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Purpose: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown., Methods: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died., Results: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication., Conclusion: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/cci/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown., Methods: Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC)., Results: No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% v 63%; P = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% v 67%; P < .001) and survival (3-year OS, 61% v 43%; P = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; P < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; P < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; P = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive., Conclusion: This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.

Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell-replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.

T cell replete HLA-mismatched haploidentical transplantation (HIDT) with post-transplant cyclophosphamide is increasingly becoming an acceptable treatment approach for patients lacking timely access to a suitably matched related donor transplant (MRDT) or matched unrelated donor transplant (MUDT). Multiple recent registry and single-center studies have shown comparable overall survival (OS) and disease-free survival (DFS) rates among HIDT, MRDT, and MUDT with a significantly lower risk of acute and chronic graft-versus-host disease (GVHD) among HIDT recipients. Candidates for allogeneic hematopoietic stem cell transplantation (HSCT) often have access to multiple donor sources, and a relevant question is whether outcomes can be improved with a younger HLA-mismatched haploidentical donor (≤35 years) rather than an older matched related donor (≥35 years) or matched unrelated donor (≥35 years). We analyzed 406 consecutive allogenic HSCT recipients, with a median age of 54 years (range, 19 to 77), after a MRDT with a donor age of ≥35 years (n = 222), MUDT with a donor age of ≥35 years (n = 91), and HIDT with a donor age of ≤35 years (n = 93). Median follow-up time for survivors was 51.5 months. Compared with MRDT and MUDT, HIDT recipients had a similar median age at time of HSCT, hematopoietic cell transplant comorbidity index, disease risk index distribution, and donor recipient sex matching. The survival estimates and relapse incidence at 3 years post-HSCT were OS (64% for MRDT, 54% for MUDT, and 62% for HIDT), DFS (55% for MRDT, 44% for MUDT, and 58% for HIDT), Transplant related mortality (TRM) (19% for MRDT, 16% for MUDT, and 18% for HIDT), and relapse (26% for MRDT, 37% for MUDT, and 24% for HIDT). HIDT recipients had better 3-year relapse rates compared with MUDT recipients (24% versus 37%, P= .048), with similar DFS and OS in a univariate analysis. MRDT recipients had a better relapse rate (26% versus 37%, P = .042) compared with MUDT recipients. Recipients of HIDT also had significantly lower rates of moderate to severe chronic GVHD compared with MRDT and MUDT recipients (P = .01). Multivariable analysis showed no effect of donor on OS, DFS, relapse, and TRM. Recipients of HIDT from a young donor ≤35 years had similar OS, lower rates of chronic GVHD, and better chronic GVHD-free, relapse-free survival compared with patients undergoing transplantation with an MRD or a MUD donor ≥35 years. This study suggests that given a situation where a choice between a young haploidentical relative and an older matched unrelated donor is to be made, one can achieve similar survival with a haploidentical donor and significantly lower rates of chronic GVHD., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM). A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group. MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up., (Copyright © 2018. Published by Elsevier Inc.)

Background: Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated., Methods: This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM)., Results: Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001)., Conclusions: Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Allografting from HLA-haploidentical donors (HID) is being increasingly utilized worldwide for patients lacking a conventional matched donor. However, its efficacy in older patients with AML and MDS is unclear. We analyzed 127 consecutive allografts for AML/MDS patients aged ≥ 60 years at our center to compare outcomes using HID to those of contemporaneous transplants using matched sibling (MRD) or matched unrelated (MUD) donors. Patient characteristics were similar except HID transplants were more likely in non-white patients and were more commonly performed with reduced intensity conditioning and a marrow graft. For MRD, MUD and HID transplants respectively, 2-year estimates of non-relapse mortality (17, 23, and 9%), relapse (32, 34, and 33%), overall survival (OS) (62, 55, and 67%) and disease-free survival (DFS) (51, 43, and 58%) were not significantly different. Maximum cumulative incidences of grade 2-4 acute GVHD were not different (27, 37, 39%), but incidences of NIH grade moderate to severe (39, 35, 15%, p = 0.028 MUD vs. HID, p = 0.026 MRD vs. HID) and severe chronic GVHD (9, 12, 0%, p = 0.030 MUD vs. HID, p = 0.009 MRD vs. HID) were significantly higher in MRD and MUD than in HID transplants. On multivariable analysis, donor type was not a significant determinant of OS, DFS, TRM, or relapse. However, male gender and high/very high Disease Risk Index (DRI) were associated with significantly higher rates of relapse (HR 1.94, p = 0.047 for male gender, HR 2.48, p = 0.004 for high/very high DRI) and lower OS (HR 1.94, p = 0.018 for male gender, HR 1.80, p = 0.025 for high/very high DRI). HIDs are an acceptable alternative to matched donors in older patients with AML and MDS.

The use of post-transplant cyclophosphamide (PTCy)-based haploidentical (haplo) transplant is increasing worldwide. However, because multiple potential haplo donors are usually available, data-driven guidance is clearly needed to help transplant centers prioritize donors. To that end, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving PTCy-based haplo transplant at a single institution. Median recipient and donor age were 52 years (range, 19 to 75) and 38 years (range, 15 to 73), peripheral blood stem cell was the stem cell source in 66%, and myeloablative conditioning was used in 41%. Median follow-up for surviving patients was 33 months (range, 7 to 130). Donor variables analyzed included age, sex, relationship, cytomegalovirus (CMV) status, ABO compatibility, HLA disparity, and several natural killer (NK) alloreactivity models. Multivariate Cox analysis was used to adjust for known patient, disease, and transplant covariates. Donor characteristics independently associated with improved survival included presence of HLA-DR mismatch, HLA-DP nonpermissive mismatch, killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch, and KIR B/x haplotype with KIR2DS2. Donor characteristics associated with inferior survival included parental donor relationship and the use of a CMV-seronegative donor for a CMV-seropositive patient. Increased HLA disparity (≥4/10 HLA allelic mismatches [graft-versus-host direction]) resulted in relapse protection at the expense of increased nonrelapse mortality with no associated survival effect. We further propose a donor risk factor scoring system to permit a more evidence-based selection algorithm for potential haplo donors. This large, single-institution analysis demonstrates the importance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the haplo donor selection process and suggests that KIR and HLA-DP genotyping should be performed routinely for haplo donor selection., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

An accurate measure of allogeneic transplant efficacy should take into account quality-of-life issues associated with graft-versus-host disease (GVHD). However, unlike death and relapse, GVHD morbidity is temporary in many patients, and this fact must be reflected in such an outcome measure. Therefore, we have defined a new composite endpoint, called current GVHD-free, relapse-free survival (CGRFS), which is the probability, at any time post-transplant, of being alive, in remission, and without clinically significant chronic GVHD, defined as moderate-severe by the National Institutes of Health consensus criteria. Chronic GVHD is considered a dynamic event, which can resolve once manifestations are quiescent and systemic immunosuppression discontinued. CGRFS is achieved through linear combination of relevant Kaplan-Meier estimates. We evaluated 422 consecutive patients receiving an allogeneic transplant at a single institution between January 2010 and July 2015. With a median follow-up of 36 months, estimated 3-year overall and disease-free survival was 60% and 54%, respectively. Conventionally defined GRFS at 1, 2, 3, and 4 years was 33%, 26%, 23%, and 22%, respectively. In contrast, the corresponding rates of CGRFS were 45%, 46%, 47%, and 49%, respectively. Patients living with active moderate-severe chronic GVHD decreased over time, quantitated at 23%, 14%, 7%, and 4%, respectively, at 1, 2, 3, and 4 years post-transplant. Whereas only approximately one-fourth of patients achieve transplant success as defined by conventional GRFS, nearly half of patients, by CGRFS, are considered cured without the morbidity of ongoing GVHD. We propose that CGRFS may represent a more dynamic and accurate estimate of long-term transplant effectiveness., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)-based myeloablative preparative regimen (fludarabine 30 mg/m2/day × 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkin's lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted 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 graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference in DFS in patients with high/very high risk disease (39% versus 37% for haplo and MUD respectively, P = .821). Grade II to IV acute GVHD was seen less often after haplo compared with MUD transplantation (43% versus 63%, P = .049), as was moderate-to-severe chronic GVHD (22% versus 58%, P = .003). Myeloablative haplo transplantation using this regimen is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. Outcomes appear at least equivalent to those seen in contemporaneous patients who underwent transplantation from MUD., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Calcineurin inhibitors (CNIs) form the foundation of current graft-versus-host disease (GVHD) prophylaxis regimens. We hypothesized that a CNI-free regimen consisting of post-transplantation cyclophosphamide (PTCy) and brief-course sirolimus would reduce chronic GVHD and nonrelapse mortality (NRM) after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation (PBSCT). Twenty-six patients (median age, 61 years) underwent unmanipulated PBSCT from an 8/8 locus-matched donor (matched related donor, n = 17; natched unrelated donor, n = 9). GVHD prophylaxis consisted of PTCy and brief-course sirolimus. Donor engraftment occurred in all patients. The cumulative incidence (CI) of grade II-IV acute GVHD, grade III-IV acute GVHD, and chronic GVHD was 46%, 15%, and 31% respectively. One-year NRM was 4%. The median time to immunosuppression discontinuation was day +138. With a median follow-up of 20 months, the estimated 2-year overall survival was 71%, estimated disease-free survival was 64%, and estimated relapse incidence was 32%. In patients with a lymphoid malignancy (eg, chronic lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin disease), 2-year disease-free survival was 100%, and there were no relapses. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rate of 21% (4 of 19 at-risk patients). GVHD prophylaxis with PTCy and sirolimus achieves consistent donor engraftment, low rates of chronic GVHD and NRM, and excellent outcomes in recipients of HLA-identical related and unrelated donor allogeneic PBSCT., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Haploidentical hematopoietic stem cell transplant (HSCT) provides an opportunity for nearly all patients to benefit from HSCT. We conducted a trial of haploidentical T cell replete allografting using a busulfan-based myeloablative preparative regimen, peripheral blood stem cells (PBSCs) as the graft source, and posttransplantation cyclophosphamide (Cy). Eligibility was limited to patients at high risk of relapse after nonmyeloablative haploidentical bone marrow transplant (BMT). Twenty patients were enrolled in the study (11 with relapsed/refractory disease and 9 who underwent transplantation while in remission and considered standard risk). Donor engraftment occurred in all 20 patients with full donor T cell and myeloid chimerism by day +30. The cumulative incidence of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) was 30% and 10%, respectively. The cumulative incidence of chronic GVHD (cGVHD) was 35%. Nonrelapse mortality (NRM) at 100 days and 1 year was 10% for all patients and 0% for standard-risk patients. With a median follow-up of 20 months, the estimated 1-year overall survival (OS) and disease-free survival (DFS) was 69% and 50%, respectively, for all patients, and 88% and 67% for standard-risk patients. Myeloablative haploidentical HSCT is associated with excellent rates of engraftment, GVHD, NRM, and DFS, and is a valid option in patients with high-risk malignancies who lack timely access to a conventional donor., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m(2) plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus

We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.