasonable therapeutic option for patients who do not have a matched sibling donor. Between 2010 and June 2020, 257 patients underwent 269 Haploidentical transplantations, including 122 children. Indications included both malignant (56.8%) and non-malignant (43.2%) diseases. Conditioning regimens included both myeloablative (57.6%) and nonmyeloablative regimens (42.4%). Peripheral blood stem cells were the predominant graft source (96.2%). Based on the disease risk index, patients were classified into early-, intermediate-, and late-stage disease. Engraftment was seen in 205 patients (76.2%) whereas 39 (14.4%) died before engraftment and 23 (8.6%) had primary graft failure. The cumulative incidence of grade II-IV acute GVHD was 47.8% with a 23.9% incidence of grade III-IV acute GVHD. Chronic GVHD was seen in 41.9% with a 15.4% incidence of extensive chronic GVHD. More than 90% had at least 1 documented infection with a 44% incidence of bacterial, 71% viral, and 38% fungal infection. The 2-year overall survival is 40.5% ± 3.2% with a higher survival among children (48.2% ± 3.4%) compared to adults (34.2% ± 4.1%). Survival was poor with late-stage disease (23.6% ± 4.3%) compared to early- (62.5% ± 7.5%) and intermediate-stage (50.3% ± 4.3%). Factors adversely affecting survival included older age of patient (P = .007), late disease status (P = .000), nonmyeloablative conditioning regimen (P = .003), bone marrow as graft source (P = .006), presence of acute GVHD (P = .069), primary graft failure (P = .000), and presence of a documented bacterial (P = .000) and fungal infection (P = .000). On multivariate analysis, older age (P = .027), presence of acute GVHD (P = .033), documented bacterial infection (P = .000), documented fungal infection (P = .000) and primary graft failure (P = .012) continued to remain significant. Haploidentical SCT offers a reasonable chance of cure for patients with both malignant and nonmalignant hematological diseases. Strategies to reduce aGVHD and infection related mortality needs to be explored further.© 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Single Cord Blood Transplantation Versus Unmanipulated Haploidentical Transplantation for Adults with Acute Myeloid Leukemia in Complete Remission

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative post-remission therapy for adult patients with acute myeloid leukemia (AML) in complete remission (CR). The availability of alternative human leukocyte antigen (HLA)-mismatched donors, such as cord blood and haploidentical related donors, could allow patients to receive allogeneic HCT who are without an HLA-matched sibling or unrelated donor. The use of these alternative donors is preferable for patients with advanced disease due to the rapid availability. However, comparative data for cord blood transplantation (CBT) and haploidentical related donor transplantation (haplo-HCT) are limited for adult patients with AML in CR. We sought to compare overall survival (OS); leukemia-free survival (LFS); graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); and chronic GVHD-free, relapse-free survival (CRFS) between single-unit CBT (SCBT) and haplo-HCT recipients for adult patients with intermediate- or poor-risk AML in CR. We retrospectively analyzed and compared the results of allogeneic hematopoietic cell transplantation in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan. Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients (P < .001 for neutrophil, P < .001 for platelet). SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT (P = .013 for grades II to IV acute GVHD; P = .006 for extensive chronic GVHD). Haplo-HCT recipients developed a higher incidence of cytomegalovirus (CMV) antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD (hazard ratio [HR], 1.17; 95% confidence interval [CI], .88 to 1.57; P = .26), relapse incidence (HR, 1.09; 95% CI, .76 to 1.58; P = .61), non-relapse mortality (HR, .83; 95% CI, .58 to 1.18; P = .32), OS (HR, .92; 95% CI, .70 to 1.20; P = .56), LFS (HR, .94; 95% CI, .73 to 1.21; P = .67), GRFS (HR, 1.12; 95% CI, .90 to 1.40; P = .27), or CRFS (HR, 1.15; 95% CI, .92 to 1.44; P = .19) between the two donor types. In the propensity score matching analysis, which identified 180 patients in each cohort, there were no significant differences in transplant outcomes between the two donor types, except for delayed neutrophil (P < .001) and platelet recovery (P < .001) and a higher incidence of grades II to IV acute GVHD (P = .052) in SCBT. SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients.

Stem Cell Transplantation for Diamond–Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.

Prognostic Impact of the Fractionation of Total Body Irradiation for Patients with Acute Myeloid Leukemia Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation

Fractionated total body irradiation (TBI) at a total dose of 12 Gy is widely used for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT); however, there is limited information regarding the optimal number of fractions. To address this issue, Japanese nationwide transplantation registry data were analyzed. Because it was found that TBI was delivered almost exclusively in 4 (n=1215, 30%) or 6 fractions (n=2697, 67%), we focused on comparing 4- versus 6-fraction TBI. Compared to 6-fraction TBI, the 4-fraction version was associated with reduced risk of overall mortality (P=.002) and relapse (P=.018), while there was no difference in the risk of nonrelapse mortality (P=.422). The 4-fraction version did not aggravate acute graft-versus-host disease (GVHD), interstitial pneumonia, or sinusoidal obstruction syndrome of the liver. Chronic GVHD developed more frequently with the use of 4-fraction TBI, although the incidence of extensive chronic GVHD was similar. Subgroup analyses revealed that the 4-fraction version provided benefits for patients in non-complete remission (non-CR) but not for those in CR at transplantation. These findings suggest the advantage of 4-fraction over 6-fraction TBI for patients with AML undergoing allogeneic HCT in non-CR.

Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Outcomes of Prospective Phase II Clinical Trial

Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Outcomes of Prospective Phase II Clinical Trial

Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: Multicenter Analysis by the Polish Adult Leukemia Group.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P=not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P=NS) in the cPNH group and 83.3%/85.3% (P=NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P=.016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.

Reduced risk of chronic GVHD by low-dose rATG in adult matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

The optimal rabbit anti-thymocyte globulin (rATG) graft-versus-host disease (GVHD) prophylaxis regimen in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. In this prospective study, we used low-dose rATG for GVHD prophylaxis in patients or donors aged ≥ 40 years with hematological malignancies receiving MSD-PBSCT. rATG was administered to 40 patients at an intravenous dose of 5 mg/kg divided over day 5 and day 4 before graft infusion. No graft failure occurred. Median times to leukocyte engraftment and platelet engraftment were 11.0 days and 13.9 days. The cumulative incidence of grades 2–4 and grades 3–4 acute GVHD at day +100 was 30.0% and 2.6%. The 2-year cumulative incidence of extensive chronic GVHD and severe chronic GVHD was 11.4% and 14.7%. 93.5% (29/31) of patients had discontinued immunosuppressive medication within 3 years after transplantation. The 2-year cumulative incidence of transplant-related mortality (TRM) and relapse was 14.0% and 22.6%. The cumulative incidence of cytomegalovirus reactivation, Epstein–Barr virus reactivation, and fungal infection was 22.3%, 12.9%, and 12.5%. Kaplan–Meier estimates for overall survival, disease-free survival, and GVHD-free and relapse-free survival 3 years after transplantation were 68.9%, 68.9%, and 54.0%. rATG for GVHD prophylaxis is tolerable and efficacious at a 5 mg/kg total dose administered over 2 days (days −5 to −4) in patients receiving allogeneic MSD-PBSCT.

Partially CD3+-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.

Abatacept Is Effective for Gvhd Prophylaxis after Unrelated Donor Stem Cell Transplantation (URD SCT) for Severe Sickle Cell Disease (SCD)

Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children &amp;gt;13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-mismatched SCT. GVHD prophylaxis included a calcineurin inhibitor and methotrexate as previously described. Abatacept (10 mg/kg) was administered on days -1, +5, +14, +28, +60, +100, +180, +270 and +365 based on efficacy described against acute GVHD with early dosing after SCT for malignant disorders.2,3 The latter 3 doses were omitted in cord transplant recipients. Result Thirteen children (7-21 years) underwent SCT (8/8 URD marrow- 7; 7/8 URD marrow or cord-6) primarily for stroke (N=6), ≥3 severe vaso-occlusive pain crises (N=4) or ≥2 acute chest syndrome episodes per year (N=3). The conditioning regimen was well tolerated. One patient had primary graft rejection after CMV infection (7%) and had autologous recovery. All other patients engrafted; neutrophils at median of 18 days (10-24), platelets at median of 28 days (16-39) and are surviving free of SCD with median follow-up of 12 months (range 4-59). Myeloid lineage donor chimerism was &amp;gt;95% and lymphoid was 39%- 100% at day+100. Two-year OS and EFS was 100% and 92.3% (95% CI, 6.57-35.7), respectively. The day+100 incidence of grade II-IV and III-IV acute GVHD incidence was 23% and 15% respectively. One-year incidence of chronic GVHD was 38%. However, only one patient (7%) developed extensive cGVHD. One patient (7%) developed posterior reversible encephalopathy syndrome and recovered. Viral replication in blood was detected in 7 of 13 patients (7 CMV, 1 EBV reactivation). No patient developed EBV PTLD or required EBV-related intervention. Conclusion In comparison to previous experience1 with RIC and URD SCT, our early observations are (1) a lower incidence of PRES (7 vs 34%) (2) low incidence of severe acute GVHD (15% vs 17% grade III -IV) despite mismatched donors, (3) low incidence of extensive chronic GVHD (7% vs 38%) and (4) no mortality despite patient age (10/13 were &amp;gt;13 years old). We attribute this gain to avoiding steroid use, and the benefit of including abatacept into the treatment regimen. The engraftment, safety, and immune reconstitution profile continue to be monitored in this ongoing trial now accruing in a Phase II cohort. As we and others work toward expanding donor options for SCD transplants, we submit that all alternate donor transplants for severe SCD are experimental and should be performed on clinical trials that track success and pitfalls. Reference: 1. Shenoy S et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016 Nov 24; 128(21): 2561-2567. 2. Koura et al. In vivo T cell costimulation blockade with abataceptfor acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013 Nov; 19(11): 1638-49. 3. Watkins BK et al. T cell co-stimulation blockade with CTLA-4 Ig (Abatacept) for acute GVHD prevention in HLA-matched and mismatched unrelated donor transplantation: Results of a Phase 2 trial. Abstract 65. ASTCT Meetings, Houston 2019. Figure Disclosures Shah: Jazz pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Abatacept, FDA approved for rheumatoid arthritis is a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs).It is used for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation in this study

Donor single nucleotide polymorphism in ACAT1 affects the incidence of graft-versus-host disease after bone marrow transplantation.

Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesteryl esters. A recent in vivo study reported that inhibiting ACAT1 enzyme activity upregulates the membrane cholesterol levels of T cells, enhancing their cytotoxic function. In the present study, we investigated whether the presence of the ACAT1 single nucleotide polymorphism rs11545566 in transplant donors affected the risk of graft-versus-host disease (GVHD) in 116 adult patients who underwent bone marrow transplantation from human leukocyte antigen-identical sibling donors, and who received GVHD prophylaxis with short-term methotrexate and cyclosporine. The frequencies of the AA, AG, and GG genotypes in the donors were 31%, 45%, and 24%, respectively. The cumulative incidences of grade II-IV acute GVHD on day 100 in patients whose donors had AA vs. non-AA genotypes were 6% and 18%, respectively, and those of extensive chronic GVHD at 2years were 7% and 32%, respectively. Multivariate analyses demonstrated that donor rs11545566 non-AA genotypes showed a trend toward a higher incidence of grade II-IV acute GVHD (P = 0.079), and were significantly associated with a higher incidence of extensive chronic GVHD (P = 0.021). These results suggest that donor ACAT1 rs11545566 genotype may be predictive of GVHD.

Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.

PF753 IMPACT OF ANTI‐THYMOCYTE GLOBULIN DOSES IN UNRELATED HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR PATIENTS WITH MYELOID NEOPLASM

Background:Anti‐thymocyte globulin (ATG) is widely used for the prophylaxis of graft‐versus‐host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). However, there is still controversy regarding the optimal dose of ATG.Aims:We analyzed the impact of ATG doses in unrelated HSCT for patients with myeloid neoplasm.Methods:This was a retrospective multi‐center study that assessed the impact of ATG doses on clinical outcomes in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing an unrelated HSCT. The patients who received peripheral blood stem cells (PBSC) transplantation after conditioning regimens containing i.v. busulfan (BU), fludarabine and rabbit ATG between 2010 and 2017 were included in this study.Results:A total of 96 patents, median age 45 years, with AML (n = 74) or MDS (n = 22) were included in our analyses. 66 patients (69%) received a myeloablative regimen (i.v. BU&gt;6.4 mg/kg). High‐ATG (ATG 9 mg/kg), intermediate‐ATG (ATG 4.5–5 mg/kg) and low‐ATG (ATG 3 mg/kg) were given in 11, 49 and 36 patients, respectively. After a median follow‐up of 23 months, the cumulative incidence of extensive chronic GVHD was 9.1% in the high‐ATG group, 13.8% in the intermediate‐ATG group and 29.7% in the low‐ATG group (p = 0.31). The rate of 2‐year relapse‐free survival was significantly higher in the intermediate‐ATG group than other groups (30% in the high‐ATG group vs. 73.2% in the intermediate‐ATG group vs. 53.8% in the low‐ATG group, p = 0.048). The rate of 2‐year overall survival was similar (45.5%, 68.5% and 44.8%, respectively; p = 0.09). The rate of chronic GVHD–free and relapse‐free survival at 2 years was significantly higher in the intermediate‐ATG group (18.2% in the high‐ATG group vs. 53.8% in the intermediate‐ATG group vs. 18.8% in the low‐ATG group, p = 0.0086).Summary/Conclusion:Our study shows that the incidence of extensive chronic GVHD was similar regardless of the doses of ATG after transplantation of PBSC from unrelated donor for patients with AML or MDS. However, the rate of relapse‐free survival and the rate of a composite end point chronic GVHD–free and relapse‐free survival were significantly higher in the intermediate dose (4.5–5 mg/kg) of ATG group.