Haplo Hematopoietic Cell Transplantation Research Articles

Outcomes with HLA-matched unrelated donor versus haploidentical hematopoietic cell transplantation

We investigated the outcomes after adult haploidentical (haplo) and matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) in a single-center study (n = 452) including 276 MUD and 176 haplo transplants. Myeloablative (37%) and reduced-intensity conditioning (63%) were performed. Graft sources included peripheral blood (50%) and bone marrow (50%). GVHD prophylaxis included tacrolimus/methotrexate (53%) and post-transplant cyclophosphamide-based (47%). In MUD versus haplo HCT recipients, a similar incidence of neutrophil engraftment (18 vs 17 days, p = 0.895), grade II-IV acute GVHD (51% vs 50%, p = 0.773), relapse (26% vs 23%, p = 0.578), non-relapse mortality (22% vs 23%, p = 0.817), 1-year disease-free survival (62% vs 63%. p = 0.921), and 1-year overall survival (73% vs 74%, p = 0.744) were observed. Earlier platelet engraftment (22 vs 27 days, p < 0.001) and higher chronic GVHD (45% vs 35%, p = 0.040) were noted in MUD as compared to haplo HCT. Allogeneic transplantation should be done promptly whenever indicated, utilizing either matched unrelated or haploidentical donors.

Post-Transplant Cyclophosphamide Eliminates Disparity in GvHD-Free, Relapse-Free Survival and Overall Survival between 8/8 Matched and 7/8 Mismatched Unrelated Donor Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

Background: Post-transplant cyclophosphamide (PTCy) has become a standard of care for graft-versus-host disease (GvHD) prophylaxis in recipients of human leukocyte antigen (HLA)-matched and mismatched unrelated donor (MMUD) allografts, generating new opportunities for successful hematopoietic cell transplantation (HCT) regardless of patient ancestry. The National Marrow Donor Program (NMDP)-sponsored 15-MMUD study, which used PTCy-based GvHD prophylaxis (PMID 3390526), demonstrated encouraging overall survival (OS) in adult patients receiving MMUD bone marrow grafts matched at ≤7/8 HLA alleles. Currently, the follow-up ACCESS study (NCT04904588) will determine if similar outcomes can be achieved using MMUD peripheral blood stem cell allografts. As part of its 5-year strategic plan, the NMDP aims to determine the extent of differences in GvHD-free, relapse-free survival (GRFS) between 8/8 and 7/8 URD allografts using PTCy and seeks to develop approaches over time to close the presumed gap in URD outcomes. Methods: The primary objective was to compare GRFS between 8/8 and 7/8 URD HCT using the Center for International Blood &amp; Marrow Transplant Research (CIBMTR) database. After analyzing primary results, secondary objectives were added to compare GRFS, OS, and other clinical outcomes among 8/8 URD, 7/8 URD, and haploidentical-related donor (Haplo) HCT. The study included adult patients (age≥18y) with hematologic malignancies (ALL, AML, MDS) undergoing first URD or Haplo HCT between 2017-2020 using PTCy-based GvHD prophylaxis. Kaplan-Meier curves were used to estimate probability of GRFS and OS. Cox regression examined the independent effect of HLA match controlling for other clinical factors on outcomes referenced to 8/8 URD HCT. A priori clinically selected factors considered as possible confounders in the regression model included disease risk index, comorbidity risk, pre-HCT Karnofsky score, conditioning regimen intensity, graft source, donor/recipient CMV serostatus, year of HCT, donor/recipient age and race/ethnicity. Final models were stratified by factors violating the proportional hazards assumption. Factors were eliminated in a backwards fashion if p-values were &amp;gt;0.10 unless inclusion affected the hazard ratio (HR) of HLA match by more than 10%. Interactions were tested against a p-value of &amp;lt;0.01. Results: Table 1 shows demographics for the three patient cohorts: Haplo (n=2772), 8/8 URD (N=1517), and 7/8 MMUD (N=540). Notable differences among the cohorts included: 8/8 URD recipients had younger, predominantly Caucasian donors and were more likely to receive myeloablative conditioning. Haplo recipients had more donor/recipient CMV seropositivity and received more reduced intensity conditioning. Otherwise patient characteristics were similar. Contrary to our expectations, multivariable regression analysis (MVA) showed no significant differences in either GRFS or OS between recipients of 8/8 and 7/8 URD HCT at 1, 2 and 3-years post-HCT ( Figure 1). Outcomes, including relapse and NRM, between 8/8 and 7/8 URD HCT were similar irrespective of conditioning intensity. However, 8/8 URD HCT associated with lower two-year moderate/severe chronic GvHD than 7/8 URD [1.30 (1.00-1.68), p=0.049]. We next compared GRFS and OS among 8/8 and 7/8 URD and Haplo at 3y after HCT. On MVA, GRFS [HR 1.15 (1.04-1.26), p=0.005] and OS [HR 1.15 (1.03-1.29), p=0.013] were significantly better in 8/8 URD compared to Haplo HCT. Differences between 8/8 URD and Haplo appeared to be driven by significantly higher NRM [HR 1.46 (1.22-1.74), p&amp;lt;0.001)] and two-year moderate/severe chronic GvHD [HR 1.28 (1.07-1.54), p=0.007] in Haplo. No significant differences were seen in GRFS or OS at 3 years when comparing 7/8 URD to Haplo. Causes of death among donor types were similar with primary disease relapse/progression, infection and organ failure being the most frequent. Conclusions: Use of PTCy-based GvHD prophylaxis seems to have resolved previously observed differences in GRFS and OS between 8/8 and 7/8 URD HCT. HCT using an 8/8 URD HCT, if available, continues to be the best option for patients lacking a matched sibling donor. Further studies comparing Haplo to 7/8 URD HCT are warranted, but will require larger numbers of 7/8 URD HCT. Both mismatched donor sources substantially increase access to HCT for patients regardless of their ancestry.

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide Expedites Donor-Derived Immune Reconstitution in a Pediatric Severe Aplastic Anemia Cohort

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in &amp;gt;90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery. In a phase III clinical trial, we treated three cohorts of pediatric (age &amp;lt;/=25 years) patients with SAA requiring alloHCT: MUD, MSD, and HAPLO. The MUD cohort included n=15 recipients of 7-8/8 HLA-matched unrelated donor grafts (n=5 7/8, n=10 8/8) with median age 14 years (range 2-17 years), following cyclophosphamide (Cy) 50 mg/kg, fludarabine (Flu) 200 mg/m 2, rabbit anti-thymocyte globulin (rATG) 9 mg/kg total dose rabbit and low dose total body irradiation (TBI) at 200 cGy. The MSD cohort included n=9 recipients of 8/8 HLA-matched sibling donor grafts with median age 15 years (range 12-24 years), following Cy 200 mg/kg and 9 mg/kg rATG. The HAPLO cohort included n=4 recipients of 4/8 HLA-matched related donor grafts with median age 8.5 years (range 2-21 years) following Cy 29 mg/kg, Flu 150 mg/m 2, 9 mg/kg rATG, and low dose TBI at 200 cGy. GvHD prophylaxis consisted of 30 days of mycophenolate mofetil, and 100 days of a calcineurin inhibitor (followed by an 8-10 week taper), with the HAPLO cohort additionally receiving post-transplant Cy (PTCy) 50 mg/kg/day on days +3 and +4. Peripheral blood lymphocyte counts and peripheral blood and bone marrow donor chimerism were evaluated on days +100, +180 and +365. Recipient characteristics were largely equivalent between cohorts, with 43% receiving IST prior to HCT. Clonality was overrepresented in the HAPLO cohort (2 of 4, 1 with monosomy 7 myelodysplastic syndrome and 1 with a large PNH clone), with only 2 of 15 in the MUD and none in the MSD cohorts. Active controlled infections at the time of HCT were additionally overrepresented in the HAPLO cohort, with disseminated pseudomonas in 1. The MUD cohort had 1 with Rhizopus invasive sinusitis (none in the MSD cohort). Achievement of neutrophil engraftment was statistically significantly delayed in the HAPLO cohort at a median of 17 days compared to 12 for MSD and 14 for MUD, p=0.004), however there were no episodes of primary or secondary graft failure. With only a single late death from intracranial hemorrhage in the MUD cohort, OS was equivalent at 2 years (100% in MSD and HAPLO cohorts, 93.3% in MUD). GvHD rates were low with only 1 (MUD) experiencing grade II acute GvHD, and 1 (MUD) experiencing mild chronic GvHD. Immune reconstitution varied by cohort with statistically significantly greater CD3 peripheral blood donor chimerism (p&amp;lt;0.001) as well as CD4 (p=0.04) and CD8 (p=0.03) T cell counts over time for the HAPLO recipients (CD3 chimerism in Fig 1, CD4 count in Fig 2; 2-way ANOVA fixed effects model). Considering a CD4 &amp;gt;200 cell/uL as clinically meaningful, we assessed the proportion of each cohort achieving this milestone at each timepoint. While each cohort had an increase in proportion achieving CD4&amp;gt;200 over time, the HAPLO cohort reached 50% with CD4 &amp;gt;200 at day +100, compared to 11% MUD and 0% MSD (p=0.09). At day +180, the proportion with CD4 &amp;gt;200 were 36% MUD, 25% MSD and 75% HAPLO (1 yr: 90% MUD, 100% MSD and HAPLO). Donor availability remains a challenge to successful transplant for patients with SAA, and haploidentical matches overcome donor limited accessibility. PTCy as GvHD prophylaxis is associated with low incidences of graft failure and severe GvHD. While PTCy might be anticipated to inhibit donor T cells and immune reconstitution, our data, albeit limited by small cohorts, demonstrates superior and more efficient CD3 donor engraftment and CD4 T cell count recovery following HAPLO HCT with PTCy compared to non-PTCy based MUD and MSD cohorts.

Sirolimus Is an Acceptable Alternative to Tacrolimus for Graft-versus-Host Disease Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.

Sirolimus Results in Similar Outcomes to Tacrolimus for Gvhd Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Background Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus (TAC) and mycophenolate mofetil (MMF) for allogeneic haploidentical (haplo) donor hematopoietic cell transplantation (HCT) has proven safe and effective. Many centers replace TAC with sirolimus (SIR) as this drug preserves regulatory T cells and may have a preferable side effect profile with less risk of kidney injury and thrombotic microangiopathy. A recent phase II single arm study reported comparable rates of grade II-IV acute GVHD with the use of SIR after haplo HCT (Bejanyan, Blood Adv. 2021). Methods We performed a retrospective cohort study comparing haplo HCT outcomes with SIR vs. TAC in combination with PTCy/MMF. All consecutive patients receiving haplo donor T cell replete peripheral blood stem cell graft HCT for hematologic malignancy at the Moffitt Cancer Center or the City of Hope Cancer Center between 2015-2020 were included. Associations with HCT related survival outcomes were assessed using Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted using the IBM SPSS analytic software version 28. Results A total of 423 patients met the inclusion criteria of which 84 (20%) received SIR and 339 (80%) received TAC. The SIR group had a higher proportion of patients >60 years (58% vs. 34%, p=<0.01), and the groups were also unbalanced in terms of diagnosis type, conditioning regimen, and cytomegalovirus serostatus (Table 1). Median follow-up was 30 months (range: 2-88 months). Neutrophil engraftment at day 30 was lower with SIR than TAC (89% vs. 95%, p=0.04), while platelet engraftment at day 60 was not significantly different (77% in SIR vs. 84% in TAC; p=0.14). For SIR and TAC, we found no significant differences in the rates of grade II-IV acute GVHD (45% vs. 47%, p=0.6), grade III-IV acute GVHD (20% vs. 15%, p=1.0) or chronic GVHD (48% vs. 55%, p=0.80). The probability of non-relapse mortality (NRM) was similar between SIR vs. TAC groups both at day 100 (19% vs. 11%, p=0.16) and at 1 year (29% vs. 28%, p=0.98) after HCT. Similarly, we observed no significant differences between the SIR and TAC groups in 2-year probabilities of relapse (23% vs. 25%, p=1.0), disease free survival (DFS; 55% vs. 55%, p=1.0) or overall survival (OS; 64% vs. 63%, p=0.99). In multivariate analysis (MVA) (Table 2), TAC was associated with faster neutrophil engraftment (OR=3.33, CI 1.20-9.26, p=0.02), but GVHD prophylaxis type had no significant impact on platelet engraftment, acute or chronic GVHD, relapse, NRM, DFS, or OS after haplo HCT. Conclusions Our study suggests that SIR is a comparable alternative to TAC in combination with PTCy/MMF for GVHD prophylaxis, resulting in overall similar clinical outcomes after peripheral blood haplo HCT. Rather than a uniform approach, the choice of TAC vs. SIR may be determined based on the side effect profile of these medications with consideration of patient medical comorbidities at HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mother Vs Father Haploidentical Donor for T Cell-Replete HCT with Ptcy Prophylaxis

Background: When several haplo donors of similar ages are available, which factors should be prioritized remains a matter of debate. This is a frequent clinical question for recipients who are undergoing haplo hematopoietic cell transplantation (HCT) from a parent donor. Although conventionally a female donor is avoided for a male recipient due to the high risk of graft-versus-host disease (GVHD), gender-mismatch (female-to-male) has not been identified as an independent predictor of worse outcomes in the setting of T cell-replete haploidentical HCT with post-transplant cyclophosphamide (PTCy) prophylaxis. On the other hand, certain (mis)matches at specific HLA loci with haplo HCT are now being recognized as predictors of survival. Thus, it has become even more ambiguous whether HLA or non-HLA factors should be prioritized for a haploidentical donor selection. Whether HLA factors trump non-HLA factors (e.g female-to-male, donor age, relationship) remains an area of active investigation. As patient and donor ages and relationships are important predictors of outcomes and are very tightly correlated to each other, we studied the effects of HLA and non-HLA factors stratified by donor relationship (mother vs father). Objective: We sought to compare the outcomes of T-cell replete haplo HCT using a mother vs father donor with PTCy prophylaxis, after accounting for (mis)matching at individual HLA loci and patient/donor age. Results: We included 57 patients with a mother (n=29) vs father (n=28) donor. Median age at HCT (23 yrs vs 27 yrs, p=0.1) and donor age (50 yrs vs 52 yrs, p=0.9) were similar in both groups. Most received RIC (79% vs 86%, p=0.5), BM graft (83% vs 75%, p=0.5), had HCT-CI >3 (46% vs 64%, p=0.2), and low/intermediate DRI (45% vs 54%, p=0.8), were CMV seropositive (86% vs 79%, p=0.04), and B-leader matched (51% vs 48%, p=0.9) and ABO matched with the donor (76% vs 64%, p=0.4). The recipient was male in 59% (mother donor) vs 61% (father donor). The median follow-up was 54 vs 28 months. Graft failure occurred in 0% vs 4%, p=0.3; the median time to neutrophil engraftment was 18 days in both groups. The cumulative incidence of grade II-IV aGVHD (65% vs 56%, p=0.3) and grade III-IV aGVHD at day 180 (31% vs 15%, p=0.2), 3-yr cGVHD (31% vs 15%, p=0.2); NRM (35% vs 26%, p=0.5), relapse (21% vs 32%, p=0.4), PFS (39% vs 36%, p=0.9) and OS was (53% vs 41%, p=0.3) in mother vs father donor, respectively. In multivariate analysis, no statistically significant differences were noted in any outcome between mother vs father donors, likely due to small number of events. However, B-leader mismatch was associated with a significantly higher risk of NRM (HR 2.7, 95% CI 1.03-7.02, p=0.04), and HLA-A mismatch was associated with a lower risk of NRM (HR 0.3, 95% CI 0.1-0.8, p=0.02), better PFS (HR 0.2, 95% CI 0.1-0.4, p<0.001) and OS (HR 0.1, 95% CI 0.05-0.4, p<0.001). HCT-CI >3 was associated with inferior PFS (HR 3.5, 95% CI 1.5-7.6, p=0.002) and OS (HR 4.1, 95% CI 1.7-9.8, p=0.002). Conclusion: HLA factors, such as B-leader mismatch (high NRM) and HLA-A mismatch (low NRM and high PFS and OS) may have a stronger prognostic impact on mortality than donor-relationship. Recognizing the limitations of the small sample size, our data suggest that among parent haplo donors, in cases where both father and mother are B-leader matched and/or HLA-A mismatched with the recipient, father should be preferred due to a 2-fold higher risk of grade III-IV aGVHD and cGVHD (although statistically non-significant) with maternal donors. However, it remains unclear whether a B-leader mismatched (and/or HLA-A matched) father be selected over a B-leader matched (and/or HLA-A mismatched) mother. Further large-scale studies are needed to comprehend these complex immunobiological relationships. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Son Vs Daughter Haploidentical Donor for T Cell-Replete HCT with Ptcy Prophylaxis

Background: A younger haplo donor is usually preferred over an older donor. However, when several donors of similar ages are available, which factors should be prioritized remains a matter of debate. This is a frequent clinical question for older recipients who are undergoing haplo hematopoietic cell transplantation (HCT) from a child donor. Although conventionally a female donor is avoided for a male recipient due to the high risk of graft-versus-host disease (GVHD), this has not been consistently seen in the setting of T cell-replete haploidentical HCT with post-transplant cyclophosphamide (PTCy) prophylaxis. Additionally, there is increasing recognition of the impact of (mis)matches at specific HLA loci with haplo HCT. Whether HLA factors trump non-HLA factors (e.g female-to-male, donor age, relationship), or vice-a-versa, is unclear. As patient and donor ages and relationships are important predictors of outcomes and are very tightly correlated to each other, we studied the effects of HLA and non-HLA factors stratified by donor relationship (son vs daughter). Objective: We sought to compare the outcomes of T-cell replete haplo HCT using a son vs daughter donor with PTCy prophylaxis, after accounting for (mis)matching at individual HLA loci and patient/donor age. Results: We included 298 consecutive patients with a daughter (n=96) vs son (n=202) donor. Median age at HCT (56 yrs vs 58 yrs, p=0.05) and donor age (27 yrs vs 29 yrs, p=0.1) were similar in both groups. Most received RIC (78% vs 76%, p=0.5) and had HCT-CI >3 (52% vs 54%, p=0.6). Fewer patients with a daughter donor received BM graft (56% vs 74%, p=0.002) and had high/very high DRI (20% vs 41%, p<0.001). Most patients were CMV seropositive (83% vs 81%, p=0.09) and ABO matched with donor (60% vs 61%, p=0.9). Significantly more patients with a daughter donor had HLA-C mismatch (97% vs 88%, p=0.01); other mismatches were similar in both groups: A (91% vs 96%, p=0.2), B-leader (43% vs 37%, p=0.6), DRB1 (92% vs 94%, p=0.5), DQB1 (86% vs 90%, p=0.3), DPB1 (76% vs 80%, p=0.4). The median follow-up was 24 vs 27 months. Graft failure occurred in 2% vs 4%, p=0.5; the median time to neutrophil engraftment was similar (20 vs 19 days). The cumulative incidence of grade II-IV aGVHD (39% vs 34%, p=0.5) and grade III-IV aGVHD at day 180 (12% vs 6%, p=0.1), 2-yr cGVHD (18% vs 12%, p=0.4); NRM (28% vs 33%, p=0.5), relapse (24% vs 29%, p=0.4), PFS (47% vs 38%, p=0.2) and OS (50% vs 46%, p=0.4) were similar in daughter vs son, respectively. In multivariate analysis, daughter donors were associated with similar risk of grade II-IV aGVHD (HR 1.2, 95% CI 0.8-1.9, p=0.3), cGVHD (HR 1.03, 95% CI 0.5-2.3, p=0.9), and NRM (HR 0.9, 95% CI 0.6-1.4, p=0.7) as sons. For survival, significant interactions were noted between donor gender and DRI. In patients with low DRI, there was no impact of donor gender, but in patients with high/v high DRI, daughter donors were associated with improved PFS (HR 0.5, 95% CI 0.2-0.9, p=0.03) and OS (HR 0.5, 95% CI 0.3-0.9 p=0.04) as compared to sons. Relapse rate was highest with son-to-mother (HR 1.7, 95% CI 1.02-2.7, p=0.04). PB graft was associated with a significantly higher risk of cGVHD (HR 3.1, 95% CI 1.5-6.4, p=0.003). High/very high DRI was associated with a high risk of relapse (HR 2.4, 95% CI 1.5-3.9, p<0.001). Patient age >50 yrs had high NRM (HR 2.03, 95% CI 1.1-3.7, p=0.02), poor PFS (HR 1.5, 95% CI 1.02-2.3, p=0.04) and OS (HR 1.6, 95% CI 1-2.5, p=0.05). There was no significant impact of specific HLA mismatches on any of the outcomes. Having 3 class II HLA (vs <3) mismatches was associated with a high risk of cGVHD (HR 3.3, 95% CI 1.3-8.7, p=0.01), with no impact on survival. Conclusion: Among child haplo donors, our data suggest that female donors do not result in any inferior outcomes as compared to male donors. A daughter may even be a preferred donor for patients with high/very-high DRI as it conferred survival benefit as compared to a son donor. This may partly be related to a higher risk of relapse seen in son donor to mother recipient. Also, certain HLA mismatches (e.g. B-leader), which have prognostic implications in haplo HCT in general, did not appear to be of significance when accounted for donor relationship and age in patients with a child donor. Further large-scale studies are needed to comprehend these complex immunobiological relationships. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA Evolutionary Divergence (HED) Informs the Effect of HLA-B-Loci Mismatch on Relapse and Disease Free Survival after Haploidentical Hematopoietic Cell Transplantation (Haplo) with Post-Transplant Cyclophosphamide (PTCY)

The Success of allogeneic Hematopoietic cell transplantation (HCT) is dependent on a potent graft versus tumor (GVT) benefit. GVT relies on tumor-associated antigens TAAs that are presented to donor T cells via human leukocyte antigens HLAs. The high diversity of HLAs allows for presentation of immense repertoire of peptides including TAAs. HLAs are polymorphic and each allele presents a different repertoire of peptides referred to as the immunopeptidome. The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. Patients with higher HED can present a more diverse immunopeptidome, including TAAs and potentially have a benefit of higher GVT after allogeneic HCT. The effect of HED was studied among cancer patients receiving immune check point inhibitors where high HED diversity was associated with better survival. Low recipient HEDs in HLA class I and DR were strong predictors for worse overall survival after matched donor HCT. The effect of HED divergence among recipients of haplo HCT with PTCY has not been evaluated. Moreover, the mismatch between donor and recipient in haplo HCT allows for assessing the effect of HED divergence in the donor and in the donor/recipient mismatched haplotype. To study the effect of HED among recipients of haplo HCT, we analyzed 322 consecutive recipient/donor pairs who received their transplant at our center with a median follow up of 57.2 months (range 18-196). HED was calculated as pairwise differences using two methods: a Grantham distance metric using a perl Script ( https://sourceforge.net/projects/granthamdist/) and manual calculation of one random sample from each analysis to verity results. Data were collected from our database where it was prospectively entered. Patient diagnosis included AML (n=122), ALL (n=68), MDS (n=41), NHL (n=50), other (n=41). Baseline recipient characteristics included a median age of 50 years (19,80), 53% white, HCT-CI≥3 in 50%, Disease risk (intermediate 53%, high/very high 33%), PBSC graft 80% and myeloablative conditioning 49%. Donor characteristics were median age 37 years (13,73), CMV positive 61%, male 61% and female donor to male recipient 21%. Pairwise divergence of HLA class I and class II showed differences in values with HLA-B, DRB1 and DQB1 contributing most to mean HED class I and II. The HED values for recipient included mean HLA class I 6.85 (HLA-A 7.08, B 8.24 and C 3.47), class II 8.58 (DRB1 10.97, DQB1 10.06 and DPB1 4.06). Donor mean HED HLA-class I was 6.5 (HLA-A 6.43, B7.93 and C 4.61), mean HLA-class II was 8.84 (DRB1 10.93, DQB1 11.24 and DPB1 4.06). The mean HEDs for the mismatched haplotype between donor and recipient were class I 6.49 (A 6.43, B 7.8, C4.94) and Class II 8.74 (DRB1 10.48, DQB1 10.06, DPB1 4.06). Next, we performed a univariate Cox model to identify HED variables that are associated with OS, DFS, NRM and relapse. Based on continuous and dichotomized divergence (median cutoff) univariate cox, a high HED in class I mismatched donor-recipient haplotype was significant for worse DFS (HR 1.11, p=0.020), and relapse (HR 1.11, p=0.02). Also, high HED in HLA B in mismatched haplotype was significant for worse OS (HR 1.07, p=0.02), DFS (HR 1.09, p=0.002), higher relapse (HR 1.10, p=0.003) and similar NRM to low HED. AS HLA-B was the biggest contributor to class I HED mean and the only predictor of outcomes in a univariate cox, we evaluated HLA-B in mismatched haplotype ( donor-recipient) further in a Multivariate analysis using dichotomization based on median level. Variables in the analysis included were age (<55, ≥55), gender, race, diagnosis, cell source, regimen intensity, HCT-CI (0-2, ≥3), DRI (low/intermediate, high/very high), CMV status; donor age (<38, ≥38), donor gender, female-donor-to-male-recipient, donor CMV status, year of transplant. The multivariate cox analysis showed that high HED (≥7.8 vs <7.8) was significant for worse DFS ( HR 1.53, 95% CI 1.09-2.16; p=0.01), higher relapse (HR 1.61, CI 1.07-2.44, p=0.024) and similar NRM and OS (table 1) . The significance was reproduced in the lymphoid and myeloid lineages. In Summary, among patients receiving haplo with PTCY, a high divergence in HLA-B mismatch haplotype increases relapse risk and worsens DFS. In addition to this being the first analysis to assess HED in a large haplo cohort, the negative consequences of HED can be mitigated by selecting donors with lower HED in the mismatched haplotype at HLA-B. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Cytogenetic Risk on Outcomes of Non-T-Cell–Depleted Haploidentical Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Baseline cytogenetics and disease status are key factors predicting the outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML). The importance of cytogenetic risk in patients with primary refractory or relapsed (R/R) AML undergoing haploidentical (Haplo) HCT is unknown. We studied the impact of cytogenetic risk in patients with R/R de novo AML with active disease who underwent non-T-cell–depleted Haplo-HCT with post-transplantation cyclophosphamide from 2010 to 2020. Four hundred forty patients with active disease at transplantation from the European Society for Blood and Marrow Transplantation database were analyzed (291 [66.1%] with intermediate-risk [AMLint] and 149 [44.1%] with adverse-risk cytogenetics [AMLadv]). Impact of baseline cytogenetic risk on various transplantation outcomes was evaluated. Pre-transplantation disease status was relapse in 48.1% and 26.8% and primary refractory in 51.9% and 73.2% of the patients with AMLint and AMLadv, respectively (P < .0001). Two-year leukemia-free survival (LFS, 35.5% versus 15.5%, P = .001) and overall survival (OS, 39.2% versus 20.1%, P = .001) were better in AMLint versus AMLadv. In multivariate analysis, the relapse rate was significantly higher (hazard ratio [HR] = 2.17 [95% confidence interval {CI} 1.57-3.0]) and LFS (HR = 1.71 [95% CI, 1.31-2.22]) and OS (HR = 1.69 [95% CI, 1.29-2.22]), significantly lower for patients with AMLadv compared to AMLint, conditioning intensity did not affect leukemia relapse rate. Non-relapse mortality (HR = 1.1 [95% CI, 0.7-1.74]) and graft-versus-host disease–free, relapse-free survival (HR = 1.37 [95% CI, 1.06-1.77]) did not differ significantly between the risk groups. Disease status before transplant (primary refractory versus relapsed) or conditioning intensity did not impact main transplant outcomes. Baseline cytogenetic risk remains a key prognostic factor for patients with R/R AML with persistent disease before non-T-cell–depleted Haplo-HCT.

CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies

Novel graft engineering strategies that allow selective T-cell depletion have made haploidentical donor (haplo) hematopoietic cell transplantation (HCT) feasible for patients lacking a matched donor. We hypothesized that selective CD45RA+ cell depletion can limit graft-versus-host disease (GVHD) through removal of naive T cells but allow for rapid immune reconstitution through adoptive transfer of memory T cells, minimizing risk of graft failure, infections and relapse. We performed a prospective clinical trial utilizing CD45RA+ depleted haplo HCT followed by donor NK cell addback to maximize the graft-versus-leukemia effect in children with high-risk hematological malignancies (NCT01807611), and present here an interim analysis.Between 2013 to 2019, 72 patients (42 males, 30 females) were enrolled. The median age was 8.1 years (range 0.6-20.8). Twenty-nine patients had acute lymphoblastic leukemia (ALL), 39 had myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), 3 had biphenotypic leukemia and 1 had Non-Hodgkin's Lymphoma. At time of HCT, 25 patients were in CR1, 24 in CR2, 4 in CR3/> and 19 had active disease. Of the 53 patients in CR, 22 had evidence of minimal residual/detectable disease (MRD) at HCT. Donors used were mothers (n=30), fathers (n=35), or sibling/other (n=6) with majority (n=62) being KIR-ligand mismatched to the recipient. All patients received serotherapy-free, reduced intensity conditioning with fludarabine, melphalan, cyclophosphamide and Total Lymphoid Irradiation. GCSF mobilized peripheral blood grafts were infused on i) Day 0 CD34 + selected graft (median CD34+: 9.85 x10 6cells/kg, range 1.96-44.64) and ii) Day +1 CD45 RA+ depleted graft (median: CD34+: 5.82 x10 6cells/kg, range 0.58-39.43); providing a large number of CD45RO+ T-cells (median CD3+ : 60.1 x10 6cells/kg, range 16.08-528.43) after depletion of CD45RA+ cells (CD3+CD45RA+ median 0, range 0-0.2 x10 6cells/kg). NK cells (median: 11.7 x10 6cells/kg; range: 1.65-99.2), isolated from a non-mobilized apheresis by CD3 depletion/CD56 selection, were infused on day +6. GVHD prophylaxis included MMF (n=61) and/or Sirolimus (n= 8) until day +42 post-HCT.The median time for neutrophil and platelet engraftment was 11 (range 9-13) and 17 days (range 10-100) respectively. One patient had primary graft failure and was successfully re-transplanted. Immune reconstitution was rapid and robust and recapitulated CD45RA depleted graft content with mean CD3, CD4 and CD8 T-cell count at day +30 of 1080, 640 and 230 cells/ul respectively. TCR Vbeta spectratyping revealed a broad repertoire by day +100 prior to the emergence of naïve T cells. The incidence of Cytomegalovirus and Adenovirus viremia was 38% (28/72) and 13% (10/72) respectively. The cumulative incidence of aGVHD was 36.1% (25.1-47.2%), aGVHD grade III-IV was 29.2% (19.1-39.9%) and chronic GVHD was 20.8% (CI: 12.3-30.9%). With a median follow-up of 3.1 years (range 0.04-8.0 years) the 3-year leukemia free survival (LFS) was 88% (CI: 76.1-100%) for patients in CR1, 70.8% (CI: 54.8-91.6%) for patients in CR2, 50% (CI: 18.8-100%) for patients in CR3/> and 21.1% (CI: 8.81-50.3) for patients with active disease (p = <0.0001). Amongst patients in CR, those with no detectible disease had 3-year LFS of 84.4% (CI: 72.7-97.9%) as compared to 68.2% (CI: 51.3-90.7%) for patients with detectible MRD at time of HCT (p=0.087). Three-year LFS was comparable for ALL and AML at 62.1% (CI 46.7-82.5%) and 58.5% (CI 44.8-76.4%) respectively (p=0.95). For the entire cohort, the 3-year OS and LFS was 68.9% and 62.2% (CI 58.9-80.6% and 51.9-74.6%), respectively. Despite the inclusion of patients with active disease and detectible MRD the cumulative incidence of relapse for the entire cohort was 26.5% (CI:16.8-37.1%), comparable to other studies with patients transplanted in MRD-negative CR. The cumulative incidence of non-relapse mortality was 11.5%, (CI, 5.3-20.4%), with 5/10 deaths occurring in the 19 patients with active disease.In conclusion, selective CD45RA+ depletion allowed for adoptive transfer of abundant memory T cells that along with NK cell addback was associated with rapid, functional immune reconstitution, resulting in low rates of graft failure, viral reactivation and relapse. Despite a higher incidence of aGVHD compared to other T-cell depleted grafts, our approach translated into promising long-term outcomes in this high-risk patient population. DisclosuresSharma: Vindico Medical Education: Honoraria; CRISPR Therapeutics: Other, Research Funding; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy. Gottschalk: Novartis: Consultancy; Catamaran Bio: Consultancy; Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Immatics: Membership on an entity's Board of Directors or advisory committees; Tidal: Consultancy; Tessa Therapeutics: Consultancy. Triplett: Miltenyi: Other: Travel, meeting registration.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Argentina: Results Comparing Matched Related, Unrelated or Haploidentical Donors. a Grupo Argentino De Trasplante De Medula Osea (GATMO) Experience

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many Acute Myeloid Leukemia (AML) patients. There are not direct comparisons of results of HCT according to donor type in our region.Objective: To evaluate the impact of donor type in different outcomes as overall survival (OS), non relapse mortality (NRM), relapse (Rel) and disease free survival (DFS) in HCT for AML patients. Secondary objective was to evaluate early variables like engraftment, Acute Graft versus Host Disease (aGVHD), CMV reactivations, fungal infections and bacteriemias.Materials and Methods: A retrospective analysis of 250 medical records was conducted, addressing all patients who received an HCT for AML in seven Argentinian centers performing all three types of transplants, between January 2012 and December 2016. Mean patient´s age was 37 years; mean donors age 34 years; forty one percent (41%) of patients and 51% of donors were male; 89 patients (36%) received a matched related Allo-SCT (Sib), 78 (31%) an unrelated Allo-SCT (UD) and 83 (33%) a haploidentical Allo-SCT (Haplo). Pretrasplant HCT-CI score was low risk in 51% of the patients, 48% of the population were in CR 1 A myeloablative-conditioning (MAC) was used in 81% of the general population, peripheral blood stem cells were used in 85%.OS and DFS were tested with Kaplan Meier and NRM and Rel with cumulative incidence. Dichotomic variables were tested with Chi2. We conducted a multivariate analysis (MVA) for time dependent variables with Cox Regression.Results: Median follow up were 1.59 years. Patient and donor gender, age, HCT-CI and MAC were similar between the three type of donors., Haplo and UD groups were more likely to be in late stage compared to Sib (64% and 62% vs. 36%; p<0.001). BM source was more frequently used in Haplo (27% vs. 8% Sib and 6% UD ; p=0.001). Engraftment was slower in the Haplo group than in Sib and UD (≥15 days) (85% vs. 35% vs. 40% respectively; p=0.001). Graft failure rates were higher in Haplo than Sib and UD (16% vs. 1% and 4%; p=0.001). CMV reactivation was also more frequent in the Haplo and UD setting (53% and 56% vs.34%; p=0.02). There was a trend to a higher aGVHD incidence in UD group (60% vs. 43% Sib vs 42% Haplo; p=0.06), with no differences in GII-IV (41% vs. 27% vs 33%; p=0.19) or cGVHD (27% vs. 22% vs. 25%; p=0.65).Early NRM (day 100) was lower in Sib (4% Sib vs 13% UD vs 12% Haplo) as well as NRM at 1-3 years, (12-15% vs 21-25% vs 27-29% respectively; p=0.04) (Figure 1). Relapse rates (1-3 years) were higher among Sib and Haplo (39-44% Sib vs 40-40% Haplo vs 21-29% UD; p=0.05) (Figure 2). DFS (1-3 years) was higher in Sib and UD compared to Haplo (50-42% vs 57-46% vs 32-31% respectively; p=0.03) (Figure 3) as was OS (1-3 years 61-51% Sib vs 65-51% UD vs 44-34% Haplo; p=0.01) (Figure 4). This difference remained significant in the early stage disease (p=0.04) but no for late stageMultivariate analysis (expressed as Hazard Ratios with 95% confidence interval) showed that pretrasplant intermediate or high risk HCT-CI score were associated with poorer OS (HR 2.40, 1.34 - 4.30) and (2.67, 1.20 - 5.95). No association was seen with the type of donor used. Late stage disease at diagnosis was associated with higher relapse rates, independent of the type of donor and type of conditioning regime used (HR 2.05, 1.16-3.64). No factor affected negatively NRM after adjustment in MVA.Conclusion: Although early toxicity was similar in both Haplo and UD when expressed as NRM (day 100), worse 1 y and 3 y NRM and higher rates of relapse were observed in Haplo, resulting in a negative impact in OS. This experience shows that Haplo HCT is a complex procedure in the real world. Larger number of patients and prospective trials are needed to establish firm conclusions regarding the best strategy for patients with AML requiring a HCT [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Outcomes and Quality-of-Life Measures Following Haploidentical Vs. Matched Related/Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Background: Haploidentical (haplo) transplantation using post-transplant cyclophosphamide (Cy) based GVHD prophylaxis is a well-established alternative donor approach for allogeneic hematopoietic cell transplantation (HCT). Although outcomes from haplo HCT have been compared to matched related (MRD) and unrelated donor (MUD) allo HCT, quality-of-life (QOL) recovery between these transplant modalities has not been described. We hypothesized that post-transplant QOL is similar between Haplo and MRD/MUD grafts. A single-institution, retrospective cohort study was therefore conducted to compare outcomes including QOL between these groups. Methods: From May 2014 through December 2019, 90 haplo, 102 MRD and 229 MUD adult 1st allo HCTs were performed. Myeloablative conditioning (MAC) for haplo grafts (n=35) included fludarabine (Flu)/ total body irradiation (TBI) and reduced-intensity conditioning (RIC) haplo transplants (n=55) included Flu/Cy/TBI. QOL was assessed prior to transplant and at days +100 and +180 by the FACT-BMT which consisted of the following subdomains: "Physical well-being," "Social well-being," "Emotional well-being," "Functional well-being," "Additional concerns," and sum of all these subdomains as "Total score." Outcomes were estimated and compared with the Kaplan-Meier and log-rank test or cumulative incidence and Gray test. FACT-BMT scores were compared with repeated measures analysis of variance. Results: Patient and transplant characteristics were comparable among the donor sources except for higher median age at HCT in MUD transplants, and haplo grafts were more commonly used non-Caucasians, used RIC regimens and bone marrow grafts (Table 1). Median transplant hospital length of stay was longer for haplo vs. MRD vs. MUD grafts (31 vs.25 vs. 25 days, p&amp;lt;0.001) with longer median time until neutrophil and platelet recovery for haplo compared to MRD and MUD grafts (20 vs. 14 vs. 15 days, p&amp;lt;0.001, and 31 vs. 21 vs. 22 days, p&amp;lt;0.001, respectively). MAC haplo HCT had a higher incidence of CMV (p=0.05) and other infections (p=0.003), but no difference in other outcomes compared to MRD/MUD grafts, including all of the QOL domains. The mean Total scores from baseline to day +180 for haplo HCT were 157-157, MRD 153-166, and MUD HCT 152-163. RIC haplo HCT was associated with higher incidences of infections (p&amp;lt;0.001) and relapse mortality (p=0.04), but lower NRM (p=0.008) and no differences in other outcomes. When comparing RIC haplo to MUD transplants there was significantly better Emotional well-being (p=0.008) and Functional well-being (p=0.011) at day+180; respective mean emotional well-being score for haplo 19-23 and MUD 16-19; mean functional well-being score for haplo 19-24 and MRD 19-19 (Figures 1a and 1b). No difference for the other QOL measures were found; the mean Total scores from baseline to day +180 for haplo HCT were 155-180, and MUD HCT were 150-158 (p=0.25). Discussion: Among MAC recipients, we observed no differences in total FACT QOL scores and individual domains among haplo, MRD and MUD HCT recipients through 6 months post-HCT. After RIC HCT, haplo recipients reported better Emotional and Functional well-being compared to those receiving a MUD graft, although Total FACT score and other QOL domains were comparable through 6 months. Future strategies to lessen infectious complications and relapse may further improve QOL outcomes. Interrogation of QOL among disease specific groups may also elucidate whether additional benefits exist between these different transplant modalities. Disclosures Gerds: Sierra Oncology: Research Funding; Gilead Sciences: Research Funding; Celgene: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Nkarta Therapeutics: Honoraria; Incyte: Honoraria; Mallinckrodt: Honoraria; Anthem, Inc.: Consultancy.

Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization

Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization

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

Alternative Donor Hematopoietic Cell Transplantation for Pediatric, Adolescent and Young Adult with Hematological Diseases

Hematopoietic cell transplantation (HCT) is the only potential curative option for many advanced hematologic diseases. Pediatrics, adolescent and young adult (PAYA) patients overall have less pre-HCT comorbidity or organ toxicity and lower transplant related morbidity and mortality risk compared to older adults. As such, a higher percentage of patients in this age group tend to receive myeloablative conditioning (MAC) over non-myeloablative regimens. Current alternative donor sources when a matched sibling donor (MSD) is not available include matched unrelated (MUD), umbilical cord blood (UCB), and haploidentical (Haplo) donors. While there are accumulating data comparing the HCT outcomes between MUD vs. Haplo or UCB in adult patients, the data are sparse in PAYA patients. In this retrospective study, we reviewed 314 consecutive patients aged 1-39 years who underwent their first allogeneic HCT using MAC at City of Hope between 1/2005-7/2018. Patients who received HCT from a matched sibling donor were excluded. Patients received HCT from either an 8/8 HLA MUD (n=196 [BM= 27%, PBSC= 73%]), UCB (n=83 [single: n=30, double: n=53]) or Haplo (n=35) donor. The most used MAC regimens were fractionated total body irradiation-based (n=234, 74%). All Haplo recipients got post-HCT cyclophosphamide (PTCy) as GVHD prophylaxis. To adjust for the difference in transplant era between UCB (predominantly performed in earlier years) and Haplo (carried out predominantly in more recent years) the comparative analyses were focused on Haplo or UCB vs. MUD. Univariate and multivariable Cox regression models were used to assess the impact of patient, disease, and treatment factors on overall survival (OS), progression-free survival (PFS), relapse/progression (RP), and non-relapse mortality (NRM). Median age of patients at the time of HCT was 24 years (range: 0.7-39), with 55% of patients being male. KPS was ≥80% in 88% of the patients and 25% had HCT-CI ≥ 2. The most common diagnoses included: ALL (48%), AML (41%), and MDS/CML (11%). DRI was high/very high in 44% of patients. Groups were balanced in general but patients in the Haplo group had higher HCT-CI (median: 2, p&amp;lt;0.01), more frequently had high/very high disease risk (49%, p&amp;lt;0.01) and higher KPS ≥80% (77%, p&amp;lt;0.01). Neutrophil engraftment was achieved at a median of 23 days (range: 10-94) in the UCB, 16 days (range: 12-32) in the Haplo and 15 days (range: 10-33) in the MUD (p&amp;lt;0.01). After a median follow up duration of 36 months (range: 5.9-36), 3-year OS was inferior among recipients of UCB-HCT (53%, 95% CI: 42-63) compared with the MUD (63%, 95% CI: 56-70; p=0.03), while similar between Haplo (62%, 95% CI:41-78) and MUD (p=0.82). The lower OS in UCB group was primarily due to the significantly higher NRM at 3 years (34%, 95% CI: 24-44) compared with the MUD (16%, 95%CI: 11-22, p&amp;lt;0.01); and 3-year NRM was not significantly different between Haplo (18%,95%CI: 6-34) and MUD (p= 0.99). On the contrary, the cumulative incidence of relapse (CIR) at 3 years was significantly lower in the UCB group (14%, 95%CI: 8-24) compared to MUD (29%, 95%CI: 23-36, p=0.01); the difference in CIR was not significant between Haplo (29%, 95% CI: 16-51) and MUD (p=0.81). PFS at 3 years was not significantly different among the three donor groups (p=0.43). Cumulative incidence of day 100 acute GvHD grade 2-4 was 61% (95% CI: 55-66) in the whole cohort, with no significant difference among the three groups (p=0.27). Cumulative incidence of chronic GVHD at 3 years was higher in the MUD group (66%: 95%CI: 59-72) compared to UCB (45%, 95%CI: 34-56, P&amp;lt;0.01) and Haplo (47%, 95% CI: 28-64, P=0.01). By multivariable analysis, patients with high/very high disease risk had worse OS (HR=1.8, 95% CI: 1.2-2.6, p&amp;lt;0.01) and PFS (HR=1.8, 95% CI: 1.3-2.5, p&amp;lt;0.01) and higher R/P (HR=2.3, 95% CI: 1.4-3.6, p&amp;lt;0.01). Neither Cord nor Haplo was significantly associated with OS compared with MUD when adjusted for Age, HCT CI, DRI, KPS, and HCT Era. In conclusion, our results indicated that in PAYA patients without a suitable MSD, outcomes of Haplo HCT are comparable to MUD HCT. By univariate analysis, UCB HCT was associated with a lower relapse rate compared to MUD. However, survival was worse in recipients of UCB HCT due to the higher NRM, possibly resulted from more infections and engraftment delays in these patients. Figure 1 Disclosures Ali: Incyte Corporation: Consultancy. Nakamura:Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Al Malki:Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy; Rigel Pharma: Consultancy.

1763. The Use of Haploidentical Donors Compared with HLA-Matched Unrelated Donors is Associated with Increased Risk of BK Viruria and Hemorrhagic Cystitis

BackgroundBK virus-associated hemorrhagic cystitis (BK-HC) is a common and often serious complication of hematopoietic cell transplantation (HCT). Studies have suggested a higher incidence of BK-HC in patients receiving haploidentical (haplo) HCTs compared with those receiving matched unrelated donor (MUD) transplants.MethodsWe retrospectively identified all adult patients receiving HCT from MUD or haplo donors at Washington University School of Medicine between January 1, 2011 and January 1, 2016. Via informatics queries, we obtained the results of every urine BK test performed on these patients. Patients with BK viruria were then evaluated for BK-HC and graded according to established criteria. The last day of follow-up was April 31, 2017.Results503 MUDs and 140 haplos were identified for inclusion in the study. Haplo patients were significantly more likely to be nonwhite (21% vs. 5%, P < 0.001) and were younger (median age: 51.5 vs. 55, P = 0.01). Conditioning regimens were also significantly different; haplos were less likely to receive myeloablative conditioning (44% vs. 57%, P < 0.001) and busulfan-based conditioning (13% vs. 39%, P < 0.001), but were more likely to receive total body irradiation-based conditioning (83% vs. 26%, P < 0.001). Haplos were also more likely to have undergone previous allogeneic HCT (26% vs. 6%, P < 0.001). The cumulative incidence of both BK viruria and BK-HC were significantly higher in haplos (both P < 0.001). This was observed at 100 days, 180 and 365 days (Table 1).ConclusionWe found a significantly higher incidence of both BK viruria and BK-HC in patients receiving haplo HCT compared MUD HCT. Significant demographic and clinical imbalances exist between our two cohorts and attribution of increased risk for BK-HC to donor type vs. other factors should be further explored. Disclosures All authors: No reported disclosures.

Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P = .03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P = .02; and HR, 4.2; 95% CI, 1.7 to 9.9; P = .001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P = .005, HR, 3.8; 95% CI, 1.5 to 9.7; P = .005; and 3.2; 95% CI, 1.3 to 7.9; P = .01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.

Selecting the Best Donor for T Cell-Replete Haploidentical Transplantation: Importance of HLA Disparity, NK Alloreactivity, and Other Clinical Variables

Lack of a matched sibling or unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation (HCT). Haploidentical (haplo) donors are readily available for nearly all such patients. However, donor selection criteria to determine the optimal haplo donor are not readily available. In order to determine which donor characteristics are most important in predicting transplant success, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo HCT with post-transplant cyclophosphamide for hematologic malignancy. Donor characteristics were evaluated by multivariate Cox analysis and correlated with overall survival (OS), disease-free survival (DFS), relapse/progression, and non-relapse mortality (NRM), while controlling for significant patient and transplant-related factors. Donor variables analyzed included age, sex, relationship to recipient, CMV status, ABO compatibility, HLA disparity and several NK alloreactivity models (KIR receptor-ligand, ligand-ligand, haplotype, B content, activating KIR-based education systems, Sekine donor licensing model). Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively, and 41% of donor-recipient pairs were non-Caucasian. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. In multivariate Cox analysis, patient/transplant characteristics associated with improved OS and DFS included recipient age <55 years, black race, CMV seronegativity, low/intermediate disease risk index (DRI), and more recent transplant year. When adjusting for significant patient/transplant variables, donor characteristics independently associated with improved overall survival included presence of HLA-DR mismatch [GVH direction] (HR 0.35, p=0.010), the presence of HLA DP non-permissive mismatch [GVH direction] (HR 0.51, p=0.033), KIR receptor-ligand mismatch (HR 0.56, p=0.023), the presence of KIR B/x haplotype with KIR2DS2 (HR 0.38, p=0.005 vs. B/x without KIR2DS2; HR 0.47, p=0.013 vs. A/A), donor CMV positivity (HR 0.49, p=0.009) and donor relation (child vs. parent - HR 0.31, p=0.016; sibling vs. parent - HR 0.48, p=0.087). Donor characteristics independently associated with reduced risk of disease relapse/progression included the presence of KIR receptor-ligand mismatch (HR 0.39, p=0.001), KIR B/x haplotype with KIR2DS2 (HR 0.43, p=0.023 vs. B/x without KIR2DS2), the presence of ≥4 (out of 10) HLA allelic mismatches [GVH direction] (HR 0.29, p=0.001), the presence of a non-permissive HLA-DP mismatch (HR 0.25, p<0.001) and the use of a non-parental donor (child vs. parent - HR 0.26, p=0.010; sibling vs. parent - HR 0.37, p=0.039). Donor characteristics associated with increased NRM included higher HLA disparity (HR 7.86, p=0.016), HLA-DR match (HR 15.99, p<0.001), absence of KIR B/x haplotype with KIR2DS2 (A/A haplotype - HR 5.03, p=0.003; B/x without KIR2DS2 - HR 3.92, p=0.034), CMV seronegativity (HR 2.99, p=0.026), and female donor-male recipient (HR 2.35, p=0.071). Adjusted 3-yr OS was improved in patients with the presence of KIR R-L mm (66% vs 50%, p=0.013), KIR B/x with KIR2DS2 (69% vs. 55% [A/A] or 43% [B/x without KIR2DS2, p=0.052 and 0.007, respectively]), HLA-DR mm (64% vs. 45%, p=0.071), and HLA-DP non-permissive mm (72% vs. 56%, p=0.026), emphasizing the importance of donor HLA and KIR typing for optimal donor selection (see figure). This large, single institution analysis demonstrates the significance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the donor selection process for haplo HCT. These results suggest that HLA-DP and donor KIR typing should be performed routinely in T cell-replete haplo HCT to assist in donor selection and risk stratification. [Display omitted] DisclosuresSolh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau.

HLA Disparity Is Associated with Improved Outcomes in Hematological Malignancies After Family HLA-Mismatched /Haploidentical HCT but Not URD

Abstract 2014▪▪This icon denotes a clinically relevant abstract Background:Previous reports have evidenced that donor-recipient HLA disparity is not associated with improved outcomes after URD hematopoietic cell transplantation (HCT). Some data indicates that Haploidentical (haplo) HCT may result in lower relapse and better outcomes than HLA-identical sibling transplantation in lymphoma. Unfortunately, HLA disparity coming along with severe GVHD and infectious diseases may counteract any benefits from this potentially intensive graft-versus-leukemia (GVL) effects. Here we investigate the impact of donor types on clinical outcomes in 233 patients with hematological malignancies from our single BMT Center. Patients and methods:The outcomes of 233 patients, median age 23 years (4–62), with leukemia undergoing HLA-matched sibling(MRD) (n=52), unrelated (URD) (n=52) and related HLA-mismatched/haploidentical (haplo) (n =129) HCT, performed during the same time period (2007–2012) in single Med Center were compared. Patients received either BUCY2 or BUFlu in HLA-identical sibling HCT, and BUCY + ATG or BUFlu +ATG in URD and haplo cohorts as conditioning regimens, followed by G-CSF mobilized unmanipulated marrow and/or peripheral blood (PB) transplantation. All HLA typing has been performed using high-resolution DNA techniques. In haplo cohort, a hundred-four patients were 3/6 identical, 4 were 4/6 identical and 21 were 5/6 identical at HLA-A,-B, and -DRB1. In URD cohort, thirty-one were 8/8 identical, 13 were 7/8 identical and 8 were 6/8 identical at HLA-A,-B,-Cw and -DRB1. The median number of infused nucleated cells and CD34+ cells were 7.5×108/kg and 5.8×106/kg, respectively. 100/129 haplo, 36/52 URD and 14/52 sibling HCT received HLA 3/6–5/6 matched unrelated CB or haplo BM co-transplantation on day –1 as “third party” cells. GVHD prophylaxis consisted of CSA, MMF and short-term MTX. Results:The median follow-up was 23 mon. (range, 2.5mon.-59.2mon.). All patients engrafted to ANC exceeding 0.5× 109/L at 13.5 d (range, 10–19 d) in matched HCT and URD vs. 125 patients engrafted in haplo patients at 13.5d (8–25d). All patients achieved platelet engraftments in both matched and URD cohorts, at 13.5 d (10–22 d) vs. 124 patients engrafted at 13.5d (9–36 d) in haplo, respectively. Univariate analyses showed that the probability of grades 1–4 acute GVHD at 100 days in MRD, URD and haplo were 42%((95% confidence interval [CI], 28%-56%) vs. 48% (CI, 34%-62%) vs. 63%(CI, 54%-71%, P=0.006), respectively. But aGVHD3-4 were only 10%(CI, 3%-21%) vs. 25%(CI, 14%-39%) vs., 19%(CI, 12%-26%, P=0.155), respectively. The 3-year relapse and TRM rates were 34.6% vs. 13% vs. 17.3%(P=0.0126) and 12.7% vs. 30.2 vs. 21%(P= 0.0496) for patients who underwent MRD, URD and haplo transplantation, respectively. The 3-year RRM rates were 29.2% vs. 24.7% vs. 11.6%(P=0.018)after matched vs. URD vs. haplo, respectively. The 3-year Over all survival(OS)probabilities were 61.8% (range, 48.5%-78.4%), 52.5% (38.6%-71.9%) and 69.8 % (61.6%-79.1%) after the matched, URD and haplo HCT, respectively. There were no differences in survival probabilities according to donor types (P= 0.2743). But further analyses indicated that the 3-year OS for patients with early/intermediate disease were 71.8%, 57.3% and 80.2%, P=0.0401, while patients with advanced disease were 36%, 31.8% and 44.2% (P=0.9633)after the matched, URD and haplo transplantation, respectively. Tests in the multivariate analyses indicated that diseases in advanced stage, long period between diagnoses and transplantation, as well as acute GVHD 3–4 were all correlated with lower survival. Conclusion:These data suggest that HLA disparity in Haplo HCT results in relatively lower relapse and RRM, accepted TRM and improvement of survival for hematological malignant patients, especially in early and intermediate disease. The GVL effect using family HLA mismatched donors may be superior to HLA-identical siblings HCT. URD HCT also have lower relapse but do not associated with improvement of OS because relatively high TRM. Family –mismatched /haploidentical HCT should not be the last choice for these patients with Hematological Malignancies. Choosing the best haploidentical donor and further reduction of relapse and infectious complications in the future will lead to better clinical outcomes. Studies with more patients enrolled are undertaken. Disclosures:No relevant conflicts of interest to declare.

Comparative Single-Center Analysis of Hematopoietic Cell Transplantation From Unrelated Umbilical Cord Blood or Haploidentical Related Donor or Mismatched Unrelated Donor in Patients with Hematologic Malignancies

Abstract 4535One of the truly revolutionary advances in hematopoietic cell transplantation (HCT) is the increasingly successful use of alternative donors, as only 1/4 of patients who require an allogeneic hematopoietic cell transplant will have a HLA-matched sibling donor. A substantial proportion of the need has been met by HLA-matched volunteer unrelated donors, but an unmet need still exists, particularly for people who need a more immediate source of hematopoietic cells in China. Thereby, three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo) related donor, and mismatched unrelated donor (MMUD) are available.We report a retrospective analysis of 95 patients with hematologic malignancies who received umbilical cord blood transplantation (UCBT) as a primary unrelated stem-cell source (n=20), or haploidentical (haplo) related donor (n=46), or mismatched unrelated donor (MMUD) (n=29), compare the days of hematopoietic reconstitution & engraftment, and rate of acute graft-versus-host disease (GVHD), and overall survival (OS). The average days of hematopoietic reconstitution (WBC >1.0*10E9) among UCBT recipients were significantly longer than those among haplo/MMUD recipients,(19.77 in UCBT,13.86 in haplo and 11.97 in MMUD, p<0.001). Whereas the average days of full engraftment (STR >95%) among haplo recipients were longer than those among UCBT/MMUD recipients,(24.85 in haplo, 19.29 in UCBT and 20.54 in MMUD, p=0.028). Multivarite analysis demonstrated no apparent differences in the rate of II-IV aGVHD (45% in UCBT, 41.3% in haplo and 55.2% in MMUD, p=0.498), so as to the rate of III-IV aGVHD (30% in UCBT, 41.3% in haplo and 17.2% in MMUD, p=0.543). Overall survival at 2 years was 75% in UCBT, 63% in haplo and 84% in MUUD (p=0.049), and the TRM was 29.4% in UCBT, 39.4% in haplo and 19.2% in MMUD (p=0.245).It shows that UCB is associated with decreased II-IV aGVHD, but hematologic recovery is slow. Haplo HCT is characterized by donor availability for transplantation and post transplant adoptive cellular immunotherapy, but may be complicated by a high transplantation related mortality (TRM). A MMUD transplant may also be an option, but GVHD may be of greater concern. These data gives us some suggestion for using donor availability to decide on the best option for each individual patient. Disclosures:No relevant conflicts of interest to declare.