Optimized BEAC conditioning regimen improves clinical outcomes of autologous hematopoietic stem cell transplantation in non-Hodgkin lymphomas.

The conditioning regimen is an important part of autologous hematopoietic stem cell transplantation (ASCT). We explored the efficacy and safety of an optimized BEAC (adjusted-dose, intermediate-dose cytarabine and reduced-dose cyclophosphamide, AD-BEAC) conditioning regimen for non-Hodgkin lymphoma (NHL). A total of 141 NHL patients received AD-BEAC or a standard-dose BEAC (SD-BEAC) conditioning regimen from January 2007 to December 2017, and 104 patients were included in the study after 1:1 propensity matching. The 5-year overall survival (OS) and progression free survival (PFS) rates were significantly higher with AD-BEAC than with SD-BEAC (82.7% vs. 67.3%, P = 0.039; 76.9% vs. 57.7%, P = 0.039). Transplant-related mortality (TRM) was 3.8% in both the AD-BEAC and SD-BEAC groups. The AD-BEAC group had lower incidence of oral ulcers and cardiotoxicity than the SD-BEAC group. An optimized BEAC conditioning regimen is an effective conditioning regimen for ASCT in NHL with acceptable toxicity, that is more effective and safer than a standard BEAC conditioning regimen.

Lesson learned in pediatric haploidentical transplantation in a low-resource environment: delivering melphalan IV and using low dose radiation reduce graft failure.

Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.

Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

Efficacy and safety of cladribine in combination with busulfan and cyclophosphamide as an intensive conditioning regimen preceding allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute myeloid leukemia.

BACKGROUND: Cladribine, an analogue of deoxyadenosine, is used for therapy of hematological malignancies. Cladribine-containing regimen has been recommended as a rescue therapy for relapsed or refractory (R/R) acute myeloid leukemia (AML). Its combination with busulfan plus cyclophosphamide (BuCy), as an intensive conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT), requires more clinical evidence. This study aimed to explore the efficacy and safety of cladribine plus BuCy administered as an intensive conditioning regimen before allo-HSCT in R/R AML patients. METHODS: Twenty-three R/R AML patients, who underwent cladribine plus BuCy intensive conditioning regimen before allo-HSCT, were retrospectively analyzed. The median (range) follow-up duration time of observation was 0.73 (0.08-2.69) years. RESULTS: The median (range) returned levels of mononuclear cells were 11.5 (6.1-18.5) x 108/kg and CD34+ cells were 5.5 (3.5-9.3) x 106/kg. The median (range) time of platelet reconstitution was 13.0 (9.0-21.0) days and neutrophil reconstitution was 14.0 (11.0-26.0) days. The incidence of conditioning regimen related toxicity (CRRT) affected 69.6% of patients; all CRRT-affected patients had grade I-II symptoms, including gastrointestinal tract (39.1%), oral cavity (26.1%), liver (8.7%), and kidney (4.3%) CRRTs. The incidence of acute graft-versus-host disease (GVDH) included 30.4% among all patients with 4.3% of grade III-IV acute GVHD, and 34.8% of chronic GVHD. During the follow-up period, 4 (17.4%) patients relapsed, and 6 (26.1%) patients died (cause of death: disease relapse, n = 3; infection, n = 2; GVHD, n = 1). The 1-year and 2-year accumulating event-free survival rates were 66.3% and 53.1%, respectively. The 1-year accumulating overall survival rate was 74.7% and 2-year survival rate was 64.0%. CONCLUSION: Cladribine plus BuCy intensive conditioning regimen before allo-HSCT exhibits favorable treatment efficacy with acceptable toxicity in R/R AML patients.

Reduced toxicity matched sibling bone marrow transplant results in excellent outcomes for severe congenital neutropenia.

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation.

Novelty in total body irradiation (TBI) as part of pre-transplant conditioning regimens lacked until recently, despite the developments in the field of allogeneic stem cell transplants. Long-term toxicities have been one of the major concerns associated with TBI in this setting, although the impact of TBI is not so easy to discriminate from that of chemotherapy, especially in the adult population. More recently, lower-intensity TBI and different approaches to irradiation (namely, total marrow irradiation, TMI, and total marrow and lymphoid irradiation, TMLI) were implemented to keep the benefits of irradiation and limit potential harm. TMI/TMLI is an alternative to TBI that delivers more selective irradiation, with healthy tissues being better spared and the control of the radiation dose delivery. In this review, we discussed the potential radiation-associated long-term toxicities and their management, summarized the evidence regarding the current indications of traditional TBI, and focused on the technological advances in radiotherapy that have resulted in the development of TMLI. Finally, considering the most recent published trials, we postulate how the role of radiotherapy in the setting of allografting might change in the future.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation.

Objective: This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Methods: Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. Results: A higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg-1) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T-cell risk system based on graft CD8+ T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8+ T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). Conclusion: A higher CD8+ T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

PURPOSE: Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS: Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS: In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION: This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Reduced-Intensity Compared to Nonmyeloablative Conditioning in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P = .1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P = .24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P = .5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P = .039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P = .002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.

Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40 years old - a secondary analysis of a CIBMTR database.

Few studies have addressed the role of reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens in older adults with Philadelphia acute lymphoblastic leukemia (Ph + ALL). The objective of this current study was to compare the outcomes of RIC/NMA versus TBI-based myeloablative (MAC) regimens in Ph + ALL patients older than 40 years old who underwent hematopoietic cell transplantation (HCT) in CR1. We used a freely available database from the CIBMTR. Transplants were performed between 2013 and 2017. With a median follow-up of 37.6 months, we have included 629 patients. We used propensity score weighting. Three-year OSs were 64% in the TBI-MAC group and 66% in the RIC/NMA group. OS was not different (HR = 0.92; p = 0.69). Three-year relapse incidences were 21.6% and 27.6% in the TBI-MAC and RIC/NMA groups. RIC/NMA was not associated with an increase in relapse rate (HR 1.02; p = 0.91). Three-year NRMs were 24.3% in the TBI-MAC group and 20.3% in the RIC/NMA group. RIC/NMA was not associated with superior NRM (HR 0.88; p = 0.57). In summary, we have shown that RIC/NMA regimens achieve outcomes comparable to TBI-based MAC in Ph+ ALL older patients in CR1 who may tolerate a TBI-based MAC regimen.

CLAG combined with total body irradiation as intensive conditioning chemotherapy prior to allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia.

Refractory or relapsed acute myeloid leukemia (R/R AML) remains the major challenge of AML treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only valid option to achieve cure, but the prognosis is still dismal. We conducted a retrospective analysis for the feasibility of CLAG regimens (cladribine, cytarabine, and granulocyte colony-stimulating factor) combined with total body irradiation (TBI) as new intensive conditioning chemotherapy prior to HSCT in R/R AML. A total of 70 patients, including 21 primary refractory and 49 relapsed AML, were analyzed. Forty-nine (70%) patients had extramedullary diseases, and 54 (77%) patients received haploidentical transplantation. Except for one who died before white blood cell engraftment, all of the 69 evaluable patients achieved measurable residual disease (MRD) negative complete remission. The 3-year overall survival (OS) and relapse-free survival (RFS) rates were 46.0% (95% confidence interval [CI], 33.5-57.7%) and 38.5% (95%CI, 26.8-50.0%). The 1-year cumulative incidences of relapse and non-relapse mortality (NRM) were 38.6% (95%CI, 27.3-49.3%) and 11.6% (95%CI: 5.4-20.3%), respectively. The presence of chronic graft-versus-host disease (cGVHD) showed a trend to be associated with a lower risk of relapse (P = 0.054) and extramedullary diseases with a higher risk of NRM (P = 0.074). Multivariate analyses identified low leukemia burden pre-HSCT (defined as bone marrow blasts ≤ 50%) and cGVHD as independent factors associated with favorable OS and RFS. In conclusion, intensive conditioning with CLAG regimens plus TBI may be an effective and well-tolerated choice for R/R AML patients undergoing allo-HSCT.

[Mobilization and conditioning protocols actualization for autologous stem cell transplantation for autoimmune diseases: Guidelines from MATHEC-SFGM-TC]. / Actualisation des protocoles de mobilisation et conditionnement pour la pratique des autogreffes de cellules souches hématopoïétiques chez les patients atteints de maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (MATHEC-SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.

Allogeneic Hematopoietic Cell Transplantation with Non-Myeloablative Conditioning and Post-Transplant Cyclophosphamide Prophylaxis in Patients with Reduced Systolic Function.

Post-transplantation cyclophosphamide (PTCy) has become standard of care for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (alloHCT), allowing for expanded donor options. However, there is scant literature examining outcomes of patients with reduced systolic function receiving PTCy. The present study aimed to describe our experience in performing alloHCT in patients with reduced systolic function, including their nonrelapse mortality (NRM), overall survival (OS), and cumulative incidence of early cardiac events (ECEs). We performed a retrospective descriptive analysis using the Johns Hopkins Hematologic Malignancy database. From 2017 through 2021, 1118 consecutive patients underwent alloHCT with nonmyeloablative (NMA) conditioning and PTCy. Forty-three of those patients had a pretransplantation left ventricular ejection fraction (LVEF) ≤45% measured by transthoracic echocardiography. Patients whose LVEF improved on treatment prior to transplantation were also included. These 2 cohorts were stratified into 2 groups-heart failure with reduced ejection fraction (HFrEF) and heart failure with recovered ejection fraction (HFrecEF)-and subgroup analyses compared NRM, OS, and cumulative incidence of ECEs, including arrhythmia, coronary artery disease, reduction in LVEF, and pericardial effusion, within 100 days post-transplantation. The median LVEF was 40% to 45% (range, 30% to 45%) for the 31 patients undergoing transplantation with HFrEF and 35% to 40% (range, 20% to 45%) for the 12 patients with HFrecEF. The NRM for all 43 patients was 16% (95% confidence interval [CI], 5% to 27%) at 100 days and 23% (95% CI, 11% to 36%) at 2 years. The NRM was 23% (95% CI, 8% to 38%) at 100 days and 26% (95% CI, 10% to 42%) at 2 years for the HFrEF cohort and 0 at 100 days and 18% (95% CI, 0 to 41%) at 2 years for the HFrecEf cohort. The OS at 3 years was 41% (95% CI, 26% to 62%), 40% (95% CI, 25% to 65%) and 38% (95% CI, 14% to 100%) in the combined, HFrEF, and HFrecEF cohorts, respectively. The cumulative incidence of any ECE was 37.2% (95% CI, 22% to 51.9%), including 39% of HFrEF subjects and 33% of HFrecEF subjects. Grade ≥3 toxicities were seen in 56% of patients. Reduced ejection fraction was the most common ECE. One death was attributable to a cardiac etiology. Cardiac toxicities seemed to be more frequent and severe in patients with a history of systolic dysfunction, but this did not lead to worse survival outcomes. This study adds to and extends the existing literature supporting the use of NMA conditioning and PTCy in patients with systolic dysfunction.

Transplantation after CD45-ADC corrects Rag1 immunodeficiency in congenic and haploidentical settings.

BACKGROUND: Mutations in the recombinase-activating genes 1 and 2 (RAG1, RAG2) cause a spectrum of phenotypes, ranging from severe combined immune deficiency to combined immune deficiency with immune dysregulation (CID-ID). Hematopoietic cell transplantation is a curative option. Use of conditioning facilitates robust and durable stem cell engraftment and immune reconstitution but may cause toxicity. Transplantation from haploidentical donors is associated with poor outcome in patients with CID-ID. OBJECTIVES: We sought to evaluate multilineage engraftment and immune reconstitution after conditioning with CD45-antibody drug conjugate (CD45-ADC) as a single agent in hypomorphic mice with Rag1 mutation treated with congenic and haploidentical hematopoietic cell transplantation. METHODS: Rag1-F971L mice, a model of CID-ID, were conditioned with various doses of CD45-ADC, total body irradiation, or isotype-ADC, and then given transplants of total bone marrow cells from congenic or haploidentical donors. Flow cytometry was used to assess chimerism and immune reconstitution. Histology was used to document reconstitution of thymic architecture. RESULTS: Conditioning with CD45-ADC as a single agent allowed robust engraftment and immune reconstitution, with restoration of thymus, bone marrow, and peripheral compartments. The optimal doses of CD45-ADC were 1.5 mg/kg and 5 mg/kg for congenic and haploidentical transplantation, respectively. No graft-versus-host disease was observed. CONCLUSIONS: Conditioning with CD45-ADC alone allows full donor chimerism and immune reconstitution in Rag1 hypomorphic mice even following haploidentical transplantation, opening the way for the implementation of similar approaches in humans.

Effect of Conditioning Regimens and Graft-versus-Host Disease Prophylaxis on the Outcomes of Umbilical Cord Blood Transplantation Performed with Cyclophosphamide/Total Body Irradiation-Based Regimens.

Umbilical cord blood (UCB) is a valuable alternative donor source for allogeneic hematopoietic stem cell transplantation. Various conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens aimed at improving the outcomes of umbilical cord blood transplantation (UCBT) have been explored; however, the differences in their effects remain unclear. This study was conducted to elucidate the differences in the effects of conditioning and GVHD prophylaxis regimens on UCBT outcomes by disease type in a nationwide, retrospective study. We retrospectively analyzed the effects of conditioning and GVHD prophylaxis regimens on the outcomes of UCBT performed with cyclophosphamide (Cy)/total body irradiation (TBI)-based regimens in patients with acute myeloid leukemia (AML; n = 1126), acute lymphoblastic leukemia (ALL; n = 620), myelodysplastic syndrome (MDS; n = 170), and lymphoma (n = 128). Multivariate analysis for overall survival (OS) demonstrated the benefit of adding high-dose cytarabine to the Cy/TBI regimen for the AML group (relative risk [RR], .76; P = .003) and lymphoma group (RR, .54; P = .02), but not for the ALL and MDS groups. In the ALL group, adding etoposide to the Cy/TBI regimen was associated with a lower OS (RR, 1.45; P = .03). For GVHD prophylaxis, a tacrolimus/methotrexate regimen was associated with a lower OS compared with a cyclosporine/methotrexate regimen in the AML group (RR, 1.26; P = .01); this difference was not observed in the other groups. These differences in OS according to the conditioning and GVHD prophylaxis regimen were attributable mainly to differences in relapse risk. Our data show that the effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes differed according to disease type. UCBT outcomes could be improved by selecting optimal conditioning regimens and GVHD prophylaxis for each disease type.

Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study.

PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).

Low-dose decitabine-intensified modified conditioning regimen alleviates aGVHD in AML/MDS patients treated with allogeneic hematopoietic stem cell transplantation.

Background: The widespread adoption of Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) has significantly improved the survival rates of patients with hematological malignancies. However, Graft-Versus-Host Disease (GVHD) remains a formidable complication, threatening patient prognosis. Recent research has indicated that decitabine (DAC), known for its hypomethylating properties may also exhibit immune-regulatory capabilities and a potential for reducing GVHD incidence and enhancing survival. Methods: We retrospectively reviewed data from AML/MDS patients who underwent Allo-HSCT at our center from January 2010 to January 2023. From a total of 251 patients with complete data, we employed propensity score matching (PSM) to create 100 matched pairs (200 patients) for comprehensive trial analysis. Patients receiving low-dose DAC-containing regimen were matched with those who did not receive DAC. Results: Patients in the DAC group exhibited a significantly lower incidence of grade II-IV acute GVHD (aGVHD) compared to non-DAC group (21% vs. 38%, P=0.013). Univariable and multivariable logistic regression analysis demonstrated DAC intervention as a protective factor against grade II-IV aGVHD (P=0.017, OR=0.47, 95% CI 0.23-0.81; P=0.018, OR=0.46, 95% CI 0.24-0.87). Multivariate competing risk regression further supported administration of decitabine as a protective factor against grade II-IV aGVHD (P=0.038, SHR=0.53, 95%CI 0.29-0.97). There was no significant difference between both groups concerning chronic GVHD, infection, disease relapse, overall survival, disease-free survival and GVHD free, relapse free survival. In MRD negative or intermediate risk subgroup, the grade II-IV aGVHD ameliorating effect of DAC was confirmed as well. Conclusion: Low-dose DAC-intensified modified conditioning regimen could improve prognosis in AML/MDS Patients treated with allogeneic hematopoietic stem cell transplantation.

BendaEAM versus BEAM as conditioning regimen for ASCT in patients with relapsed lymphoma (BEB): a multicentre, randomised, phase 2 trial.

Background: Replacement of carmustine (BCNU) in the BEAM regimen (BCNU, etoposide, cytarabine, melphalan) with bendamustine (BendaEAM) before autologous stem cell transplantation (ASCT) is feasible in lymphoma. However, randomised trials are lacking. Here, we present the first trial addressing this topic. Methods: This multicentre, randomised, phase 2 study (BEB-trial) conducted at four haematological centres in Austria and Switzerland compares BEAM with BendaEAM in patients with relapsed lymphoma. Both regimens were administered intravenously before ASCT, in BEAM according to the standard protocol (300 mg/m2 BCNU on day -6), in BendaEAM, BCNU was replaced by 200 mg/m2 bendamustine given on days -7 and -6. Eligible patients were aged 18-75 years and had mantle cell lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma in first or second remission or chemosensitive relapse. The primary endpoint of the study was to evaluate whether replacement of BCNU by bendamustine reduces lung toxicity, defined as a decrease of the diffusion capacity of the lung for carbon monoxide by at least 20% at three months after ASCT. Data analyses were performed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02278796, and is complete. Findings: Between April 20, 2015, and November 28, 2018, 108 patients were enrolled; of whom 53 were randomly assigned to receive BendaEAM (36 male, 17 female) and 55 to receive BEAM (39 male, 16 female). All patients engrafted rapidly. Lung toxicity did not differ between groups (BendaEAM: n = 8, 19.5%; BEAM: n = 11, 25.6%; risk difference = -6.1%: 95% confidence interval: -23.9% to 11.7%). Acute toxicities of at least grade 3 were comparable in both groups (BendaEAM: 35.8%, BEAM: 30.9%). Overall survival (BendaEAM: 92.5%, BEAM: 89.1%) and complete remission (BendaEAM: 76.7%, BEAM: 74.3%) after 1 year (median follow-up: 369 days) were similar. No difference in quality of life was observed. Interpretation: Results were similar for both regimens in terms of survival and response rates. A phase 3 non-inferiority study is required to investigate whether BendaEAM can be considered as an alternative to BEAM. Funding: Mundipharma.