Reduced Toxicity Conditioning Research Articles

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Reduced toxicity conditioning for hematopoietic stem cell transplantation in children with Diamond-Blackfan anemia.

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Reduced-toxicity conditioning regimen with low dose post-transplantation cyclophosphamide and low-dose anti-thymocyte globulin as graft-versus-host disease prophylaxis for haploidentical stem cell transplantation in older patients.

We retrospectively analyzed outcomes in 55 patients ≥ 55 years of age with hematologic malignancies treated with fludarabine, cytarabine, busulfan, and low-dose cyclophosphamide as the conditioning regimen between January 1, 2019, and November 30, 2023. Neutrophil engraftment was successful in all patients within 28 days, with 54 patients (98.2%) achieving complete donor chimerism. The cumulative incidence of non-relapse mortality was 0% at 30 days, 7.5% at 100 days, and 19% at 1 year. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 25% (95%CI, 15-38%), whereas that of grade III-IV aGVHD was 9.1% (95% CI, 3.3-19%). The cumulative incidence of extensive chronic graft-versus-host disease at 1 year was 3.6% (95%CI, 0.66-11%). The cumulative incidences of relapse, overall survival, and GVHD-free/relapse-free survival at 1 year were 9.0%, 71.6%, and 67.1%, respectively. An RIC conditioning regimen, including a combination of lower PTCy/ATG as GVHD prophylaxis, followed by haplo-SCT, might be a promising option for appropriately selected older patients.

Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).

Reduced toxicity (FluBu3) versus myeloablative (BuCy) conditioning in acute myeloid leukemia patients who received first allogeneic hematopoietic stem cell transplantation in measurable residual disease-negative CR1.

In the present study, reduced toxicity (FluBu3) and myeloablative (BuCy) conditioning were compared in patients with AML who received first allogeneic HSCT in MRD-negative CR1. The study included 124 adult patients who underwent HSCT from an HLA-matched (8/8) sibling, unrelated, or 1-locus mismatched (7/8) unrelated donor (MMUD). The median age was 45 years and intermediate cytogenetics comprised majority (71.8%). The 2-year OS, RFS, CIR and NRM for BuCy (n = 78, 62.9%) and FluBu3 (n = 46, 37.1%) groups were 78.3% and 84.5% (p = 0.358), 78.0% and 76.3% (p = 0.806), 7.7% and 21.5% (p = 0.074) and 14.3% and 2.2% (p = 0.032), respectively. At the time of data cut-off, relapse and NRM were the main causes of HSCT failure in each of the FluBu3 and BuCy arms. Among patients, 75% of relapsed FluBu3 patients had high-risk features of either poor cytogenetics or FLT3-ITD mutation compared with 16.7% of BuCy patients. The majority of NRM in the BuCy group was due to GVHD (73%), half of whom received MMUD transplantation. To conclude, the FluBu3 reduced toxicity conditioning showed comparable post-transplant OS and RFS to BuCy and was associated with significantly reduced NRM that was offset by a trend towards higher risk of relapse even in MRD-negative CR1 population.

Impact of Different Fludarabine Doses in the Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation

The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning regimens because of limited nonhematologic toxicities. Few reports assess the impact of different dose of Flu on the clinical outcomes and the Flu doses vary across reports. To compare the effect of Flu dose, the clinical outcomes of patients who received Flu and busulfan (FB; n = 1647) or melphalan (Flu with melphalan (FM); n = 1162) conditioning for unrelated bone marrow transplantation were retrospectively analyzed using Japanese nationwide registry data. In the FB group, high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were given to 1334 and 313 patients, respectively. The 3-year overall survival (OS) rates were significantly higher in the HFB group than in the LFB group (49.5% versus 39.2%, P < .001). In the HFB and LFB groups, the cumulative incidences were 30.4% and 36.6% (P = .058) for 3-year relapse and 25.1% and 28.1% (P = .24) for 3-year nonrelapse mortality (NRM), respectively. In the multivariate analysis for OS and relapse, Flu dose was identified as an independent prognostic factor (hazard ratio: 0.83, P = .03; hazard ratio: 0.80, P = .043). In the FM group, high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were given to 118 and 1044 patients, respectively. The OS, relapse, and NRM after 3 years did not differ significantly between the HFM and LFM groups (48.3% versus 48.8%, P = .92; 23.7% versus 27.2%, P = .55; 31.9% versus 30.8%, P = .67). These findings suggest that high-dose Flu was associated with favorable outcomes in the FB group but not in the FM group.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning

BackgroundNo comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. MethodsWe retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. ResultsThe median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III–IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III–IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. ConclusionMMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Selecting the Right Alternative Donor: Comparison of Outcomes of HLA-Mismatched Alternative Donor Hematopoietic Cell Transplantations in Adult Patients with Acute Lymphoblastic Leukemia Regarding KIR-Ligand Mismatch

Background: Allogeneic hematopoietic cell transplantation from cord blood (CBT) or haploidentical donor (HIDT) has proved to be a viable option for patients unable to find a human leukocyte antigen (HLA)-matched conventional donor. However, few single-centered studies have compared outcomes of the two alternative donor transplantations in adult acute lymphoblastic leukemia (ALL). Aim: Our aim is to compare outcomes of adult ALL patients treated with CBT with those treated with HIDT. Secondly, we tried to find out factor that could be considered in selecting donor for alternative donor transplantation to improve clinical outcomes. Methods: We compare outcomes of adult ALL patients treated with CBT (n=134) between 2008 and 2022 with those treated with HIDT (n=47) between 2018 and 2022.Conditioning regimen for CBT consisted of total body irradiation (12Gy) plus cytarabine (9g/m 2) plus fludarabine (150mg/m 2). Graft-versus-host disease (GVHD) prophylaxis was attempted using tacrolimus and mycophenolate mofetil. For HIDT, we used reduced toxicity conditioning (RTC) regimen including fludarabine (150mg/m 2) plus busulfan (6.4mg/kg). GVHD prophylaxis was done with ATG 1.5mg for 4 days plus short course methotrexate (MTX) (15mg/m 2) plus tacrolimus. Killer cell immunoglobulin-like receptor (KIR) ligand mismatch was calculated in both GVH and HVG direction using HLA-KIR ligand database, and its effect on clinical outcomes of alternative donor transplantation was investigated. Results: In HIDT, CD34+ cell count (´10 6/kg) was significantly higher (7.4 vs. 0.1, P&amp;lt;0.001), and the patients were older (49 vs. 33.5, P&amp;lt;0.001) compared to CBT. Other characteristics, such as cytogenetic risk and leukocyte count at diagnosis, did not show significant difference between the two groups. Incidence of acute GVHD II-IV (51.1% vs. 50.0%), III-IV (25.5% vs. 17.9%), and moderate to severe chronic GVHD (10.8% vs. 11.0%) between HIDT vs. CBT were similar. After median follow-up of 39.4 months (range: 5.5-167.4), HIDT showed higher cumulative incidence of relapse (CIR) compared to CBT (47.9% vs. 18.9%, P&amp;lt;0.001), which remained true even after stratifying by age subgroup (Age&amp;lt;40: P=0.033, Age≥40: P=0.002). Conversely, CBT showed higher non-relapse mortality (NRM) than HIDT (22.8% vs. 9.0%, P=0.038), but the same was true only in the older age subgroup (Age&amp;lt;40: P=0.484, Age≥40: P=0.002). These effects summed up to produce comparable results in estimated 3-year disease-free survival (DFS) of CBT and HIDT (58.4% vs. 43.5%, P=0.103), especially in the older subgroup (38.7% vs. 40.7%, P=0.897). Multivariate analysis also revealed that HIDT was related with higher relapse (HR 3.47; 95%CI 1.92-6.27, P&amp;lt;0.001), and CBT with higher NRM (HR 4.18; 95%CI 1.42-12.3, P=0.009). GVH direction KIR ligand mismatching worked for lower 3-year DFS in CBT (40.3% vs. 74.4%, P=0.007), although CIR and NRM did not show significant difference (27.8% vs. 15.6%, P=0.178; 35.0% vs 18.4%, P=0.057, respectively). On the other hand, the mismatch resulted in lower incidence of acute GVHD II-IV (32.0% vs. 54.2%, P=0.011). The trend remained when such effect was investigated separately in CBT and HIDT, but it was not statistically significant (33.3% vs. 53.1%, P=0.082; 28.6% vs. 57.6%, P=0.053, respectively). Conclusions: Our data shows higher NRM in CBT, and unexpected higher relapse rate in HIDT. Age of the patient should be considered when choosing CBT, because in older patients CBT showed notably worse NRM compared to HIDT. Higher incidence of relapse in HIDT may be attributable to ALL disease characteristics itself or insufficient elimination of leukemic cells by RTC regimen with stronger GVHD prophylaxis. Similar to what is known in acute myeloid leukemia, GVH direction KIR incompatibility showed protective effect against acute GVHD in ALL. However, the mismatch resulted in worse DFS in ALL patients treated with CBT, but not in those treated with HIDT. Possible explanation to this phenomenon is that the number of NK cells in cord blood was insufficient for mismatch-induced graft-versus-leukemia effect, while its immune response against infected cells was suppressed by the same mechanism that resulted in lower acute GVHD. Keywords: Acute lymphoblastic leukemia, Cord blood transplantation, Haploidentical donor transplantation, HLA-mismatched transplantation, Killer-cell immunoglobulin like receptor

Myocardial Fibrosis Improves in Young Patients with Sickle Cell Disease after Hematopoietic Cell Transplantation

Introduction: Cardiovascular complications are a leading cause of early mortality in patients with sickle cell disease (SCD). Chronic anemia, iron overload and repeated microvascular ischemic insults with reperfusion injury often result in progressive myocardial injury and maladaptive remodeling in SCD patients. Patients with SCD develop diffuse myocardial fibrosis, which can be detected by quantifying the myocardial extracellular volume (ECV) using cardiovascular magnetic resonance (CMR) imaging. Our group and others have previously shown that diffuse myocardial fibrosis is highly prevalent in both children and young adults with SCD, including those who have normal ventricular size and function by echocardiography. Additionally, we have shown that the disease modifying therapies (DMT) such as hydroxyurea or chronic transfusions do not appear to be protective against development of diffuse myocardial fibrosis. In a retrospective study, we found no difference in the myocardial ECV in patients who began DMT early (less than 6 years of age) versus later in life (at least 6 years or after) (Morin CE and Sharma A et al. Blood 2023.). Hematopoietic cell transplantation (HCT) can cure SCD, but myocardial effects of the therapy are unknown. Our goal was to evaluate cardiovascular parameters of function and injury, especially the progression of diffuse myocardial fibrosis, by comparing serial CMR studies performed before and after HCT in patients with SCD. Methods: We performed prospective CMR evaluation of children and young adults with SCD who received a matched sibling donor (MSD) or haploidentical donor (HAPLO) HCT following a reduced toxicity conditioning on a clinical trial (NCT04362293). CMR was performed pre-HCT, and at 1 month, and 12 months post-HCT. CMR-derived ventricular and atrial volumes were calculated. ECV was measured from T1 maps with a modified Look-Locker inversion recovery (MOLLI) sequence in short-axis. T2 and T2* maps were obtained. Regions of interest in the mid-ventricular septum were identified for analysis. We report descriptive statistics for CMR measures along with paired t-tests comparing patient ECV levels at 1-month and 12-months post-HCT to their respective baseline ECV. Results: Our study cohort consisted of 14 patients with SCD who underwent HCT and had serial CMR evaluations available. Thirteen patients had HbSS genotype and one had HbSC genotype. All patients were receiving DMT, either with hydroxyurea or chronic transfusions prior to HCT. Participants were majority male (57%) with median age of 15.2 years (range 6.8-21.3) at the pre-HCT CMR. Six received an MSD HCT and 8 received a HAPLO HCT. Ten patients each had follow up CMR evaluations performed at 1 month, and 12 months post-HCT. At 1 and 12 months post-HCT ejection fraction was preserved while biventricular volume and cardiac index decreased (Table 1). Compared to pre-HCT, ECV decreased from median 29% [range 27-38] to 28% (range 21-35, P= 0.061) at 1 month and 27% (range 24-31, P= 0.043) at 12 months post-HCT. There was no difference in the cardiac chamber sizes or the ECV measurements of those who received a MSD versus HAPLO HCT. Conclusions: We observed an improvement in cardiac chamber sizes with preservation of cardiac function as early as one month after HCT in patients with SCD. We further noted a reduction in ECV indicating a decrease in diffuse myocardial fibrosis in these young patients with SCD. To our knowledge, this is the first study to show that diffuse myocardial fibrosis can improve in patients with SCD after HCT. In addition to further corroborating the organ function protective effects of HCT in patients with SCD, these data further demonstrate the use of CMR as an essential non-invasive tool to assess the effects of therapeutic interventions on SCD-cardiac injury.

Treosulfan-Based Reduced-Toxicity Conditioning for Elderly Patients with High-Risk Myelodysplastic and Myeloproliferative Disease for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative treatment for patients (pts) with high-risk myeloid malignancies. Despite advances in the supportive care over the past decades, alloHCT is still associated with significant toxicity, especially in the elderly population. The choice of an adequate conditioning regimen has become essential in order to prevent treatment-related morbidity and mortality. Since myeloablative conditioning (MAC) is mostly restricted to the younger population due to the high toxicity, reduced-intensity conditioning (RIC) provides an alternative solution. However, especially for pts with high-risk disease, a potential increase in the incidence of relapse must be taken into account. The advent of reduced-toxicity conditioning regimens (RTC), mostly based on treosulfan in combination with fludarabine, offers a balance between a favorable toxicity profile and a strong anti-neoplastic effect. Considering the increasing rates of alloHCT among older pts in the past decades, finding the optimal conditioning regimen is still an unmet need for this collective. The objective of this study is to analyze the outcome of pts aged ≥60 years who underwent alloHCT for myelodysplastic or myeloproliferative disease and received a treosulfan-based conditioning. In order to maximize the anti-leukemic effect of the conditioning in this population we chose the myeloablative dose of treosulfan of 14g/m2 daily. Materials and methods We retrospectively analyzed the outcome of adult pts ≥60 years with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myelofibrosis (MF) who underwent their first allo-HCT from a matched or mismatched donor over a period of 10 years at the adult Bone Marrow Transplantation Unit of our institution. The conditioning consisted of a combination of treosulfan 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0) for MDS and treosulfan, 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -3 for CMML and MF. Endpoints of this analysis were engraftment rate (together with time to engraftment), relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM). Continuous variables were illustrated as median values. NRM, RFS and OS for the whole cohort were analyzed with the Kaplan-Meier method and presented as survival functions. Results Between 01/2012 and 12/2022 91 consecutive elderly pts were eligible for this analysis. Patient and transplant characteristics are listed in Table 1. The median follow-up after allo-HCT was 3.12 years (4 months-10.5 years). Median age was 65 years, 76% (n = 69) of patients had an EBMT (European Society for Blood and Marrow Transplantation) risk score of ≥ 4. In 20 of 91 pts (22%) a 9/10 matched unrelated donor was selected, due to the lack of a more suitable donor. The standard graft versus host disease (GVHD) prophylaxis was a combination of calcineurin inhibitors (CNI) +/- mycophenolate mofetil and Anti-T-lymphocyte globulin (ATG) (n= 85, 94%). Neutrophil engraftment was achieved in 98% (n= 89) of pts. The median time to engraftment was 13 days (12, 15). Fourteen of 91 pts (15%) developed severe (grade III-IV) acute GVHD, and 44% (n= 40) had chronic GVHD of any grade. Considering early toxicity, 2 patients of 91 (2%) died before day +30 after alloHCT due to transplant-related toxicity, overall 6 of 91 (7%) in the first 100 days after alloHCT. The 2-year OS was 55% (95% CI, 44.7-.66.2) (Figure 1) and RFS was 48.5% (95% CI, 38.9-60.5). The 2-year NRM was 37% (95% CI, 33.5-39.5). No significant differences have been observed in the outcome of the different disease entities. Main causes of death were infections (n= 15, 32%), GVHD (n=13, 27.7%) and disease relapse (n= 13, 27.7%). Conclusions Our retrospective analysis suggests that a treosulfan-based RTC with myeloablative potential in an elderly and frail population of pts with high-risk myeloid diseases is feasible, with an excellent engraftment rate and a limited early toxicity, and promotes disease control. We report a 2-year NRM of 37%, which was partially due to severe GvHD in a cohort of pts with a relatively high-proportion of mismatched donors (20%). The role of post-transplant cyclophosphamide as backbone of the GvHD prophylaxis of RTC regimes should be further evaluated, in prospective trials.

Fludarabine and Melphalan Reduced Toxicity Versus a Myeloablative Fludarabine and Busulfan Conditioning Regimen for Acute Myeloid Leukemia

Introduction: The optimal induction regimen for an allogeneic hematopoietic cell transplant (allo-HCT) for a young adult patient diagnosed with acute myeloid leukemia (AML) remains to be defined. Among reduced intensity regimens (RIC), retrospective registry data from both CIBMTR and EBMT would suggest that a Fludarabine / Melphalan (Flu/Mel) regimen was superior to a Fludarabine / Busulfan x 2 (Flu/Bu2) regimen. The need for a myeloablative conditioning regimen over a RIC has been evaluated in at least six randomized clinical trials (RCT), and the results have yet to be uniform. Published meta-analysis suggests equipoise. The studies are further limited by including a heterogenous group of conditioning regimens, especially in the reduced intensity arm; they all come from developed countries, a mix of AML and MDS in most studies, and variation in age groups enrolled in them. In India and developing countries, there remain significant challenges with multi-drug resistant infections, financial constraints, and challenges with intensive care support. We hypothesize that in this setting, a reduced toxicity regimen, such as a combination of Fludarabine with Melphalan (140 mg/m 2) (Flu/Mel), may be preferable to a myeloablative regimen. Methods: A single-center retrospective analysis was undertaken to study the impact of a reduced toxicity Flu/Mel regimen versus a myeloablative Fludarabine combined with Busulfan (130 mg/m 2/day x 4 days) regimen (Flu/Bu4). All consecutive patients in all age groups with a diagnosis of AML who underwent an allo-HCT between Jan 2005 and Dec 2021 were included in this analysis. The conditioning regimen used was as per physician discretion with a broad guideline within the department to use a myeloablative Flu/Bu4 regimen in a young fit patient with high-risk features such as high-risk ELN at diagnosis, CR2, and beyond, or requiring more than one cycle of induction chemotherapy to achieve a complete remission (CR). Results: 439 patients underwent an allo-HCT for a diagnosis of AML at our center in the given time. The median age was 33 years (range: 1 - 63), and there were 267 (60.8%) males. The transplants were done in CR1 in 236 (54%), CR2 in 90 (20.5%), CR3 in 13 (3%), and in relapsed/refractory or with active disease in 100 (22.8%). The majority were matched sibling/related donors (MRD) in 284 (64.7%), followed by matched unrelated (MUD) in 75 (17.1%) and haploidentical in 80 (18.2%). The conditioning regimen used was Flu/Mel in 170 (38.7%), Flu/Bu4 in 185 (42.1%), and a mix of other regimens in 84 (19.1%). At an actuarial median follow-up of 4 years, the overall survival (OS) and event-free survival (EFS) of the entire cohort were 40.8% ± 3.0% and 38.6% ± 3.0%, respectively. The EFS of cases in CR1, CR≥2, and in relapsed/refractory/active disease were 47.7% ± 3.8%, 45.0% ± 5.5%, and 12.3% ± 3.6%, respectively. The baseline characteristics and clinical outcome of cases that received a Flu/Mel condition versus Flu/Bu4 conditioning are summarized in Table 1. In summary, baseline characteristics were comparable between the two groups, except that significantly more cases underwent a haploidentical transplant in the Flu/Bu4 group. In contrast, in the Flu/Mel group, there were significantly more cases in CR1, and the median age was also significantly older. The 5-year KM EFS of the Flu/Mel and Flu/Bu4 cohort was 51.7±3.9% and 43.9±3.9% (P-value = 0.297), respectively (Figure 1). On univariate analysis, only CR1 status before transplant and the presence of chronic GVHD impacted EFS positively, and on multivariate analysis, only CR1 status affected EFS. Conclusion: In conclusion, in one of the most extensive retrospective studies comparing a uniform reduced toxicity conditioning regimen with Flu/Mel versus a standard myeloablative Flu/Bu4 conditioning regimen, we find no significant advantage of Flu/Bu4 over a Flu/Mel conditioning regimen.

Thiotepa, Busulfan and Fludarabine Conditioning Regimen in Adult Patients Undergoing Allogeneic Stem Cell Transplantation for Lymphoid Malignancies. a Study on Behalf of Geth-TC

Background: The optimal conditioning regimen in allogeneic hematopoietic stem cell transplant (alloHCT) for lymphoid malignancies remains unclear. Reduced intensity regimens (RIC) allow older and more comorbid patients to receive alloHCT since lower non-relapse mortality (NRM) is observed, but disease control may still be a concern. The use of reduced toxicity conditioning regimens allows better disease control with a cost of higher toxicity. To date, no data are available regarding the use of thiotepa, busulfan and fludarabine (TBF) in adult patients allografted for lymphoma. Our aim is to describe survival outcomes and treatment-related toxicities of patients with lymphoid malignancies conditioned with TBF. Methods: Between December 2011 and July 2022, 116 patients diagnosed with lymphoid malignancies received a first alloHCT conditioned with a TBF-based regimen in 9 Spanish institutions. All consecutive patients were included in the study and data were collected retrospectively. Low-dose TBF was defined as the use of 5 mg/kg of thiotepa (T5) while a high-dose TBF was considered as the administration of 10 mg/Kg of thiotepa (T10). Main outcome variables were overall survival (OS), progression-free survival (PFS), NRM, relapse incidence (RI), cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences. Results: Baseline characteristics are summarized in Table 1. The median age was 52 (range 23-70) years and 62.1% of the patients were males. Aggressive B-cell lymphoma was the most common diagnosis (43.1%). Seventy-seven (66.4%) patients received T10, and 39 (33.6) T5. Median follow-up among survivors was 46.9 (range 16.9-136.5) months. At 3 years, OS, PFS, NRM and RI were 54.7% (95% confidence interval [CI], 45.5-63.9%) ( Figure 1), 44.9% (95% CI, 35.7-54.1%), 34.9% (95% CI, 27.1-44.9%) and 20.2% (95% CI, 14-29.2%), respectively. Of the 53 patients who died during follow up, causes of death were: 12 relapses and 41 transplant toxicities (16=infections, 8=GVHD, 5=endothelial complications, 1=traumatism, 11=missing). Fifty-one percent of toxicity-related deaths were observed during the first 3 months from transplant. All but 2 patients engrafted. The cumulative incidence of neutrophil engraftment at day +30 was 91.4% (95% CI, 86.3-96.8%). The cumulative incidence of grade II-IV aGVHD at day +100 was 25.4% (95% IC, 18.5-34.9%), with 8 patients presenting grade III-IV aGVHD. The 3-years cumulative incidence of all grade cGVHD was 29.8% (95% CI, 22.5-39.6%), with 15 patients presenting with moderate-severe cGVHD. Seventeen patients developed venooclusive disease (14.7%) with a median time from alloHCT infusion of 14 (range 7-93) days. On univariate analysis, no prognostic factors were found in terms of NRM, OS and PFS. However, higher doses of thiotepa were associated to a lower relapse incidence (13.2% vs 35%, p=0.0075) without differences in terms of NRM. The use of myeloablative conditioning (vs RIC) showed a trend towards a lower relapse incidence although it was not statistically significant (9.4% vs 24.5%, p=0.059) with no impact in NRM rates. On multivariate analysis these results could not be confirmed. Conclusions: In our series, TBF conditioning regimen allows efficient disease control at the expense of increased incidence of severe early toxicities. Despite higher NRM, TBF conditioning regimen showed similar OS rated compared to other regimens used for lymphoid malignancies. This regimen could be considered for fit patients with high-risk lymphoid diseases.

Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation

AbstractPrimary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (&amp;gt;10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

Long-Term Follow-up of AML Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after Primary Induction Failure

Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is the standard consolidation treatment for most patients with adverse-risk acute myeloid leukemia (AML). Achieving complete remission (CR) before HCT has been associated with improved clinical outcomes. Thus, AML patients with primary induction failure (PIF) are often not considered for immediate allogeneic HCT, despite being the only curative option. Most recently, Stelljes et al. reported similar survival rates after a median follow-up of 37 months for relapsed/refractory AML patients who either proceeded directly to allogeneic HCT or underwent intensive remission induction prior to HCT within the ASAP trial (Stelljes et al., ASHAnnual Meeting 2022). Yet, the effect of immediate allogeneic HCT in this clinical setting for long-term prognosis is still largely unclear. Thus, we explored long-term clinical outcomes of AML patients with PIF undergoing allogeneic HCT with active disease at our institution over a period of 30 years between 1989 and 2019, and investigated associations with molecular and clinical features. Methods We retrospectively analyzed AML patients undergoing allogeneic HCT after PIF at the University Medical Center Freiburg (Germany) between 1989 and 2019. PIF was defined as never achieving CR during induction or re-induction, assessed either by cytomorphology or molecular measurable residual disease as defined by the NCI (Version 23.06d, Code C70622). All clinical examinations and laboratory analyses were performed as part of standard clinical care. Statistical analyses were performed considering the entire cohort as well as distinct transplant periods: i) 1989-2000, ii) 2001-2010, and iii) 2011-2019. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Other endpoints were time to relapse and time to non-relapse mortality (NRM). Results We included 220 patients in this retrospective single-center study, with a median follow-up of 8.5 years (range: 0.06-25.4). Median age of patients was 55 years (range: 20-75), increasing over time as reduced toxicity conditioning became more established (1989-2000: 13.9%; 2011-2019: 61.8%). Patients received in median two lines of treatment before HCT (range: 1-6). Blast count in bone marrow before initiation of allogeneic HCT was in median 36% (range: 0-95%). Molecular risk was assessed in 63.2% of patients, while genetic information was missing in 36.8% of AML cases. 39.8% of AML patients were disease-free after 1 year, 25.2% after 5 and 18.7% after 10 years from allogeneic HCT (Fig. 1A). 206 patients (93.6%) were alive at day 30 after HCT and 59 patients (26.8%) were alive at the time of the analysis. Median OS was 1.05 years, with 1-year, 5-year, and 10-year OS rates being 50.4%, 29.8%, and 21.6%, respectively (Fig. 1A). Survival rates were largely stable over time. 5-year OS in patients treated between 1989-2000 was 28.7%, in those receiving HCT between 2001 and 2010 28.7%, and 30.3% in patients transplanted between 2011 and 2019 (Fig. 1A). NRM was 29.3% after 5 years and 32.5% after 10 years (Fig. 1A). Over time, relapse rates decreased, with 5-year relapse rates of 45.7% between 1989 and 2000 and 33.3% between 2011 and 2019 (Fig. 1A). The main cause of death after HCT was AML progression/relapse (57.8%), while infections (19.3%), GvHD (11.2%), and treatment-related toxicity (8.4%) were leading causes of NRM. In Cox regression analyses incorporating known molecular and clinical risk factors, poor performance status (ECOG &amp;gt; 1 vs. 0-1; DFS: p=0.001, HR 2.26, 95% CI 1.37-3.73; OS: p=8*10 -5, HR 2.76, 95% CI 1.66-4.58,), adverse genetic risk at AML diagnosis (vs. intermediate/favorable risk; DFS: p=0.03, HR 1.6, 95% CI 1.1-2.4; OS: p=0.01, HR 1.7, 95% CI 1.1-2.6), and long diagnosis-to-HCT interval (DFS: p=0.01, HR 2.7, 95% CI 1.2-6.1; OS: p=0.005, HR 3.1, 95% CI 1.4-6.8) were strongly and independently associated with unfavorable DFS and OS (Fig. 1B). Conclusion We here demonstrated that immediate allogeneic HCT in AML patients with active disease represents a valid alternative to intensive remission induction prior to HCT and provides long-term survival and cure in a significant proportion of patients, suggesting to proceed with allogeneic HCT in patients with refractory disease as soon as a donor is available. The benefit of hypomethylating agents and venetoclax therapy prior to allogeneic HCT remains to be elucidated.

Successful Treatment Outcomes of Hematopoietic Stem Cell Transplantation with Reduced-Toxicity Conditioning Regimen Incorporating Treosulfan in Pediatric Patients with XIAP Deficiency

Background X-linked inhibitor of apoptosis (XIAP) defciency is an inherited primary immunodefciency characterized by chronic infammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and infammatory bowel disease (IBD). Although hematopoietic stem celltransplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory. Methods We have performed HSCT with treosulfan based RTC regimen for pediatric patients with non-malignant disorders since January 2016, and reviewed the medical records of patients with XIAP deficiency who underwent treosulfan based HSCT to investigate outcomes of HSCT for patients with XIAP deficiency. Results Since January 2016, 4 patients with XIAP deficiency had undergone HSCT using RTC regimen consisted of fludarabine (150-180 mg/m 2), treosulfan (42 g/m 2), rabbit ATG (5-7.5 mg/kg), and thiotepa (10 mg/kg). All patients were male and received HSCT (2 from URD and 2 from HFD) at median 13.7 years old (range, 12.8-15.3), median 2 years (range, 0.5-3.9) after diagnosis of XIAP. They all achieved engraftment and complete donor chimerism at the time of last evaluation. One patient who received HFD HSCT developed acute GI GVHD grade 3 and VOD within 1 month from HSCT, which was recovered after treatment with systemic steroid and defibrotide. Except the patient, there was no fatal acute regimen related toxicity ≥ CTCAE grade 3. Two patients developed chronic GVHD: one had limited disease which was resolved after systemic steroid therapy and the other had extensive disease. During the median 43 months (range, 33.1-63.0) follow-up, all survived without disease recurrence. Conclusions HSCT with treosulfan based RTC regimen is promising treatment option for pediatric patients with XIAP deficiency, with successful engraftment and low treatment-related toxicity. However, further studies including a larger multicenter trial and measures to refine the regimen are mandate to verify efficacy and safety of this regimen.

Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.

Reduced toxicity conditioning and a high CD34+ cell dose can achieve full donor chimerism in DOCK8 deficiency.

Biallelic mutations in the dedicator of cytokinesis 8 (DOCK8) gene were identified as the cause of combined immunodeficiency in 2009. Survival rates without hematopoietic stem cell transplant in patients with DOCK8 deficiency decline from 87% at 10 years to 33% at 30 years. Hematopoietic stem cell transplant is therefore the recommended treatment for cure of DOCK8 deficiency. However, patients with DOCK8 deficiency have multiple infectious comorbidities; hence, they cannot tolerate myeloablative conditioning. Reduced intensity conditioning reduces the risk of transplant-related mortality but increases the possibility of mixed chimerism. Mixed chimerism in children with immunodeficiency increases the risk of autoimmunity and the need for long-term immunoglobulin infusion. Here we have sought to devise a strategy for reducing the possibility of mixed chimerism without increasing the risk of transplant-related mortality. To balance the risk of transplant-related mortality and mixed chimerism, we used treosulfan-based reduced toxicity conditioning with a high CD34+ cell dose and differential T-cell capping for HLA-matched and haploidentical transplants. We are able to report that by using the aforementioned novel strategy, we achieved excellent transplant outcomes in the first cohort of high-risk patients with DOCK8 deficiency from India. High CD34+ cell dose and reduced toxicity conditioning can achieve full donor chimerism in DOCK8 deficiency.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH REDUCED‐TOXICITY CONDITIONING FOR PEDIATRIC RELAPSED OR REFRACTORY ALK‐POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA

Introduction: For children and adolescents with refractory or relapsed (r/r) anaplastic large cell lymphoma (ALCL), consolidation by allogeneic hematopoietic stem cell transplantation (SCT) after re-induction chemotherapy offers long-time cure. In CNS-negative patients, total body irradiation (TBI)-based conditioning regimens were increasingly replaced by Treosulfan-based regimens without irradiation over the last decade. To describe the efficacy of the different conditioning regimens, we performed a population-based analysis of pediatric patients with r/r ALCL consolidated by allogeneic SCT in Germany between 2013 and 2021. Methods: Patients with r/r ALK-positive ALCL enrolled in the NHL-BFM registry 2012 consolidated by an allogeneic SCT were analyzed. Data was extracted from the NHL-BFM registry 2012 and the German pediatric registry for SCT (PRST). Three-year progression-free survival (PFS) and overall survival (OS) were calculated from SCT. Four patients with CNS involvement at relapse were excluded from this analysis. Results: Twenty-five CNS-negative patients with a median age of 8 years (range, 0.9–17.6) at SCT were included. All patients had received ALCL99 front-line chemotherapy. Indications for SCT were progression during front-line treatment in 5 (20%), persisting minimal residual disease (MRD) positivity by in 4 (16%), relapse within one year of diagnosis in 15 (60%), and late (>1 year) relapses in one (4%) patient. Two patients received the SCT for a second relapse or progression. Re-induction therapy before SCT was heterogeneous, including ALK-inhibitors, brentuximab vedotin, vinblastine, and chemotherapy. From 21 patients with available data, MRD was positive in 5, and negative in 16 patients before SCT. The conditioning regimen was Treosulfan/Fludarabin/Thiotepa in 21 and TBI-based in 4 patients. Seventeen patients were transplanted from a matched unrelated donor (MUD), 7 from a matched sibling donor (MSD), and one from a haploidentical related donor. Median follow-up after SCT was 2.9 years (range, 1.0–9.2). PFS was 80% ± 8% and OS was 96% ± 4%. One patient died of complications of chronic graft-versus host disease. There was no difference in PFS between patients receiving TBI- or Treosulfan-based conditioning. We observed a non-significantly higher PFS after SCT in 20 patients older than 4 years (85% ± 8%) compared to five younger patients (60% ± 22%, p = .23), and a higher PFS in patients transplanted from a MUD (94% ± 6%, n = 17) compared to an MSD (57% ± 18%, n = 7; p = .023). Conclusion: The outcomes after allogeneic SCT were comparable with previous reports with mainly TBI-based conditioning, indicating that TBI can be replaced by reduced-toxicity conditioning in CNS-negative relapse patients. The observations of possibly inferior outcomes in younger patients after SCT and of improved outcomes for children transplanted from unrelated donors warrant further investigation. Keywords: non-Hodgkin (pediatric, adolescent, and young adult), stem cell transplant No conflicts of interests pertinent to the abstract.