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Abstract In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p

Abstract Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

ObjectiveTo determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT).MethodsThis was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed.ResultsAmong 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74–3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%).ConclusionsPH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II–IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III–IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

Abstract Hematopoietic stem cell transplantation (HSCT) is an integral part of the treatment strategy in patients with a hematological disorder. Chemotherapy-induced nausea and vomiting (CINV) is still an issue in patients who undergo HSCT. While several guidelines for the antiemetic therapy against CINV have been published, there is no detailed information about appropriate antiemetic drugs for each conditioning regimen in HSCT. Various studies reported that the triplet of 5-HT3RA, NK1RA, and dexamethasone appears useful in HSCT. However, each antiemetic has unique adverse effects or interactions with specific drugs. Here, we review the literature relating to clinical trials on the prevention of CINV, and summarize the information to clarify the benefit of antiemetic regimens.

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P

Abstract Background There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). Methods We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. Results Median age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. Conclusions Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

Abstract Background Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD. Methods Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis Results No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II–IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis. Conclusion These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.

Abstract Background The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. Results The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II–IV GVHD (HR 1.6; 95% CI 1.1–2.4) and NRM (HR 2.6; 95% CI 1.5–4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8–1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8–1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4–2.6) and chronic GVHD (HR 1.7; 95% CI 1.2–2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9). Conclusions The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.

Abstract: Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P

Due to the increasingly strict word/character restrictions enforced by most scientific publications, we identified a need for a master document illustrating the “Scientific Methods” that may be applicable to the majority of observational and registry-based studies in hematopoietic cell transplantation (HCT). The purpose of this study is to serve as a reference document that describes the data source, study endpoints and statistical analyses utilized most commonly in retrospective studies in HCT. To this end we compile, define and reference the methodology commonly used in HCT research. While it is recognized that the scientific methodology may periodically require updates due to the evolving landscape of transplant research, such as newer study endpoints and statistical methods, this manuscript describes frequently used methodologies.

Hematopoietic stem cell transplantation (HSCT) has become a potentially curative therapy for an increasing number of malignant and non-malignant conditions. As survival rates continue to improve, the focus of patient care has shifted from managing not only immediate but also long-term complications. Endocrine disorders are among the most prevalent late effects following HSCT. Detecting and treating such conditions offer new challenges, as well as opportunities to reduce preventable morbidity and mortality associated with HSCT. Our objective is to summarize recent literature and describe practical approaches to screening for and managing endocrine-related late effects. We focus on dyslipidemia, diabetes, thyroid disorders, osteoporosis, and hypogonadism. Mechanisms, monitoring, and management recommendations for each disorder are outlined. Growing data on these disorders in the post-transplant setting highlight the need for future study and evidence-based guidelines.

Dosing regimens for antithymocyte globulin (ATG) and anti-CD52 antibody (alemtuzumab) for graft vs. host disease prophylaxis (GVHD) are empiric or weight-based, and do not account for individual patient factors. Recently, it has been shown that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered to predict transplantation outcome. Similarly, we wanted to analyze if the recipient ALC interacts with alemtuzumab dosing to predict outcomes. We retrospectively compared 364 patients, 124 patients receiving ATG (anti-thymocyte globulin) for GVHD prophylaxis, and undergoing unrelated first allogeneic transplant for myeloid and lymphoid malignancies (group 1) to 240 patients receiving alemtuzumab (group 2), in similar time period. There was no difference in survival or acute and chronic GVHD between 60 and 100 mg of alemtuzumab dosing. Unlike ATG (where the pre-transplant recipient ALC interacted with ATG dose on day of its administration (day 1) to predict OS and DFS (p = 0.05), within alemtuzumab group, the recipient ALC on second day of alemtuzumab administration (day 2) and its interaction with alemtuzumab dose strongly predicted OS, DFS and relapse (p = 0.05, HR-1.81, 1.1–3.3; p = 0.002, HR-2.41, CI, 1.3–4.2; and p = 0.003, HR-2.78, CI, 1.4–5.2), respectively. ALC (day 2) of 0.08 × 109/lit or higher, had a specificity of 96% in predicting inferior DFS. Like ATG, there is definite but differential interaction between the recipient peripheral blood ALC and alemtuzumab dose to predict OS, DFS, and relapses.

Abstract Background Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17). Results The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27–35) and 32 % (28–35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/ relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18–25) and 21 % (18–24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76) and 73 % (67–78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.

A cute graft-versus-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-versus-host disease. We examined outcome following diagnosis of grade II-IV acute graft-versus-host disease according to time period, and explored effects according to original graft-versus-host disease prophylaxis regimen and maximum overall grade of acute graft-versus-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft-versus-host disease (n=497 for 1999–2001, n=962 for 2002–2005, n=1,446 for 2006–2010). The median (range) follow-up was 144 (4–174), 97 (4–147) and 60 (8–99) months for 1999–2001, 2002–2005, and 2006–2010, respectively. Among the cohort with grade II-IV acute graft-versus-host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999–2001, 2002–2005, and 2006–2012, respectively (P

The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope-binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 versus 429), -B (230 versus 92), -C (365 versus 349), and -DRB1 (153 versus 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into six HLA-A (A01, A01A03, A01A24, A02, A03, A24), six HLA-B (B07, B08, B27, B44, B58, B62), two HLA-C (C1, C2), and five HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II–IV acute graft-versus-host disease (hazard ratio =1.78, P=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II–IV (hazard ratio=3.11, P=0.002) and III–IV (hazard ratio=3.15, P=0.01) acute graft-versus-host disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II–IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available. Future studies are needed to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation.

Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611-8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs' of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3-5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables "carry the weight" and that traditional HSCT data has been "worn out". "Breaking through" the predictive boundaries will likely require additional types of inputs.

Allogeneic hematopoietic cell transplantation has an established role in the treatment of adults with acute lymphoblastic leukemia whose survival when recipients of grafts from adult unrelated donors approaches that of recipients of grafts from sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood transplants, 546 peripheral blood progenitor cell transplants and 140 bone marrow transplants. The characteristics of the recipients and their diseases were similar except cord blood recipients were younger, more likely to be non-Caucasians and more likely to have a low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match depending on the source of the graft. Most adult donor transplants were matched at the allele-level considering human leukocyte antigens-A, -B, -C and –DRB1. In contrast, most cord blood transplants were mismatched and considered antigen-level matching; 57% were mismatched at two loci and 29% at one locus whereas only 29% of adult donor transplants were mismatched at one locus and none at two loci. There were no differences in the 3-year probabilities of survival between recipients of cord blood (44%), matched adult donor (44%) and mismatched adult donor (43%) transplants. Cord blood transplants engrafted slower and were associated with less grade 2–4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. The survival of cord blood graft recipients was similar to that of recipients of matched or mismatched unrelated adult donor grafts and so cord blood should be considered a valid alternative source of stem cells for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor.