Related Donor Hematopoietic Cell Transplantation Research Articles

Good engraftment after reduced intensity targeted busulfan-based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies.

Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18years of age. The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3years (range: 3.7-18.8years). The median administered busulfan AUC was 67.4mg/L×h (range: 60.7-80mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1years (range: 2.0-11.1years), whereas T-cell donor chimerism was frequently mixed. This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.

Regimen Intensity and Age Affect Transplant-Related Outcomes after Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Registry Study

Background: Serotherapies such as anti-thymocyte globulin (ATG) and alemtuzumab (AL) are added to conditioning chemotherapy for matched related donor (MRD) hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) to facilitate engraftment and prevent graft-vs-host disease (GVHD). Most reports show ATG added to myeloablative (MA) conditioning; however, the use of AL has increased with investigation of different intensity regimens. The aim of this study was to compare HCT-related outcomes across common conditioning approaches to determine superiority. Methods: Retrospective data on baseline patient and HCT characteristics, and HCT outcomes were collected on 352 SCD patients >1 yr post-HCT at 14 Sickle cell Transplant Advocacy and Research (STAR) Alliance centers. Patients with a non-MRD (n=117) or without serotherapy (n=26) were excluded, leaving 209. MA included busulfan (BU) cumulative dose (CD) >8mg/kg or TBI ≥800 cGy; other regimens were termed non-MA (nMA). Summary statistics were presented as median (IQR) for continuous variables and count (%) for categorical variables. Comparisons were made using two-sample hypothesis tests, with p-value of < 0.05 as significant. Time-to-event analyses followed out to 3 years (censored after) and considered 4 outcomes. The first 3 were estimated via the Kaplan-Meier method: (1) overall survival (OS); (2) rejection-free survival (RFS); with death and rejection as events; (3) severe GVHD-free, RFS (GRFS), with death, RFS and severe GVHD as events; and (4) GVHD was estimated by Fine-Gray competing risk analyses, considering death as a competing event and censoring for rejection. Results: 209 patients received MRD HCT with MA+AL (66, 32%), nMA+AL (49, 23%), MA+horse (hATG) (71, 34%), or MA+rabbit (rATG) (23, 11%). Median recipient and donor age at HCT were 8.4yr (IQR: 5.1, 13.0) and 9.3 (5.1, 15.0) and similar across cohorts. MA+AL had a less severe clinical phenotype and nMA+AL had decreased pulmonary function; other baseline characteristics were similar (data not included). Conditioning for MA+AL included bu/cyclophosphamide (cy) (64%) or bu/fludarabine (flu) (36%), for MA+hATG bu/cy (68%) or bu/cy/flu (32%), for MA+rATG bu/cy (83%) or bu/flu (17%), and for nMA+AL melphalan/flu (92%) plus thiotepa (TT) (8%). GVHD prophylaxis was primarily calcineurin inhibitor and methotrexate or mycophenolate mofetil (91.4%). In MA, serotherapy was proximal timed with AL starting day -5 or -6 at a median (IQR) CD of 1.05mg/kg (0.8, 1.5), hATG starting day -3 at 90mg/kg (90), or rATG starting day -5 at 10mg/kg (9.6, 10.1); in nMA, AL was distal timed starting day -22 at a CD of 1.98mg/kg (1.0, 2.8). Stem cells were bone marrow in all, and GCSF primed in 15.4% of MA+AL and 4% of nMA+AL. Total nucleated and CD3 cell doses were similar across cohorts. nMA+AL had shorter median follow up at 2y (1, 4) vs 3y (2, 6) overall. nMA+AL had earliest time to neutrophil engraftment, required less platelet infusions, and had a shorter hospital stay at median 13d (12, 15), 8 infusions (4,13), and 21d (18, 26), respectively. Readmissions were highest for MA+AL at 77% (vs 64% overall). Graft rejection occurred only in nMA+AL (4, 8.2%) and MA+rATG (2, 8.7%). Table 3-yr CI of grade III/IV aGVHD was highest in nMA at 12% (CI: 0.05, 0.23) vs 0-7%, p=0.130 and for any cGVHD was significantly higher in nMA+AL at 33% (0.19, 0.46) vs 9-19%, p=0.001. 3-year OS was excellent at 94.4% (91.3, 97.7) and comparable per cohort. 3-year RFS was lowest though not significantly in nMA+AL at 87% (0.78, 0.97) vs 91-97%, p=0.260. 3-year GRFS was significantly lower in nMA+AL at 69% (0.57, 0.83) vs 83-94%, p=0.001. When age controlled GRFS in nMA+AL ≥13y was significantly lower at 59% (0.40, 0.88) vs 74-100%, p=0.007. Figure Conclusions: Despite small cohort sizes and retrospective nature, this study allowed for direct comparison of common approaches to MRD HCT for SCD. Outcomes were collectively excellent. nMA had earlier engraftment, less transfusion needs, and shorter hospital stay, although significantly more cGVHD and lower 3-yr GRFS influenced by older age. Current clinical trials in nMA+AL include TT and abatacept to mitigate this difference. We previously reported an association between MA and cardiac dysfunction (Stenger et al. Transplant Cell Ther 2023). Potential benefit of nMA must be balanced against risk of rejection and GVHD, thus providers should carefully consider such when selecting conditioning.

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value <0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [<1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation.

The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129, the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, and 189. Donors were additionally defined for the presence of NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to those with 52Asp (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.24-2.71; P= .002) and lower in those with MICA-STR mismatch than in those with STR match (HR, 0.66; 95%CI, 0.54-0.79; P= .00002). Relapse was lower with NKG2D-72Thr donors than with 72Ala donors (relapse HR, 0.57; 95%CI, 0.35-0.91; P= .02). The protective effects of patient MICB-52Asp with donor MICA-STR mismatch and NKG2D-72Thr were enhanced when all 3 features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB, and NKG2D germ line variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.

Posttransplant cyclophosphamide beyond haploidentical transplantation.

Posttransplant cyclophosphamide (PTCy) has practically revolutionized haploidentical (Haplo) hematopoietic cell transplantation (HCT). Comparisons between Haplo with PTCy and unrelated donor (URD) with conventional graft-versus-host disease (GVHD) prophylaxis have shown comparable overall survival with lower incidences of GVHD with Haplo/PTCy and led to the following question: is it PTCy so good that can be successfully incorporated into matched related donor (MRD) and URD HCT? In this review, we discuss other ways of doing PTCy, PTCy in peripheral blood haploidentical transplants, PTCy in the context of matched related and matched unrelated donors, PTCy with mismatched unrelated donors, and PTCy following checkpoint inhibitor treatment. PTCy is emerging as a new standard GVHD prophylaxis in haploidentical, HLA-matched, and -mismatched HCT.

Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.

Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compare the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Given changes to treatment regimens and differences in length of follow-up, two treatment periods were defined a priori: 2000-2010 and 2011-2018. The SMR of patients treated during the period 2000-2010 and who survived one year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI: 3.20-5.21), and 8.62 (95% CI: 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMR were 2.89 (95% CI: 1.54-4.94), 3.12 (95% CI: 1.90-4.82), and 4.75 (95% CI: 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by five years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after ten years and after five years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond five years to be comparable to that of the general US population.

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard Gvhd Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard GVHD Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS Background: Post-transplant cyclophosphamide (PTCy) is frequently used after allogeneic hematopoietic cell transplant (HCT) as it results in lower rates of graft versus host disease (GVHD). In addition to its predominant use in haploidentical and HLA mismatched donor HCT, PTCy showed potential to become the standard of care GVHD prophylaxis in a setting of HLA matched related and unrelated donor HCT as well (Bolaños-Meade, Lancet 2019). However, recent registry study reported higher risk of relapse after PTCy-based vs.calcineurin inhibitor (CNI) and methotrexate (MTX) GVHD prophylaxis in patients with acute myeloid leukemia (AML) receiving matched sibling donor HCT (Nagler, Transplant Cell Ther 2022). Thus, additional studies are needed to determine whether the benefit of GVHD prevention with PTCy comes at the cost of compromising the graft versus leukemia effect yielding higher relapse of AML and myelodysplastic syndromes (MDS) after HCT. In this retrospective study, we compared the HCT outcomes of PTCy-based vs. CNI-based GVHD prophylaxis in patients with AML and MDS. Methods: We included patients with AML and MDS who received an allogeneic HCT in first or second complete remission at our institution from 1/1/2014 to 12/31/2019. Patients received either a PTCy-based or a CNI-based GVHD prophylaxis regimen. CNI-based regimen consisted of either CNI/sirolimus +/- other (CNI/Siro group) or CNI/MTX +/- other (CNI/MTX group). The graft source in all the patients was peripheral blood (n=582) or bone marrow (n=23). Results: Total of 605 patients were identified: 442 with AML and 163 with MDS (Table 1.). GVHD prophylaxis with PTCy was used in 137 (23%), CNI/Siro in 402 (66%) and CNI/MTX in 66 (11%) patients. The PTCy group had higher proportion of patients who were Caucasian, received haploidentical donor HCT, reduced intensity (RIC) or non-myeloablative (NMA) conditioning or a bone marrow graft. Otherwise, baseline characteristics were similar between the GVHD prophylaxis groups. With a median follow up of 47 months, 149 (25%) patients relapsed, and 265 (44%) patients died. The probability of relapse at 2 years after HCT was similar between the GVHD prophylaxis groups: 23% in PTCy, 26% in CNI/Siro and 23% in CNI/MTX (p=0.94) (Figure 1). Similarly, there were no significant differences in 2-year overall survival (OS) between the groups: 58% in PTCy, 62% in CNI/Siro and 69% in CNI/MTX (p=0.33). We also observed no differences in non-relapsed mortality (NRM) between the groups. Median time to post-HCT relapse was 175 days in PTCy group, 180 days in CNI/Siro group and 131 days in CNI/MTX group. Management for post-HCT relapse included chemotherapy alone (n=58), chemotherapy +/- targeted therapy (n=53), chemotherapy + donor lymphocyte infusion (n=6), second HCT (n=3) and supportive care (n=29). GVHD prophylaxis groups did not differ by type of treatment used for relapse. Post-relapse OS at 2 years was 6% in PTCy, 20% in CNI/Siro and 31% in CNI/MTX groups (p=0.34). In multivariable analysis, the type of GVHD prophylaxis regimen did not significantly influence the post-HCT relapse, NRM, OS or post-relapse survival. Relapse was affected by DRI (p<0.001) and by type of conditioning regimen (p=0.002). NRM was influenced by HCT-CI (p=0.007) and by type of conditioning regimen (p=0.006). OS was inferior with high/very high risk DRI (p<0.001) and HCT-CI ≥ 3 (p<0.001). Survival after post-HCT relapse was better in patients relapsing >12 months after receiving HCT (p=0.003) and in those receiving treatment other than supportive care (p<0.001). Conclusion: In patients with AML and MDS receiving allogeneic HCT, we found similar risk of relapse and survival with PTCy-based and standard GVHD prophylaxis regimens. Survival after post-HCT relapse was also similar between the GVHD prophylaxis groups. The findings of this study support the use of PTCy-based regimen as GVHD prophylaxis after allogeneic HCT in patients with AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-505 Fractionated Total Body Irradiation and Fludarabine Based Conditioning Regimen With Post-Transplant Cyclophosphamide (PTCy) for Mismatched Related and Unrelated Donors HCT for Acute Leukemia and MDS

Allogeneic hematopoietic cell transplantation (HCT) remains the only curable treatment option for malignant hematological disorders. Conditioning regimen and GVL are both important in preventing graft rejection, relapses and GVHD. Choice of regimen depends on the diagnosis, patient characteristic, donor type, disease status and graft source. We present the outcome of patients undergoing FTBI/Fludarabine myeloablative conditioning for mismatched (related or unrelated) donor HCT and PTCy as GVHD prophylaxis. We plan to assess toxicity, outcomes and feasibility of this regimen. To evaluate HCT outcomes in patients undergoing mismatched (related and unrelated) donor transplantation with FTBI/ fludarabine based regimen with posttransplant cyclophosphamide (PTCy). Retrospective design. Single academic center. 155 patients underwent conditioning with FTBI/fludarabine with PTCy-based GVHD prophylaxis for hematologic malignancy at City of Hope from January 2015 to December 2021. All patients received radiation dose ≥ 1200 cGy with fludarabine and GVHD prophylaxis with PTCy 50 mg/kg on days +3 and +4, mycophenolate mofetil (MMF) on days +5 to +35, and tacrolimus or sirolimus started on day +5. Using EMRs, detailed information was obtained on baseline demographics, disease and transplantation characteristics like donor type, CMV status, ABO compatibility, acute & chronic GVHD and relapse data. The primary study outcome is overall survival. Secondary outcomes are GRFS, NRM, relapse, aGVHD, cGVHD and DFS. One hundred and fifty-five patients with median age of 38 (range 9-60) received FTBI/fludarabine based conditioning with PTCy. 56.8% of patients were male and 97.5% had a Karnofsky performance status ≥ 80 with a HCT comorbidity index ≥ 3 in 36.1% cases. The main reason for transplantation was ALL (46.5% cases) and AML (36.1%cases). The median donor age was 31 with 67.1% haplo donors & 32.9% mismatched unrelated. With a median follow-up of 24 months (range: 3 to 81), 100-day NRM was 1.9%, 2-year relapse rate was 11.8%, 2-year OS was 80.1%, and DFS 76.9%. FTBI/ fludarabine is well tolerated MAC regimen in mismatched donors with leukemia and MDS with low transplant related mortality and good outcomes. The study shows FTBI/fludarabine based conditioning regimen as a promising regimen which needs to be studied in future prospective randomized trials.

Enhancing Administrative Claims Data: Feasibility, Validation and Application of Linking Medicare Claims Data and National Marrow Donor Program Search Data.

Administrative claims data provide real-world service utilization of acute myeloid leukemia (AML) treatment, but lacks insight into treatment delays or barriers. The National Marrow Donor Program (NMDP)/Be The Match Search (Search) data contains information on donor search, but lacks information on treatment received if allogeneic hematopoietic cell transplant (HCT) is not performed. We hypothesized that linking these two data sets would create a rich resource to define factors associated with receiving HCT that could not be evaluated with either data set alone. A subset of 2010-2016 Medicare administrative claims data was linked with Search data. A total of 5,351 patients with AML age 65-74 years (HCT = 607, no HCT = 4,744) were identified using Medicare. These patients were then linked to 93,800 records with a donor search between 2009 and 2016. Patient date of birth, sex, disease, ZIP code, transplant center/hospital, and diagnosis date were used for matching. Exploratory analysis was conducted to identify predictors associated with receiving HCT for patients with AML who received a search. The data sets were successfully linked, showing high sensitivity and specificity. The final cohort included 5,085 patients with AML (HCT = 533, no HCT = 4,552). Of 97 patients who received HCT without a matched search, more than 85% received a related donor HCT. Of those not receiving HCT, 609 had a matched NMDP search and 3,943 did not have a matched NMDP search. Multivariate analysis showed time to search, age, diagnosis year, race/ethnicity, and neighborhood education status associated with receiving HCT. Methods herein demonstrate the feasibility of linking Search and Medicare data. Similar methods may be applied to answer critical questions regarding barriers to HCT, thereby identifying areas to improve access to care.

Haploidentical versus Matched Unrelated versus Matched Sibling Donor Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching those of matched donor HCT. Here we compared haploidentical donor HCT versus HLA-matched unrelated donor (MUD) HCT and HLA-identical sibling donor (MSD) HCT in a cohort in which all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD HCT). The most common diagnoses were acute myelogenous leukemia and myelodysplastic syndrome. In multivariate analysis, the haploidentical group was found to have significantly higher nonrelapse mortality (NRM) (hazard ratio [HR], 3.2; 95% confidence interval [CI], 2 to 4.9; P < .001) and inferior progression-free survival (HR, 1.8; 95% CI, 1.4 to 2.4; P < .001) and overall survival (OS; HR, 2.2; 95% CI, 1.6 to 3; P < .001) compared with the MUD group. Relapse was the most common cause of death in all groups. Among causes of NRM, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than the other groups. The haploidentical group also had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis, and cardiovascular toxicities and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of natural killer cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to have particularly high NRM and lower OS in the haploidentical group compared with the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior to those of HLA-matched donor HCT.

Randomized Trial of Tacrolimus and Methotrexate Versus Tacrolimus, Reduced Dose Methotrexate, and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease after Myeloablative Related and Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose (“mini”)-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT.Methods: Patients <70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power.Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P<0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P<0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P<0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P<0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06).Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. [Display omitted] DisclosuresHamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Outcomes of Haploidentical Stem Cell Transplantation in Patients with Fanconi Anemia; A Systematic Review

IntroductionFanconi anemia (FA) is the most common inherited cause of bone marrow failure syndrome, with an incidence of approximately 1 out of 100,000 births per year and a prevalence of 1 in 360 000 live births. Clinical presentation is variable, ranging from classic Fanconi phenotype to absence of somatic abnormalities. Despite advances in understanding disease genetics and pathogenesis, hematopoietic stem cell transplant (HSCT) remains the only curative treatment option for FA patients. However, the future risk of solid organ malignancies persists post-transplant. Although outcomes of allogeneic HSCT for FA are improving steadily but remains suboptimal and often limited by donor availability- especially in countries lacking matched unrelated donor registry. For patients lacking a suitable donor, a trial of androgen is considered but is not curative, and around half of patients will not respond. Haploidentical HSCT has been successfully utilized in the management of acquired severe aplastic anemia and hematological malignancies but only limited published literature is available on its use in inherited bone marrow failure syndromes. We conducted this systematic review to explore survival outcomes of FA patients receiving haploidentical HSCT to assess feasibility of this treatment for patients lacking a matched donor.MethodsWe conducted a literature search on Pubmed, Cochrane, Google Scholar, open grey, and embase databases using the keywords; Haploidentical Transplant and Fanconi anemia. We screened 236 articles according to the Prisma diagram. After thoroughly reading the titles and abstracts, 13 articles were included for data extraction, and results were compiled.ResultsWe analyzed thirteen studies with haploidentical transplant as a treatment for FA, 7 were retrospective, and 6 were prospective. Diagnosis of FA was established by chromosomal breakage analysis and genetic mutation testing. The preferred donor for a haploidentical transplant was a first-degree relative and mother/sibling in most cases. The total number of patients with FA and other disorder who received haploidentical transplants were n=340. The median age at HSCT was 6.7 (0.25-44) years. Two hundred six were male, and 134 were female. The most common conditioning regimen for FA patients was fludarabine, cyclophosphamide, and total body irradiation (TBI) followed by anti-thrombocyte globulin. Mehta. et al. evaluated haploidentical transplant without TBI in the conditioning regimen. The most common regimen to prevent graft versus host disease (GVHD) was cyclosporin and mycophenolate mofetil. Uppulur. R et al., Bonfim. C et al., Thakar. M.S et al. and Ayas, M et al. also used post-transplant cyclophosphamide for in vivo T cell depletion. Zubicaray. J et al and Strocchio. L et al. did not use any post-transplant therapy. Cumulative Overall survival reported was 79.1%. Cumulative acute GVHD was seen in 38.2%, while cumulative chronic GVHD was seen in 18.6% of patients. The most common adverse events were acute and chronic GVHD, Evans syndrome, steroid-induced osteoporosis, and diabetes. Respiratory syncytial virus, pneumonia, candida sepsis reactivation, hemorrhagic cystitis, and mucositis were the most common infections.ConclusionFanconi anemia is an inherited bone marrow failure syndrome with somatic abnormalities and increased risk of hematological and solid organ malignancies. In FA, allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with matched related donor HCT and has shown excellent long-term survival. Currently, limited data is available reporting outcomes of haploidentical HSCT for FA patients. More studies are required to establish safety and efficacy profiles. [Display omitted] DisclosuresAnwer: Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding.

Consolidative CD8+ Memory T-Cell Donor Lymphocyte Infusion Augments Donor Chimerism with a Low Risk of Gvhd Following Matched Related Donor Hematopoietic Cell Transplantation

IntroductionMixed chimerism (MC) after allogeneic hematopoietic cell transplantation (HCT) is associated with an increased risk of disease relapse. An unmanipulated donor lymphocyte infusion (DLI) can convert MC to full donor chimerism (FC) but can also precipitate severe acute graft-versus-host disease (GVHD). We recently showed in a phase I trial that a subset of purified CD8+CD44hi memory T cells derived from HLA-matched sibling donors may induce graft-versus-tumor reactions in patients with relapsed hematologic malignancies following allogeneic HCT with objective responses in 25% of patients and a low incidence of GVHD (Muffly et al, 2016 ASH Abstract #4615). Here we report on the preliminary results of a phase II study using CD8+ memory T-cell DLI as consolidative therapy early after transplant for patients with MC to assess the rate of conversion to FC, the risk of GVHD, and the prevention of disease relapse.MethodsPatients: Eligible patients were 18-75 years of age with a high-risk or refractory hematologic malignancy who underwent nonmyeloablative allogeneic HCT from a matched sibling donor using total lymphoid irradiation and antithymocyte globulin conditioning, and who had MC (<95% donor CD3+ cells) at day +30. Patients were without acute GVHD at the time of the CD8+ memory T-cell DLI and were on tacrolimus or cyclosporine monotherapy for GVHD prophylaxis at the time of DLI.CD8+ memory T cells: Phenotypic CD8+ memory T cells were isolated from matched sibling donors following two days of unmobilized apheresis using a tandem immunomagnetic selection strategy including CD45RA depletion followed by CD8+ enrichment on the CliniMACS Plus instrument. Cell purity was determined by flow cytometry analysis. CD8+ memory T cells were infused between day +30 and day +70 at a dose of 5 x 106 cells/kg, which was determined in the prior phase I trial to be the maximum dose that could be collected from two apheresis products.Study Endpoints: Following DLI, patients were assessed for the development of acute and chronic GVHD, conversion from MC to FC (≥95% donor CD3+ chimerism) within three months, and for disease relapse. Secondary outcomes included the incidence of adverse events, invasive infections, non-relapse mortality, overall survival, and disease-free survival.ResultsPatient characteristics and outcomes after DLI are summarized in Table 1. Nine patients received CD8+ memory T-cell DLI at a median of 42 days post-HCT (range 33-62 days). The cell product was highly enriched for CD8+/CD45RA-/CD45RO+ cells, and flow analysis confirmed the selected cells were phenotypically consistent with the CD8+ T effector memory subset with a post enrichment purity of ≥96% (range 96.4-98.8%) in all patients. Median age of the patients was 60 years (range 30-71 years) with a median follow up of 306 days post-HCT (range 131-747 days). Diagnoses included non-Hodgkin lymphoma (n=5), acute myeloid leukemia (n=2), myelodysplastic syndrome (n=1), and Hodgkin lymphoma (n=1). Median donor CD3+ chimerism at day +30 was 88% (range 23-93%).CD8+ memory T-cell DLI was well tolerated with no adverse events. Six of the nine patients (67%) converted from MC to FC within three months post-DLI with a median donor CD3+ chimerism of 97% (range 95-100%). Two patients developed grade II acute GVHD (skin only) that was treated to resolution. One patient developed mild chronic GVHD. No patients developed severe acute GVHD (grade III-IV) or extensive chronic GVHD. No patients developed invasive infections, and non-relapse mortality was 0%. Of the three patients who failed to convert from MC to FC, two had residual disease at the time of transplant, one of whom had early disease relapse at day +88. Four of the six patients who converted to FC were in complete remission (CR) at the last follow up. One of the three patients with persistent MC was in CR at the last follow up. For the entire study cohort, the median disease-free survival is 1.1 years and the median overall survival is not yet reached.ConclusionsConsolidative CD8+ memory T-cell DLI following nonmyeloablative matched related donor HCT is well tolerated, converted six of nine patients (67%) with MC to FC, and was associated with a low rate of GVHD with no cases of severe acute or extensive chronic GVHD in this study. Patients continue to accrue to trial, and further accrual and longer follow up are needed to determine if this strategy will reduce relapse rates for high-risk patients with MC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Biologically Assigned HLA-Identical Versus Haploidentical Related Donor Hematopoietic Stem Cell Transplantation

Comparison of Biologically Assigned HLA-Identical Versus Haploidentical Related Donor Hematopoietic Stem Cell Transplantation

Hematopoietic Cell Transplantation for Sickle Cell Disease.

Sickle cell disease (SCD) is a severe autosomal recessively inherited disorder of the red blood cell characterized by erythrocyte deformation caused by the polymerization of the abnormal hemoglobin, which leads to erythrocyte deformation and triggers downstream pathological changes. These include abnormal rheology, vaso-occlusion, ischemic tissue damage, and hemolysis-associated endothelial dysfunction. These acute and chronic physiologic disturbances contribute to morbidity, organ dysfunction, and diminished survival. Hematopoietic cell transplantation (HCT) from HLA-matched or unrelated donors or haploidentical related donors or genetically modified autologous hematopoietic progenitor cells is performed with the intent of cure or long-term amelioration of disease manifestations. Excellent outcomes have been observed following HLA-identical matched related donor HCT. The majority of SCD patients do not have an available HLA-identical sibling donor. Increasingly, however, they have the option of undergoing HCT from unrelated HLA matched or related haploidentical donors. The preliminary results of transplantation of autologous hematopoietic progenitor cells genetically modified by adding a non-sickling gene or by genomic editing to increase expression of fetal hemoglobin are encouraging. These approaches are being evaluated in early-phase clinical trials. In performing HCT in patients with SCD, careful consideration must be given to patient and donor selection, conditioning and graft-vs.-host disease regimen, and pre-HCT evaluation and management during and after HCT. Sociodemographic factors may also impact awareness of and access to HCT. Further, there is a substantial decisional dilemma in HCT with complex tradeoffs between the possibility of amelioration of disease manifestations and early or late complications of HCT. The performance of HCT for SCD requires careful multidisciplinary collaboration and shared decision making between the physician and informed patients and caregivers.

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

Granulocyte Colony-Stimulating Factor Is Safe and Well Tolerated Following Allogeneic Transplantation in Patients with Sickle Cell Disease

Background: Granulocyte colony-stimulating factor (G-CSF) is used after hematopoietic cell transplantation (HCT) to enhance neutrophil recovery in patients rendered neutropenic by the agents used in the preparative regimen (PMID: 9187067). G-CSF is contraindicated in patients with sickle cell disease (SCD) due to reported life-threatening complications ascribed to sickle vasculopathy, presumably secondary to leukocytosis and granulocyte activation (PMID: 11880644). Complications include severe vaso-occlusive pain crises, splenic engorgement, rupture, and death (PMID: 19513902). Individuals with sickle trait tolerate G-CSF without toxicity (PMID: 29743574, PMID: 27167356).The safety/toxicity of using G-CSF to enhance neutrophil recovery following HCT for SCD has not been previously described in the context of vasculopathy that is present in recipients but whose hematologic milieu is altered by transfusions and donor product infusion. Aim/Method: The hypothesis that G-CSF use would be safe in SCD patients following HCT was tested in a multicenter trial (NCT 03128996). Patients underwent HCT from matched or one-antigen mismatched (at HLA-A, -B, -C, -DRB1 if marrow; -A, -B, -DRB1 loci if cord) related or unrelated donor products between 2004 and 2019 following reduced intensity conditioning (RIC) which included hydroxyurea, alemtuzumab, fludarabine, melphalan +/- thiotepa. The regimen results in short-term marrow suppression followed by recovery. GVHD prophylaxis included tacrolimus, short-course methotrexate or mycophenolate or prednisone, and since 2018, abatacept. All patients underwent transfusions prior to commencing conditioning to reduce Hemoglobin S (Hb S) levels to &amp;lt;45%. G-CSF was commenced on day +7 post-HCT and continued until the absolute neutrophil count (ANC) was &amp;gt;1.5x103 cells/mL on 3 successive days. The clinical course, outcomes, and toxicities in the first 100 days post-HCT were evaluated as best representing the period of G-CSF influence on SCD recipients. Results: Sixty-four patients with SCD were evaluated post-HCT. The median age at HCT was 10.67 years (range, 1-21). HCT was performed for stroke/increased transcranial doppler velocity (N=32), acute chest syndrome (N=24) and vaso-occlusive episodes (VOE) (N=38). Twenty-nine and 35 patients received related and unrelated donor HCT respectively; 24 were mismatched at one antigen or allele locus. Graft sources included marrow (46), cord (12), peripheral blood (3), marrow + cord (2) and CD34 selected graft with T cell add-back (1). G-CSF was administered for a median of 9.4 days (range 6-33 days) post HCT. Neutrophil engraftment occurred at a median of 14.35 days (range 10-38), platelets at median of 25.2 days (range 12-89). Three patients recovered platelets beyond day 100. Seven patients had primary graft rejection and autologous reconstitution of hematopoiesis. Chimerism analysis in the remaining patients included a median of 93% (range 41-100% in the myeloid lineage; N=30), 89% (range 26-100% in the lymphoid lineage; N=36) and 93% (range 48-100% in whole blood; N=45) on day 100. The incidence of grade I-II and III-IV acute GVHD was 23.4% and 17% respectively during first 100 days. A total of 23 episodes of bloodstream and 7 non-bloodstream sites of bacterial infection were observed in 22 patients. No patient developed SCD related symptoms following post-HCT G-CSF administration. Organ toxicities noted in 17 of the 64 patients were variable [most common were hypertension (4), posterior reversible encephalopathy (3), and renal dysfunction (3)] and expected as part of the transplant process. Conclusion: In this cohort of SCD patients who underwent HCT from different donor sources following RIC and G-CSF to enhance neutrophil recovery, we noted no toxicities attributable to G-CSF. Specifically, no SCD related symptoms or extended hospitalization were encountered in any patient attributable to G-CSF administration. Commencing conditioning at a Hb S level &amp;lt;45% (the pre-alemtuzumab level) and chemotherapy induced destruction of native sickle hematopoiesis may be important factors in mitigating G-CSF related SCD complications post-HCT despite persistent vasculopathy and an inflammatory state. In this setting, G-CSF can be safely administered to SCD patients post-HCT. Disclosures No relevant conflicts of interest to declare.

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

Outcomes of myeloablative, T cell deplete unrelated donor hematopoietic stem cell transplantation at a single center.

e19525 Background: Myeloablative conditioning (MAC) and unrelated donor (UD) hematopoietic cell transplantation (HCT) are associated with increased non-relapse mortality (NRM) compared with matched related donor (MRD) HCT [18%, 21%, and 32% for MRD, Matched UD (MUD), and mismatched MUD (MMUD), respectively, p &lt; 0.001] (Saber et al, 2012). Our center uses alemtuzumab as means of T cell depletion to mitigate NRM risk in UD HCT. Here, we report outcomes utilizing this strategy. Methods: We retrospectively analyzed adult patients (pts) who received alemtuzumab-based T cell deplete MAC UD HCT from August 2012 to December 2017. Outcomes were estimated via Kaplan Meier and cumulative incidence methods. Results: Sixty-eight pts underwent T cell deplete MAC UD HCT for AML/MDS (n = 32), ALL (n = 18), lymphoma (n = 5), and other diseases (n = 13). Thirty-nine (57.4%) underwent a MUD HCT, while 29 (42.4%) underwent a MMUD (≤ 9/10 match) HCT. Median follow up was 35.5 months (m) (range 1.5 – 71.1). Median age was 46 years (range 21 - 68), 58.8% were male. Nineteen AML pts (67.9% of all AML) were considered high risk defined as secondary AML (n = 3), CR2 or more (n = 9), primary induction failure (n = 6) or having gross residual disease at time of HCT (n = 1). At 24 m, overall survival (OS) for the entire cohort was 65.3% (95%CI (CI) 53.5%- 77.2%), GVHD relapse-free survival (GRFS) was 54.8% (CI 42.8%- 66.9%), NRM was 10.4% (CI 4.5%- 19.2%), and relapse incidence (RI) was 27.3% (CI 17.1%- 38.5%). None of the 68 pts had graft failure or rejection. In the AML/MDS cohort, at 24 m OS was 52.3% (CI 33.9%- 70.7%), GRFS was 41.4% (CI 23.9%- 59%), NRM was 9.7% (CI 2.4%- 23.2%), and RI was 39.1% (CI 21.8%- 56.2%). Non-AML/MDS pts at 24 m had OS, GRFS, NRM and RI of 76.8% (CI 62.6%- 90.9%), 66.7% (CI 51.3%- 82.08%), 11.1% (CI 3.4%- 23.9%), and 16.7% (CI 6.6%- 30.6%), respectively. The table summarizes our outcomes. Conclusions: We show that alemtuzumab-based MAC conditioning for UD HCT has the benefit of being well tolerated with low NRM and high GRFS, while having comparable RI and OS compared to published outcomes of T cell replete MAC UD HCT (Saber et al, 2012). However, the retrospective nature without a comparator is a major limitation which necessitates a future prospective study to validate these findings. [Table: see text]

Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p&lt;0.001) and chronic GVHD (HR 0.34, p&lt;0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; 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 ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.