The ideal outcome of allogeneic hematopoietic cell transplantation (allo-HCT) is based on survival that is free of morbidity. The most common causes of treatment failure and morbidity after HCT are relapse, graft-versus-host disease (GVHD), and nonrelapse death. A composite endpoint that measures survival free of clinically significant negative events may be a useful way to determine the success of allo-HCT. We assessed GVHD and relapse-free survival (GRFS) where the events were acute GVHD grades III to IV, chronic GVHD requiring immunosuppression, relapse, or death in 531 consecutive adult patients who received an allo-HCT between 2006 and 2014 at our center. Median follow-up of living patients was 46 months (range, 12 to 123). HLA matched related donor (MRD, n = 198, 37%), matched unrelated donor (MUD, n = 205, 39%), and haploidentical donor with post-transplant cyclophosphamide (HID, n = 128, 24%) were used. Thirty-six percent of patients had a high/very-high Dana Farber disease risk index (DRI). Estimated rates of GRFS at 1 and 2 years after MRD, MUD, and HID transplantations were 34% and 26%, 26% and 17%, and 33% and 31%, respectively, with MRD recipients having a better GRFS than MUD (P < .05). On multivariable analysis, peripheral blood stem cell source (HR, 1.34; P = .04), MUD (HR, 1.41; P = .003), and high/very high DRI (HR, 1.66; P = .001) were all associated with a worse GFRS post-HCT. These data suggest that GRFS can be predicted by patient disease risk, stem cell source, and donor type. Importantly, MUDs produce inferior GRFS to MRDs, whereas HIDs do not.

The composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) has recently been introduced as a tool to assess the success of allogeneic hematopoietic stem cell transplantation (HSCT) and has been incorporated into recent randomized trials of GVHD prophylaxis by the Blood and Marrow Transplant Clinical Trials Network. As developed, GRFS incorporates "chronic GVHD requiring systemic immunosuppression" as a measure of clinically significant chronic GVHD (cGVHD). However, the decision to start patients on immunosuppressive therapy for cGVHD is subjective and physician-dependent. We elected to assess a modification of the GRFS (m-GRFS) that uses a potentially more objective measure of cGVHD, specifically the development of National Institutes of Health grade moderate or severe cGVHD. A total of 613 patients who underwent a first allogeneic HSCT after an HLA-identical sibling (matched related donor [MRD]; n = 212), an 8/8 matched unrelated donor (MUD; n = 251) or T cell-replete haploidentical donor (HID) transplant with post-transplantation cyclophosphamide (n = 150) were included in this analysis. In the HID group, 86 patients (54%) received peripheral blood stem cells as the graft source. The median duration of follow-up was 50.2 months. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95% confidence interval [CI], 32% to 40%) and 28% (95% CI, 25% to 32%), respectively. The 2-year m-GRFS was 30% (95% CI, 24% to 36%) for MRD graft recipients, 24% (95% CI, 19% to 30%) for MUD graft recipients, and 33% (95% CI, 26% to 41%) for HID graft recipients. A multivariate Cox model for m-GRFS identified donor type, Disease Risk Index (DRI) risk, donor-recipient sex mismatch, and year of transplantation as significant predictors of m-GRFS. Patients who received a MUD graft had worse m-GRFS compared to MRD graft recipients (hazard ratio [HR], 1.39; P = .003), whereas HID graft recipients had a similar m-GRFS as MRD graft recipients (HR, 1.10; P = .43). HID was associated with better m-GRFS compared with MUD (HR, .79; P = .046). These data show that m-GRFS is significantly affected by several modifiable factors, including donor type, donor-recipient sex match, and DRI. Adjusting donor choice and earlier referral of patients for evaluation of transplantation to improve the DRI can potentially overcome the negative impact of these factors.

Relapse remains a major cause of mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). The impact of donor type on post-relapse survival (PRS) has not been widely examined. We compared the survival outcomes for patients relapsing after haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide with those relapsing after matched-related donor transplantation (MRDT) or matched-unrelated donor transplantation (MUDT) at our institution. Two hundred and thirty-seven consecutive HCT recipients with relapse occurring after HIDT (N = 48), MUDT (N = 87) and MRDT (N = 102) were included in this analysis. Median age was 49 years (19-77 years) and the median time to relapse was 156 days (12-2465) after HCT. HIDT recipients had similar median time to relapse (5.8 vs 4.8 vs 5.5 months, P = 0.638) compared with MUDT and MRDT, respectively. One-year PRS was worse among HIDT recipients compared with MRDT and MUDT (17% vs 46% vs 40%, P o 0.05). In a multivariate analysis, time to relapse ( o3 vs 43 months post transplant), no use of donor lymphocyte infusion (DLI) following relapse, higher Dana Farber disease risk index and HCT comorbidity index scores at the time of transplant and delayed platelet engraftment post transplant were all predictive of worse PRS. This analysis shows that 1-year PRS is inferior among HIDT when compared with MRDT or MUDT. Lower use of DLI after HIDT may have contributed to this inferior survival. INTRODUCTIONAllogeneic hematopoietic cell transplantation (HCT) is considered to be a curative modality for many patients with high-risk hematologic malignancies. Transplantation using a matchedrelated sibling if available leads to improved outcomes when compared with other graft sources. 1 HLA-haploidentical donor transplantation (HIDT) using a T-cell-replete graft with posttransplant cyclophosphamide has emerged as an alternative graft source for patients lacking a matched-related (MRD) or matchedunrelated (MUD) donor. [2][3][4][5] The use of HIDT with post-transplant cyclophosphamide has been shown to yield low rates of transplant-related mortality, adequate disease control, robust immune reconstitution and overall survival (OS) similar to that seen with optimally MUD transplantations. 2,6 Relapse remains the main cause of treatment failure after HCT with~30-40% of patients relapse with their original malignancy. 7 Outcomes after relapse after HCT remain poor with a high early mortality and only a small percentage of patients achieving a long-term second remission and prolonged OS. The effect of graft donor source at the time of transplantation on post-relapse survival (PRS) has not been well established. In a recent CIBMTR (Center for International Blood and Marrow Transplantation Research) analysis, patients with relapsed acute myelogeneous leukemia after mismatchedunrelated or double cord transplantation had a worse PRS than recipients of a matched sibling or matched-unrelated HCT. 8 The available treatment options for relapsed patients include i...

A second allogeneic hematopoietic stem cell transplantation (HSCT) using the same donor or another fully matched donor is an effective treatment approach for a subset of patients relapsing after a matched related (MRDT) or matched unrelated donor transplant (MUDT). There are limited data on the use of haploidentical transplantation (HIDT) with post-transplant cyclophosphamide in the setting of a second HSCT after an MRDT or MUDT. We analyzed the outcomes of 20 patients who received HIDT with post-transplant cyclophosphamide as a second HSCT after an MRDT (n = 10) or MUDT (n = 10). The median time from the first to the second HSCT was 20.7 months (range, 2.7 to 65.8). Ten patients had acute myelogenous leukemia/myelodysplastic syndrome, 6 had acute lymphoblastic leukemia, 2 had chronic lymphoblastic leukemia, and 2 had myeloproliferative neoplasms. All patients received cytoreductive therapy before HIDT, with 12 (60%) achieving complete remission and 8 (40%) with active disease at the time of transplant. All patients achieved sustained engraftment with median times to neutrophil and platelet engraftment of 17.5 days (range, 14 to 44) and 32 days (range, 15 to 99), respectively. Nineteen patients (95%) achieved full donor chimerism in both the T cell and myeloid lineages at day 30 post-HSCT. The cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease at 180 days were 36% and 10%, respectively. The cumulative incidence of moderate to severe chronic graft-versus-host disease was 13% at 1 year post-HIDT. At a median follow-up of 38 months, the probability of overall survival, disease-free survival, nonrelapse mortality, and relapse post-HIDT were 52%, 39%, 29%, and 33% at 1 year and 34%, 31%, 29%, and 40% at 3 years, respectively. These data suggest that HIDT is an effective strategy to treat relapsed hematologic malignancies after MRDT or MUDT. Further studies to confirm these observations are warranted.

Lack of a matched sibling or unrelated donor (MUD) can be a significant barrier to allogeneic transplantation in patients who stand to benefit from this procedure. HLA-haploidentical (haplo) donors are readily available for nearly all such patients. Haplo transplantation has inherent advantages over MUD transplantation including the lower cost of graft acquisition, greater availability of donors for ethnic minorities, and immediate access to the donor in patients in whom delay is undesirable. We enrolled a total of 30 patients on a prospective phase II trial utilizing a TBI-based myeloablative preparative regimen (fludarabine 25 mg/m2/d x 3 d and TBI 150 cGy bid on d -4 to -1 [total dose 1200cGy]) followed by infusion of unmanipulated peripheral blood stem cells (PBSC) from a haploidentical family donor. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF through d 35, and tacrolimus through d 180. Median patient age was 46.5 years (range 24-60). Transplant diagnosis included AML [16], ALL [6], CML [5], MDS [1] and NHL [2]. Using the recently published Dana Farber disease risk index (DFDRI), patients were classified as low [4], intermediate [12], high [11], and very high [3] risk. No patient experienced graft failure, with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by Day +30. Acute GVHD, grades II-IV and III-IV, was seen in 44% and 24% respectively. The cumulative incidence of chronic GVHD was 57% (severe in 7%). After a median follow-up of 17 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate was 84%, 76%, 5%, and 19%. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0% respectively, compared with 44% and 46% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative MUD transplantation, outcomes were statistically similar with 2-yr OS and DFS being 84% and 76% respectively after haplo transplant vs. 70% and 62% respectively after MUD transplant. In patients with DFDRI low/intermediate risk disease, 2-yr DFS was superior following haplo compared with MUD transplants (100% vs. 73%, p=0.042), whereas there was no difference in DFS in patients with high/very high risk disease (44% vs. 35% for haplo and MUD respectively, p=0.898). Grade II-IV acute GVHD was seen less often following haplo compared with MUD transplant (44% vs. 63%, p=0.052), as was moderate-to-severe chronic GVHD (21% vs 61%, p=0.004). Myeloablative haplo transplantation is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. It may provide a benefit over MUD transplantation due to more rapid access to donors, lower graft acquisition costs, less GVHD, and at least equivalent DFS. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.