R-BEAM versus Reduced-Intensity Conditioning Regimens in Patients Undergoing Allogeneic Stem Cell Transplantation for Relapsed Refractory Diffuse Large B Cell Lymphoma

Allogeneic stem cell transplant (alloSCT) is considered in diffuse large B cell lymphoma (DLBCL) patients with chemorefractory disease or who have relapsed after autologous SCT. Here we present the first report of alloSCT using the R-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan) conditioning regimen in DLBCL patients.We retrospectively compared long-term alloSCT outcomes of DLBCL patients who received either R-BEAM (n = 47) or reduced-intensity conditioning (RIC) regimens (n = 23).Seventy patients (median age, 53 years) with DLBCL received alloSCT between January 2005 and December 2017. The median number of pretransplant therapies was 3, and 17 patients (24%) received prior autologous SCT. All received rituximab as a frontline or salvage therapy before alloSCT. The donor was unrelated in 42 patients (60%), and peripheral blood stem cells were commonly used (96%). The 6-month cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) was 36.2% and 8.7% for R-BEAM and RIC, respectively (P = .03). Median follow-up of surviving patients after R-BEAM and RIC was 3.1 and 5.5 years, respectively. Three-year overall survival (OS) after R-BEAM and RIC was 34.4% and 43.4%, respectively (P = .48). At 3 years, R-BEAM was associated with a similar relapse rate (25.5% versus 26.1%, P = .96), nonrelapse mortality (NRM; 39.7% versus 39.1%, P = .98), and relapse-free survival (RFS; 34.8% versus 34.7%, P = .75) compared with RIC. In multivariable analysis lower Karnofsky performance score was associated with lower OS (hazard ratio, .96; P = .05), whereas chemorefractory disease was associated with a higher relapse risk (hazard ratio, 8.8; P = .04). No difference in OS, relapse, NRM, or RFS was noticed between R-BEAM and RIC. R-BEAM regimen seems to be feasible and results in equivalent rates of long-term OS, relapse, NRM, and RFS compared with RIC. However, a significantly higher rate of severe acute GVHD was noticed.     

Transplantation from Matched Siblings Using Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin: A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those ≤45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens.     

T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Hodgkin Lymphoma Relapsed after Autologous Transplantation: Reduced Incidence of Relapse and of Chronic Graft-versus-Host Disease Compared with HLA-Identical Related Donors

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n?=?34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n?=?30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P?<?.005). With a median follow-up of 47 months, 3-year overall survival (OS), 3 -year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were 53%, 44% and 17%, respectively. Recipients of Haplo-SCT were less likely to experience disease relapse (3-year cumulative incidence of relapse, 13% versus 62%; P?=?.0001) and chronic graft- versus-host disease (GVHD; 3% versus 32%; P?=?.003), resulting in improved PFS (60% versus 29%; P?=?.04) and GVHD-free/relapse-free survival (47% versus 17%; P?=?.06). The 3-year OS did not differ between the 2 groups (56% versus 54%; P?not significant), and NRM was higher after Haplo-SCT, but the difference did not reach statistical significance (26% versus 9%; P?=?.09). On multivariate Cox regression analysis, receipt of Haplo-SCT (hazard ratio [HR], .17; P?=?.02) and achieving optimal disease control (complete remission before SCT: HR, .6; P?<?.0001) were the only independent variables associated with a reduced risk of disease relapse. Haplo-SCT is a valid option for patients with HL relapsing after ASCT, with a reduced incidence of relapse compared with HLAid SCT.     

Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P?=?.24; OS 31% versus 49%, P?=?.17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P?=?.62; OS 50% versus 38%, P?=?.46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.     

Combination of the Hematopoietic Cell Transplantation Comorbidity Index and the European Group for Blood and Marrow Transplantation Score Allows a Better Stratification of High-Risk Patients Undergoing Reduced-Toxicity Allogeneic Hematopoietic Cell Transplantation

This study was conducted to determine whether the integration of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score would improve individual capacity for stratification of high-risk HCT candidates. A total of 442 consecutive patients receiving an allogeneic HCT after reduced-toxicity conditioning was included. Final HCT-CI and EBMT scores were calculated and validated. Then, patients were grouped into a 6-category new combination model according to the HCT-CI (0, 1 to 2, ≥3) and EBMT scores (0 to 3, 4 to 7), and the model's predictive capacity was also evaluated. Median HCT-CI and EBMT scores were 3 and 4, respectively. Increased HCT-CI was associated with higher 4-year nonrelapse mortality (NRM) and lower 4-year overall survival (OS), whereas a high EBMT score was associated with higher 4-year NRM. The HCT-CI showed a trend for a better predictive capacity than the EBMT score (c-statistic .6 versus .54, P = .1). According to the new model, patients within HCT-CI of 0 and HCT-CI of 1 to 2 groups had similar risk of NRM independently of their EBMT score. Within the HCT-CI ≥ 3 group, patients with low EBMT score showed lower NRM (25% versus 40%, P = .04) and a trend to higher OS (52% versus 36%, P = .06) than patients with a high EBMT score. Moreover, patients with HCT-CI ≥ 3 and EBMT score 0 to 3 had similar outcomes than those with HCT-CI of 1 to 2. In conclusion, the combination of HCT-CI and the EBMT score is feasible and might contribute to a better identification of high-risk patients, improving selection of best allogeneic HCT candidates.     

Comparison between Upfront Transplantation and different Pretransplant Cytoreductive Treatment Approaches in Patients with High-Risk Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P < .0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.     

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.     

Hypoalbuminemia at Day +90 Is Associated with Inferior Nonrelapse Mortality and Overall Survival in Allogeneic Hematopoietic Cell Transplantation Recipients: A Confirmatory Study

Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5?g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P?<?.0001). This was also the case for OS (hazard ratios, 6.86 [95% CI,?4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P?<?.0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS.     

Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Unresponsive Mantle Cell Lymphoma: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research

Patients with chemorefractory mantle cell lymphoma (MCL) have a poor prognosis. We used the Center for International Blood and Marrow Transplant Research database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced-intensity/nonmyeloablative conditioning (RIC/NST), during 1998-2010. We analyzed nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients (median age, 54 years) received MA, and 128 patients (median age, 59 years) received RIC/NST. Median follow-up after allo-HCT was 35 months in the MA group and 43 months in the RIC/NST group. At 3 years post-transplantation, no significant between-group differences were seen in terms of NRM (47% in MA versus 43% in RIC/NST; P = .68), relapse/progression (33% versus 32%; P = .89), PFS (20% versus 25%; P = .53), or OS (25% versus 30%; P = .45). Multivariate analysis also revealed no significant between-group differences in NRM, relapse, PFS, or OS; however, receipt of a bone marrow or T cell–depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Our data suggest that despite a refractory disease state, approximately 25% of patients with MCL can attain durable remission after allo-HCT, and conditioning regimen intensity does not influence outcome of allo-HCT.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO)

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatmentA total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph⁺ ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph⁺ ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph⁺ ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).     

Outcomes of Haploidentical Transplantation in Patients with Relapsed Multiple Myeloma: An EBMT/CIBMTR Report

Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% CI, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P =.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P?=?.001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM.     

Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation

Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous–allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous–allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous–allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.     

Donor-Specific Anti-HLA Antibodies in Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: Risk of Graft Failure,Poor Graft Function,and Impact on Outcomes

The presence of donor-specific anti-HLA antibodies (DSA) is associated with a 10-fold increased risk of graft failure in haploidentical stem cell transplantation (haplo-SCT). Consensus guidelines from the European Society for Blood and Marrow Transplantation set a mean fluorescence intensity (MFI) >1000 as a cutoff for DSA positivity. In the absence of an alternative donor, it is recommended that patients undergo desensitization therapy, especially with high DSA levels (>5000 MFI). The aim of this study was to analyze the impact of DSA on risk of graft failure and poor graft function, as well as on major outcomes in a consecutive cohort of patients who were systematically screened for DSA before haplo-SCT. A total of 141 consecutive patients were candidates for unmanipulated haplo-SCT with post-transplantation cyclophosphamide (PT-Cy) at our center between January 2012 and January 2018, and 135 were analyzed for the presence of HLA antibodies. Of these 134 patients underwent haplo-SCT. HLA antibodies were detected in 40 patients, including 19 with DSA and 21 without DSA. Ten of the 19 patients with DSA underwent transplantation using that donor, whereas 2 underwent a desensitization program before transplantation. Only 2 patients experienced primary graft failure (1.4 %), both of whom were without DSA. Twenty patients developed a poor graft function (15%). The 3-year overall survival (OS), 3-year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were analyzed according to the presence or absence of DSA. No statistically significant difference was found. No impact of the presence of DSA on the risk of developing graft failure and poor graft function was revealed. Major outcomes of transplantation were analyzed separately in patients with poor graft function and those with good graft function. The 3-year OS, 3-year PFS, and 1-year NRM in good graft function and poor graft function populations were 62% versus 20% (P < .0001), 53% versus 20% (P < .0001), and 12% versus 40% (P = .009), respectively. The presence of low-level DSA in the absence of desensitization did not correlate with the risk of developing graft failure and poor graft function. Patients who experienced poor graft function had worse outcomes than patients with good graft function.     

Does the Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI) Predict Transplantation Outcomes? A Prospective Multicenter Validation Study of the Kanto Study Group for Cell Therapy

Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years were 59% and 20%, respectively (n = 243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P = .01, OS: P = .003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n = 186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P = .304, P = .996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P = .005 and P = .005, respectively). Multivariate analysis identified age >50, performance status (PS) <90, donor type (HLA-mismatched/unrelated donor), and the flexible HCT-CI ≥4 as significant predictors for worse OS at 2 years. However, the flexible HCT-CI did not remain a significant predictor for NRM at 2 years in multivariate analysis, whereas age, PS, and donor type did. The HCT-CI did not consistently predict both NRM and OS, but it still can be a useful tool in combination with other factors, such as PS and age. Furthermore, the HCT-CI, although potentially useful for capturing pretransplantation comorbidity and risk assessment, may need further validation before its adoption for routine clinical use.     

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.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable: A Retrospective Nationwide Study of the Japan Society for Hematopoietic Cell Transplantation

To date, there are no data focusing on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). This study aimed to evaluate outcomes and prognostic factors in patients with MDS/MPN-U after allo-HSCT using Japanese nationwide registry data. The primary endpoint was 3-year overall survival (OS); secondary endpoints included the cumulative incidence of relapse and nonrelapse mortality (NRM). We evaluated the prognostic factors for 3-year OS by univariate analysis using the log-rank test. In our cohort of 86 patients with MDS/MPN-U, we found a 3-year OS of 48.5%, cumulative incidence of relapse of 23.7%, and NRM of 26.3%. The 3-year OS was significantly worse in patients age ≥50 years compared with those age <50 years (38.1% versus 65.0%; P = .049) and in patients with disease progression compared with those without disease progression (28.4% versus 57.2%; P = .042). Our results suggest that allo-HSCT may offer a curative option for patients with MDS/MPN-U, and that age and disease status could be important indicators in helping clinicians determine treatment options for these patients.     

Impact of Pretransplantation Conditioning Regimens on Outcomes of Allogeneic Transplantation for Chemotherapy-Unresponsive Diffuse Large B Cell Lymphoma and Grade III Follicular Lymphoma

Patients with chemorefractory non-Hodgkin lymphomas generally have a poor prognosis. We used the observational database of the Center for International Blood and Marrow Transplant Research to study the outcome of 533 patients with refractory diffuse large B cell lymphoma (DLBCL) or grade III follicular lymphoma (FL-III) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA; n = 307) or reduced-intensity/nonmyeloablative conditioning (RIC/NST; n = 226) between 1998 and 2010. We analyzed nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplantation had a Karnofsky performance score of ≥90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3 years, MA allo-HCT was associated with a higher NRM compared with RIC/NST (53% versus 42%; P = .03), similar PFS (19% versus 23%; P = .40), and lower OS (19% versus 28%; P = .02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative risk [RR], .52), reduced risk of relapse/progression (RR, .42), and superior PFS (RR, .51) and OS (RR, .53), whereas MA conditioning was associated with reduced risk of relapse/progression (RR, .66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT.     

Busulfan- or Thiotepa-Based Conditioning in Myelofibrosis: A Phase II Multicenter Randomized Study from the GITMO Group

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS).Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.     

Efficacy of high-dose corticosteroid-based treatment for chronic lymphocytic leukemia patients with p53 abnormalities in the era of B-cell receptor inhibitors

PurposeHigh-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion.Patients and methodsOutcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14).ResultsHigher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p < 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p < 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58).ConclusionHDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.