Differences in Graft-versus-Host Disease Characteristics between Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors.

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.

Fludarabine and Total-Body Irradiation Conditioning before Ablative Haploidentical Transplantation: Long-Term Safety and Efficacy.

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.

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation.

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.

Who Is a Better Donor for Recipients of Allogeneic Hematopoietic Cell Transplantation: A Young HLA-Mismatched Haploidentical Relative or an Older Fully HLA-Matched Sibling or Unrelated Donor?

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.

Superior Survival of Black Versus White Patients Following Post-Transplant Cyclophosphamide-Based Haploidentical Transplantation for Adults with Hematologic Malignancy.

Available evidence from large registry studies has shown inferior survival for black adult patients following both unrelated donor and cord blood transplantation. Post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) is being increasingly used in ethnic minorities. However, no studies of the impact of race on outcomes following HIDT have been reported. We analyzed 203 consecutive patients (123 white, 80 black) who underwent first HIDT using PTCy for hematologic malignancy at a single institution. Median recipient age was 53 (range, 19-75) years. Peripheral blood stem cells (PBSCs) were used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative (MA) in 41%. After a median follow-up of 36 months, the estimated 3-year overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were significantly better in black patients, compared with white patients (72% [95% confidence interval (CI), 60% to 81%], 65% [95% CI, 52% to 75%], and 25% [95% CI, 16% to 35] versus 50% [95% CI, 40% to 59%], 45% [95% CI, 36% to 54%], and 39% [95% CI, 31% to 47%], respectively; P < .001 for OS and DFS, P = .015 for CIR). In contrast, 3-year nonrelapse mortality was similar between black (11%) and white (16%) patients, as were the incidences of acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD. Improved survival was noted in all subgroups of black patients-younger versus older, male versus female, lower versus higher disease risk index, MA versus non-MA conditioning, or PBSC versus marrow stem cell source. In multivariate analysis, black race was independently associated with better OS (hazard ratio [HR], .47; P = .003), DFS (HR, .49; P = .003), and relapse (HR, .49; P = .01). Black patients achieve superior outcomes to their white counterparts following PTCy-based HIDT due to a decreased incidence of disease relapse.

Selecting the Best Donor for Haploidentical Transplant: Impact of HLA, Killer Cell Immunoglobulin-Like Receptor Genotyping, and Other Clinical Variables.

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.

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation: A Single-Center Analysis of 613 Adult Hematopoietic Cell Transplantation Recipients Using a Modified Composite Endpoint.

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.

Current Graft-versus-Host Disease-Free, Relapse-Free Survival: A Dynamic Endpoint to Better Define Efficacy after Allogenic Transplant.

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.

Factors Predicting Graft-versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Cell Transplantation: Multivariable Analysis from a Single Center.

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.

Impact of Donor Type on Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia.

Allogeneic hematopoietic cell transplantation (alloHCT) is considered the most potent postremission antileukemic therapy in adults with acute leukemia. We analyzed 172 consecutive acute leukemia patients transplanted in complete remission after a T cell-replete alloHCT from either a matched related (MRD, n = 54), unrelated (MUD, n = 67), or haploidentical (haplo, n = 51) donor to look for patient-, disease-, and transplant-related factors associated with post-transplant outcomes. Patients included 123 acute myeloid leukemia patients (first complete remission [CR], n = 94; second CR, n = 28; third CR, n = 1) and 49 acute lymphoblastic leukemia (ALL) patients (first CR, n = 39; second CR, n = 9; third CR, n = 1) with a median age of 50 years (range, 19 to 74). Median follow-up for surviving patients was 38 months. Cumulative incidence of nonrelapse mortality at 1 and 3 years was 6% and 17%, respectively. The estimated rates of 3-year overall survival, disease-free survival, and relapse incidence were 59%, 50%, and 33%, respectively. In multivariate analysis, risk factors for inferior survival included diagnosis of ALL, high risk disease risk index, and use of a female donor for a male recipient. Donor type (MRD, MUD, haplo) had no impact on any transplant outcome. Given the favorable outcomes associated with alloHCT in acute leukemia and lack of effect of donor type, a strong case can be made for transplanting acute leukemia patients in remission as soon as any donor becomes available.

T Cell-Replete HLA Haploidentical Donor Transplantation with Post-Transplant Cyclophosphamide Is an Effective Salvage for Patients Relapsing after an HLA-Matched Related or Matched Unrelated Donor Transplantation.

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.

Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index.

Outcomes of 475 consecutive patients undergoing first allogeneic transplantation for hematologic malignancy performed using T-replete HLA-haploidentical donors and post-transplantation cyclophosphamide (HIDT; n = 116) were compared with contemporaneous patients transplanted from 10 of 10 HLA allele-matched unrelated donors (MUDT; n = 178) or HLA-identical sibling donors (MRDT; n = 181). Uniform supportive care measures and assessments were used. Median follow-up was 45 months. HIDT patients were more likely than MUDT patients to be black (44% versus 2%; P < .001). At 2 years after transplantation, estimates of overall survival were 57% for HIDT, 59% for MUDT, and 72% for MRDT (P not significant [NS] for HIDT versus MUDT; P = .02 for HIDT versus MRDT); corresponding disease-free survival rates were 54%, 50%, and 56% (P NS for both comparisons). The respective cumulative incidences (CIs) of nonrelapse mortality were 17%, 16%, 14%, and those of relapse were 29%, 34%, and 30% (P NS for all). The respective CIs of acute graft-versus-host disease (GVHD) grade II-IV were 41%, 48%, and 28% (P = NS for HIDT versus MUDT; P = .005 for HIDT versus MRDT). At 2 years, the respective CIs of moderate/severe chronic GVHD were 31%, 47%, and 44% (P = .004 for HIDT versus MUDT; P = .032 for HIDT versus MRDT) and 19% of HIDT recipients, 42% of MUDT recipients, and 35% of MRDT recipients were on systemic immunosuppressive treatment (P = .007 for HIDT versus MUDT). In recipients of peripheral blood stem cell grafts, the incidence of moderate-severe chronic GVHD was significantly lower in HIDT recipients compared with MUDT recipients (2-year CI, 25% versus 48%; P = .002). In a multivariate analysis incorporating Disease Risk Index and other significant covariates, survival (hazard ratio [HR], 1.31; P = .15) and disease-free survival (HR, 0.96; P = .79) were not significantly different between HIDT and MUDT recipients, but the incidence of chronic GVHD was lower in HIDT recipients (moderate-severe, HR, 0.59; P = .007). HIDT produced similar long-term survival with lower rates of chronic GVHD than optimally matched MUDT. HIDT should be considered a standard of care option for patients lacking a matched sibling donor.

Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host Disease Incorporating Rituximab.

Chronic graft-versus-host disease (cGVHD) is a significant determinant of overall outcome and quality of life in survivors of allogeneic hematopoietic cell transplantation. Standard initial therapy of cGVHD is based on prolonged use of corticosteroids and a calcineurin inhibitor and has not changed for over 3 decades, despite limited efficacy and long-term toxicity. Rituximab is an attractive agent for the upfront treatment of cGVHD because of its favorable toxicity profile, efficacy in steroid-refractory cGVHD, and ability to serve as a steroid-sparing agent in autoimmune diseases. We hypothesized that a corticosteroid-free regimen incorporating rituximab would result in improved outcomes when used for the initial treatment of cGVHD. Twenty-five patients (median age, 56 years; range, 29 to 77) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute graft-versus-host disease. cGVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients, respectively. cGVHD severity (National Institutes of Health grade) was mild, moderate, and severe in 3, 14, and 8 patients, respectively. All patients received rituximab 375 mg/m(2) × 4 weekly doses, then 1 dose every 3 months × 4 doses, in addition to mycophenolate mofetil and either tacrolimus or sirolimus. No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise, treatment was deemed a failure and patients were treated off study. Twenty-two of 25 patients (88%) responded to treatment. Of the 22 responding patients, the median time to maximum response was 161 days (range, 35 to 300 days) with maximum response being complete in 21 of 22 patients and partial in 1 patient. Excluding the 3 patients taken off study for treatment failure, corticosteroids were used sparingly, with only 2 patients receiving any steroids for a median of 15 days (range, 13 to 18 days). Immunosuppression was discontinued in 17 of 22 evaluable patients (77%) with a median time to discontinuation of 300 days (range, 138 to 488 days). After immunosuppression discontinuation, cGVHD did recur in 7 patients after a median of 166 days (range, 21 to 393 days), requiring reinstitution of systemic immunosuppression (estimated cGVHD recurrence rate of 37%). With a median follow-up of 27 months, estimated 2-year overall survival is 82%. This regimen utilizing rituximab in the initial therapy of cGVHD is effective and avoids the use of corticosteroids in the majority of patients. In permitting early discontinuation of immunosuppression while obviating the need for prolonged exposure to systemic corticosteroids, this regimen may result in reduced treatment-related morbidity and mortality associated with cGVHD and its treatment.

Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors.

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.

Does total body irradiation conditioning improve outcomes of myeloablative human leukocyte antigen-identical sibling transplantations for chronic lymphocytic leukemia?

An allogeneic hematopoietic cell transplantation from an HLA-identical donor after high-dose (myeloablative) pretransplantation conditioning is an effective therapy for some people with chronic lymphocytic leukemia (CLL). Because CLL is a highly radiosensitive cancer, we hypothesized that total body irradiation (TBI) conditioning regimens may be associated with better outcomes than those without TBI. To answer this, we analyzed data from 180 subjects with CLL receiving myeloablative doses of TBI (n = 126) or not (n = 54), who received transplants from an HLA-identical sibling donor between 1995 and 2007 and reported to the Center for International Blood & Marrow Transplant Research. At 5 years, treatment-related mortality was 48% (95% confidence interval [CI], 39% to 57%) versus 50% (95% CI, 36% to 64%); P = NS. Relapse rates were 17% (95% CI, 11% to 25%) versus 22% (95% CI, 11% to 35%); P = NS. Five-year progression-free survival and overall survival were 34% (95% CI, 26% to 43%) versus 28% (95% CI, 15% to 42%); P = NS and 42% (95% CI, 33% to 51%) versus 33% (95% CI, 19% to 48%); P = NS, respectively. The single most common cause of death in both cohorts was recurrent/progressive CLL. No variable tested in the multivariate analysis was found to significantly affect these outcomes, including having failed fludarabine. Within the limitations of this study, we found no difference in HLA-identical sibling transplantation outcomes between myeloablative TBI and chemotherapy pretransplantation conditioning in persons with CLL.

Impact of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide-based transplantation.

BACKGROUND: Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. OBJECTIVE: To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). STUDY DESIGN: The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. RESULTS: Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3-4 acute GVHD (vs. 0-1) was associated with inferior 3-yr overall survival (OS 47% vs. 64%, p=0.041), due to higher NRM (25% vs. 10%, p=0.013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% vs. 58%, p=0.027) and a trend towards lower relapse (24% vs. 36%, p=0.08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% vs. 4%, p=0.010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3-4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, p<0.001 and HR3.35, p<0.001, respectively). In addition, grade 3-4 acute GVHD predicted worse OS (HR 1.80, p=0.007) and DFS (HR 1.55, p=0.041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. CONCLUSION: In summary, both grade 3-4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

Immunosuppression-Free Status at 1 Year after Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide.

The development of chronic graft-versus-host disease (GVHD) in 1-year survivors after matched related or unrelated hematopoietic cell transplantation was shown to be associated with higher nonrelapse mortality (NRM) and worse overall survival (OS). The impact of chronic GVHD requiring immunosuppression (IS) for recipients of haploidentical transplantation (HIDT) with post-transplantation cyclophosphamide (PTCy) who have survived to 1 year post-transplantation has not been studied previously and was investigated for this analysis. A total of 322 adult patients who underwent HIDT at our center were included in this study. The effect of IS-free status on post-transplantation outcomes was assessed. The median follow-up for survivors was 63.9 months (range, 18.3 to 165 months). A total of 163 patients (65%) were IS-free at 1 year post-HIDT. Baseline characteristics of this group were similar to those of patients still requiring IS, except for higher percentages of female donor-male recipient pairs (28% versus 15%; P =.03) and female donors (48% versus 30%; P =.008). Logistic regression to identify patients more likely to be on IS at 1 year post-HIDT identified the use of a female donor as a significant risk factor (odds ratio, 2.11; P = .009). In a Cox regression analysis, patients requiring IS at 1 year post-transplantation had higher NRM (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.80 to 6.72; P < .001) and showed a trend toward worse disease-free survival (DFS) (HR, 1.59; 95% CI, .95 to 2.66; P =.08), with no impact on OS (HR, 1.44; 95% CI, .90 to 2.31; P = .13) or relapse (HR, .77; 95% CI, .37 to 1.61; P = .49). These results indicate that use of a female donor is a significant risk factor for requiring IS at 1 year post-HIDT. Additionally, chronic GVHD requiring IS at 1-year post-HIDT no significant effect on relapse but is associated with higher NRM and a trend toward worse DFS.

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant.

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.

Salvage second hematopoietic cell transplantation in myeloma.

Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM.

Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD).

Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.