Matched Unrelated Donor Research Articles

A Real-World Efficacy of Letermovir Primary Prophylaxis for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single-Center Retrospective Analysis

Introduction: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. Methods: We retrospectively analyzed 167 consecutive patients who underwent allo-HSCT between August 2022 and May 2023, who received LET 240 mg/day, to evaluate the efficacy and safety of LET in primary prophylaxis for clinically significant CMV infection (csCMVi), defined as CMV disease or CMV viremia reactivation, in real-world situations in China. Results: Among the enrolled 167 patients, 95.21% (159/167) of patients underwent a haploidentical donor (HID) transplant and 4.79% (8/167) a matched unrelated donor (MUD) transplant. 96.41% of the recipients were CMV seropositive, and only 6 recipients were CMV seronegative but donor seropositive. The median interval from allo-HSCT to the administration of LET was 7 (2-55) days. A total of 121 patients received LET within 14 days after HSCT. With the median follow-up 162(74-397) days post-HSCT, the incidence of CMV viremia was 11.98% (20/167). 3 patients developed CMV viremia after discontinuation of LET medication. Among the 20 patients with CMV viremia, the median duration of preemptive therapy was 9 (3-28) days, and the peak level of CMV-DNA was 1867 (1228-22383) copies/ml. Only 1 patient developed refractory CMV viremia with prolonged preemptive anti-CMV treatment. No patients were diagnosed with clinically significant CMV disease. Patients who developed CMV viremia or not were similar with respect to the CMV IgG status of the recipient at HSCT, donor CMV IgG, and GVHD incidence. Notably, the CMV viremia incidences of patients who received LET within 14 days and after 14 days post-HSCT were 7.44% and 23.91%, respectively (p=0.005). The incidence of EBV viremia was 17.16% (29/169), and 9 developed PTLD. The six-month overall survival was 93.4±2.1% in all patients who received LET prophylaxis. Meanwhile, LET prophylaxis was well tolerated. No drug-related death or permanent discontinuation was reported due to toxicity. Conclusion: Letermovir was effective and safty as primary prophylaxis of csCMVi, particularly initiating early post-HSCT.

Addition of Inotuzumab Ozogamicin to the Conditioning Regimen of Allogeneic Stem Cell Transplantation (allo-SCT) for Relapsed CD22 (+) Lymphoid Malignancies: Long-Term Survival Results

Background: Inotuzumab ozogamicin (InO) is a humanized antibody-drug conjugate that targets CD22+ B-cells. InO demonstrated antitumor activity and manageable toxicity in phase 1/2 trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) as a single agent and in combination with rituximab. In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014). Herein we report long-term survival outcomes. Methods: InO was infused intravenously (iv) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2. Bendamustine 130 mg/m 2 iv daily on days -5 to -3 together with 30 mg/m 2 iv of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m 2 iv on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis. Results: The study included 26 patients. Median age was 59 (range, 26-70) years. Disease types: CLL [n=11 (27%) ; 64% with TP53 mutations (either alone, or with other mutations such as BTK, CDH2, ZMYM3); 22% with complex cytogenetics; 75% with unmutated IGHV; mantle cell lymphoma ( MCL) [n=8 (31%); 83% had Ki 67 >30%; 25% TP53 mutation; and 25% blastoid histology]; Follicularlymphoma (n=5, 19%), and diffuse large b cell ( DLBCL[n= 2; (8%)]. Median # prior treatments was 2.5 (range, 1-6). Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1). At study entry, 18 (69%) patients were in CR, 7 (27%) in PR, and 1 (4%) had SD. Eleven (42%) received their transplants from matched sibling donors (MSDs) and 15 (58%) from matched unrelated donors (MUDs). The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of InO were 4, 2 and 20 patients, respectively. No DLT was observed. Forty-two percent of patients never experienced severe neutropenia and 77% never experienced platelet counts < 20K x 10 9/L. Only 1 patient developed veno-occlusive disease, confounded by the simultaneous manisfestation of hyper-acute GVHD related to prior nivolumab pre-alloSCT. Treatment-related mortality (TRM) at 2-years was 12%. With a median follow-up of 48.7 months (range, 3.6-82.8), the 5-year overall survival (OS) and progression-free survival rates (PFS) were 84% and 80%, respectively. Seven of 8 (87.5%) patients with PR/SD at study entry converted to CR after allo-SCT. There was no significant difference in OS or PFS by histology subtype. Patients who received a transplant from MSDs had OS and PFS rates of 100% v 79% ( P = .060) and 64% ( P = .032) for those who received MUDs, respectively (Figure 1). We compared results of this trial to a group of patients (n=56) with relapsed lymphoid malignancies who received allo-SCT at our center in a preceding prospective trial using BFR conditioning without InO and the same GVHD prophylaxis (clinicaltrials.gov #NCT00880815) which was previously published. There was no statistically significant difference in patients, disease (including histology, disease status pre-transplant) or transplant characteristics between the 2 groups. We found no statistically significant differences in engraftment times, incidence and grades of liver toxicity, TRM, risk of acute grade II-IV or III-IV GVHD. However, the study group containing InO had a higher incidence of extensive chronic GVHD (mainly de novo) than the control group (50% vs 25%, P = .019), respectively. There was a trend in patients with NHL to have a better 5-year OS (93% vs 68%) and 5-year PFS (93% vs 58%, Figure 2) in the study group vs the control groups. We did not observe such a trend in patients with CLL (5-year PFS 62% vs 59%): this could be related to small #patients, level of expression of CD22, more adverse mutations in the study group. Conclusions: Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

Outcome of Children with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) with Hypodiploidy or BCR-ABL1 Fusion Given Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Results from the Prospective Forum Study

Introduction: Hypodiploid karyotype (HYPO) and bcr-abl1 fusion (BCRABL) define high-risk BCP-ALL subtypes, with historically worse outcomes. Many front-line treatment protocols recommend allogeneic HSCT for these patients (pts), either in first complete remission (CR1) irrespective of response (adolescents/young adults with HYPO), if minimal residual disease (MRD) signals persist at specific time points (younger pts with HYPO and all pts with BCRABL), or following leukemic relapse. We have assessed the outcomes of BCP-ALL pts aged 4 to 18 years (y) with either HYPO or BCRABL who participated in the phase III ALL SCT PED FORUM study (EudraCT: 2012-003032-22) and underwent HSCT from either a matched sibling (MSD) or matched unrelated donor (MUD). Patients and Methods: Between 2014 and January 2023, 741 evaluable BCP-ALL pts were enrolled in FORUM (Table 1). HYPO was present in 61 pts, BCRABL in 82 pts, and neither lesion in 598 pts (NEITHER). 43/61 (70%), 40/82 (49%) and 215/598 (36%) pts with HYPO, BCRABL and NEITHER were in CR1, respectively (p= n.s.). Prior to HSCT, 82 of 101 HYPO/BCRABL pts with available MRD data were MRD negative by PCR and/or flowcytometry (<10-4). Total body irradiation (TBI) + VP16 was administered to 42 and 50 pts in the HYPO and BCRABL groups, respectively, while 18 HYPO and 30 BCRABL pts received non-TBI conditioning (busulfan or treosulfan + fludarabine and thiotepa, as per study protocol). Randomization determined allocation to TBI/non-TBI treatment arms until randomization closure in 03/2019, while treatment in some pts was dictated by lack of access to TBI, or contraindication to TBI in individual pts. An MSD was available in 14 (23%) and 24 (29%) HYPO and BCRABL pts, respectively. Notably, 24 out of 143 pts (17%) with HYPO/BCRABL received immunotherapy before HSCT (blinatumomab, inotuzumab ozogamicin, and/or CAR-T cells). Post-HSCT, 14 out of 82 BCRABL pts (17%) received a tyrosine kinase inhibitor (TKI), either prophylactically or pre-emptively. Results: With a median follow-up of three years post-HSCT, the 5-y probabilities of overall survival (OS) for pts with HYPO, BCRABL and NEITHER were 0.79±0.06, 0.83±0.05, and 0.74±0.02 (p=n.s.), while those of event-free survival (EFS) were 0.73±0.06, 0.65±0.07, and 0.61±0.02, respectively (p=n.s.). The 5-y cumulative incidence of relapse (CIR) for HYPO/BCRABL and NEITHER pts was 0.21±0.04 and 0.29±0.02 (p=0.036), and 5-y non-relapse mortality (NRM) was nearly identical for these groups (0.07±0.2 and 0.08±0.1). Among pts who received TBI, 5-y OS and EFS for HYPO, BCRABL, and NEITHER groups were 0.76±0.08 and 0.70±0.08, 0.89±0.05 and 0.70±0.10, and 0.80±0.03 and 0.71±0.03, respectively (p=n.s., Figure 1), while 5-y CIR and NRM post TBI were 0.15±0.06 and 0.11±0.05, 0.15±0.06 and 0.11±0.05, and 0.20±0.02 and 0.07±0.02, for the three groups, respectively (p=n.s.). The 3-y GvHD-free/relapse-free survival (GRFS) was similar between HYPO/BCRABL and NEITHER (0.60±0.06 and 0.58±0.03, respectively) and reached a plateau at 5-years (0.60±0.06 and 0.57±0.03, respectively). In subgroup analyses of pts in CR1 and >CR1, comparable outcomes were observed for HYPO, BCRABL, and NEITHER, hence results were not affected by the remission status. BCRABL and NEITHER pts receiving non-TBI conditioning had inferior outcomes (5-y EFS of 0.56±0.10 and 0.47±0.04, respectively) with a high 5-y CIR (0.36±0.09 and 0.43±0.04, respectively) as compared to those who received TBI. Similar 5-y OS and EFS were seen in HYPO pts whether receiving TBI (0.76±0.8 and 0.70±0.08) or chemo conditioning (83±0.09 and 83±0.09). Rates of NRM and acute/chronic graft-versus-host disease were similar in pts receiving TBI/ non-TBI conditioning and in BCRABL/HYPO vs. NEITHER pts. In multivariate analysis adjusted for CR status, conditioning and MRD, EFS did not differ between HYPO/BCRABL and NEITHER pts. Conclusions: Children receiving HSCT for treatment of BCP-ALL with either hypodiploidy or bcr-abl1 fusion showed outcomes comparable to BCP-ALL pts without these genetic lesions. CIR and EFS reached plateaus beyond 3 y post-HSCT, indicating that approximately two-thirds of these pts can be cured by HSCT with low rates of treatment-related mortality. Pts with BCRABL achieved favorable outcomes without the need for long-term or lifelong TKI therapy.

Comparison of Hematopoietic Stem Cell Transplantation and Repeated Immunosuppressive Therapy As Second-Line Treatment for Relapsed/Refractory Severe Aplastic Anemia

The optimal treatment for patients with severe aplastic anemia (SAA) who fail or have relapse after an initial course of immunosuppressive therapy (IST) has not been established. We conducted a retrospective study to compare the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated IST (n = 33) as salvage therapy for relapsed/refractory SAA between 2007 and 2022. In the repeated IST group, patients were treated with antithymocyte globulin (ATG) (n = 16) or high-dose cyclophosphamide (HD-CTX) (n = 17). The overall response rate was 42.4% at 6 months, and 60.6% at 12 months. In the HSCT group, 6 were matched sibling donor (MSD), 7 were matched unrelated donor (MUD), and 23 were haploidentical donor (HID). All patients achieved neutrophil engraftment and no primary graft failure was observed. The rate of platelet engraftment was 88.9%, with a median time of 16 days. The cumulative incidences of grade II-IV, III-IV acute GVHD was 36.1% ± 0.7%, 13.9% ± 0.3% at day +100, and chronic GVHD was 36.2% ± 0.7% at 5 years. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3-, 6- and 12-months post treatment (63.9%, 83.3% and 86.1%, respectively, P < 0.001). The estimated 5-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) were similar; however, the estimated 5-year failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 55.2% ± 9.2%, p = 0.049). In multivariate analysis, age ≤ 35 years at salvage HSCT was the only favorable factor for OS and FFS ( p = 0.019, 95% CI 0.019-0.706). These results suggest that HSCT and repeated IST are both effective for refractory/relapsed SAA in the salvage setting. Considering the superior FFS in the HSCT cohort, especially in younger patients (age ≤ 35 years), we recommend HSCT instead of a second IST for these patients.

Outcome of Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplant with Post-Transplant Cyclophosphamide - a Single Center Experience

Objective: The survival of multiple myeloma (MM) patients has improved significantly in the past decade with the development of new effective treatments including immunomodulators, monoclonal antibodies, and chimeric antigen receptor T cell (CAR-T) therapy. However, to date, none of the available treatments is curative for MM. In high-risk and relapsed patients, allogeneic stem cell transplant (allo-SCT) achieved long term survival in carefully selected MM patients. Here, we report our experience in MM patients who received allo-SCT at Thomas Jefferson University Hospital (TJUH). We aim to define the role of allo-SCT in the new era of MM treatment. Method: We retrospectively analyzed data of 57 MM patients who received allo-SCT at TJUH from 1996-2023. We used EZR software to analyze post-transplant outcomes including overall survival (OS) and disease-free survival (DFS) with Kaplan Meier method. Cumulative incidence (CI) calculated by EZR was used to determine relapse rate (RR) and non-relapse mortality (NRM). Median time to neutrophil and platelet engraftment was analyzed by Excel 2022. Results: The median age was 53 years old (range from 34-68 years old); 29 females and 28 males. Mean follow up time was 57.9 months (range from 0 to 253.6 months). Thirty-two patients received reduced intensity conditioning, 11 patients received myeloablative conditioning regimen, and 5 patients received non-myeloablative conditioning regimens. Thirty-one patients received matched related donor (MRD), 3 patients received matched unrelated donor (MUD), 21 patients received haploidentical (HI), and 2 patients received mismatched unrelated donor stem cell grafts. Time to neutrophil and platelet engraftment data was available for 33 and 29 patients, respectively. The median time to neutrophil engraftment was 12 days (range from 3-23 days). and the median time to platelet engraftment was 16 days (range from 6-51days). The 3-year and 5-year probabilities of OS were 53.2% (95% confidence interval is 38.7% to 65.7%) and 48.3% (95% confidence interval is 33.9% to 61.3%) respectively. The 3-year and 5-year probability of DFS were 37% (95% confidence interval is 21.6% to 52.5%) and 26.2% (95% confidence interval is 12.6% to 42%) respectively. Since 2009, most of the patients (33/36) in this study received post-transplant cyclophosphamide. Thus, we compared the OS for patients who received allo-SCT before 2009 and after 2009. The 5-years OS was 28.6% (95% confidence interval is 7.8% to 42.5%) and 62.7% (95% confidence interval is 43% to 77.2%) for patients who received allo-SCT before 2009 and after 2009 respectively (P=0.029). Among 43 patients with available relapse date data, the CI of relapse at 3 years was 36.9% (95% confidence interval 21.5%-52.4%) and the CI of NRM at 3 years was 26.1% (95% confidence interval 14%-39.9%). Thirty-five patients were evaluable for acute graft versus host disease (GVHD). Nine patients developed grade I-IV acute GVHD (25.7%) and 2 patients experienced grade III-IV acute GVHD (5.7%). Four out of 35 evaluable patients experienced chronic GVHD (11.4%): 2 patients had mild to moderate scleroderma, one patient had severe chronic skin GVHD and one had severe lung chronic GVHD. For 36 patients received allo-SCT after 2009, 3 died from relapse, 3 patients died from infection, 2 died from GVHD, 2 from unknown cause, one from brain bleeding, one from non-infectious pulmonary failure and one from acute heart failure. Conclusion: In MM patients with high-risk feature or relapsed/refractory disease, allo-SCT can be curative for approximately a third of the patients. Post-transplant cyclophosphamide coupled with contemporaneous MM treatments significantly increased the survival of allo-SCT MM patients in the modern era.

Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide in the Chilean National Health System. a Single Center Study

Haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide (Haplo-PTCy) is the most common transplantation modality in low-and-middle-income countries (LMIC). Registry data has shown comparable outcomes when using haploidentical donors versus Matched Unrelated Donors (MUD) in patients with acute leukemias. In the Chilean Public Health System Haplo-PTCy was incorporated in 2016 for adults up to 60 years old. We analyzed all adult patients who received an Haplo-PTCy at Hospital del Salvador, in a prospective registry study between 2016 and 2021. The primary outcome was overall survival (OS). Secondary outcomes were event-free survival (EFS), cumulative incidence of relapse, and incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day +100. Overall survival and EFS were estimated using the Kaplan-Meier method. The cumulative incidence of relapse was calculated using relapse as the primary event and death without relapse as a competing event. Acute GVHD is shown as absolute incidence at day +100. All statistical analyses were performed with R. This study was done in compliance with the Helsinki Declaration and was approved by the Institutional Review Board. Eighty-five Haplo-PTCy were performed in 82 patients (Table 1). Three-second Haplo-PTCy were excluded from this analysis. The median age was 25 years (range, 15-51), and 65% were male. Ninety-four percent of patients had a neoplastic disease (77/82), and the most common diagnosis was acute lymphoblastic leukemia (57%). Forty-seven percent proceeded to transplant in the first complete response. Most of the patients (76%) presented a low hematopoietic cell transplantation (HCT)-specific comorbidity index. Conditioning was mostly myeloablative (96%). The median dose of CD34+ cells infused was 8.1 x 106/kg (range, 2.4-10.0). No patient needed a desensitization regimen. Cytokine release syndrome (CRS) was common (86%) but no grade 3 CRS was observed. Primary graft failure was observed in one patient (1.2%). Poor graft function was observed in 11 patients (13%). Five patients (6.1%) died before engraftment. The incidence of grade II-IV aGVHD at day +100 was 29% (grade IV was not observed). With a median follow-up of 33 months (range 0-84), the estimated 3-year OS and EFS were 68.3% (95% CI 59-79%) and 64.6% (95% CI 55-76%), respectively (Figure 1). In patients with neoplastic disease (n=77), the 3-year cumulative incidence of relapse was 23% (95% CI 15-33%). Haplo-PTCy is feasible in LMIC. This cohort of cases, mostly young patients with neoplastic disease, shows encouraging survival with an acceptable aGVHD and relapse incidence.

Letermovir Prophylaxis for Cytomegalovirus Reactivation in β Thalassemia Major Children after Hematopoietic Cell Transplantation

Background: Cytomegalovirus(CMV) is one of the most important infections following allogeneic haematopoietic stem cell transplantation (HSCT). Although Letermovir is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV seropositive patients. There are limited data for letermovir as primary CMV prophylaxis in pediatric patients . The objective of the study was to analyze the the use of letermovir for prophylaxis from CMV infection in β thalassemia major children undergoing allo-HSCT in a single center. M ethods : This study was an retrospective, single-center evaluation of β thalassemia major pediatric recipients treated by allo-HSCT in the First Affiliated Hospital of Guangxi Medical University. 34 patients included in the study were CMV-seropositive, underwent allo-HSCT, and were started on letermovir for primary CMV prophylaxis between June 2022 and July 2023. CMV monitoring was performed 2 times a week until day +100 after HSCT. The primary end point was CMV reactivation on days +100. Results: 34 patients were analyzed. 20 patients were transplanted from haploidentical donor, 9 patients were transplanted from matched-related donor, 5 patients were transplanted from matched-unrelated donor. The median followed-up was 129 days (range, 50-405 days).The median age was 9 years (range, 2-16 years). The GVHD prophylaxis for matched-related donor group was cyclosporine-based , and the GVHD prophylaxisfor haploidentical and matched-unrelated donor groups were tacrolimus-based. Letermovir start at median 21 days (range 10-35 days) after HSCT. The median weight at the initiation of letermovir was 18.8 kg (range, 12-25 kg). The dose of letermovir was 240mg and 120mg orally once daily in tacrolimus co-administration and cyclosporine co-administration, respectively. During the follow-up period , CMV reactivation was observed in 8 patients totally (23.5%). Among them, 6 patients(17.6%) were in haploidentical donor group. 1 patient (2.9%) in matched-related group and 1 patient (2.9%) in matched-unrelated donor group was CMV reactivated, respectively. Throughout letermovir prophylaxis, the median CMV DNAemia level was 1945 copies (range,526-3800 copies), and the CMV DNAemia lasting time were 17.5 days (range,15-59 days). No patients developed clinically significant CMV infection. 1 patient died because of pulmonary infection of mucor. No serious hepatotoxicity, nephrotoxicity or letermovir intolerance was described. Conclusion: Our data support letermovir prophylaxis efficacy and safety in β thalassemia major children after allo-HSCT.

Real World Clinical Characteristics, Treatment Patterns and Outcomes of R/R B-Cell ALL Adult Patients in Latin America

Introduction. Acute lymphoblastic leukemia (ALL) frequently affects mainly children and young adults. ALL has seen important progresses in diagnosis techniques and treatment approaches in the last decade. However, in some developing countries, there are inequalities in ALL management, such as heterogeneous access to diagnosis technologies (e.g., cytogenetic and molecular profiling) and access to target therapies treatments. To date, there is scarce data on those impacts in treatment patterns and real-world outcomes of adult relapsed/refractory (R/R) B-cell ALL (R/R ALL) patients in Latin America (LA). Therefore, this study aims to describe treatment patterns, clinical characteristics, and outcomes of R/R ALL adult patients treated in LA. Methods. This was a retrospective multicenter non-interventional study to evaluate treatment patterns, clinical characteristics and outcomes conducted in Argentina, Brazil, and Colombia. The study included patients ≥ 18 years old at diagnosis with confirmed R/R ALL between January 1, 2015, to December 31, 2019 that received at least one line of treatment for R/R ALL. Data collected from medical records was considered for the analysis, which was descriptive in nature, as no hypothesis has been tested. Results: A total of 71 patients diagnosed with R/R ALL were included in the study (23 from Argentina, 27 from Brazil, and 21 from Colombia). Table 1 shows the demographics and clinical characteristics. The median age at diagnosis was 31 years (Q1-Q3: 24.0-46.0), 56.3% were male, and 50% were White/Caucasian patients. At diagnosis, the most common comorbidities were diabetes, hypertension, gastrointestinal disease, and thyroid disease, with 11% each. At diagnosis, most patients presented with poor or intermediate cytogenetic risk prognosis, in 55.1% and 31.6%, respectively. Most of the patients presented with good performance status, 50.9% ECOG 0 and 36.8% ECOG 1. As for treatment patterns, patients received up to six treatment lines (LOT-1 to LOT-6), with a median of 2.0 LOTs (Q1-Q3: 1.5-3.0) within the R/R setting. Fifty-three (74.6%) out of the 71 patients enrolled in the study received two lines of R/R treatment (up to LOT-2), and 27 patients (38%) received 3 lines (up to LOT-3). The median treatment duration of LOTs were 3.4 months (Q1-Q3: 1.14 - 5.7), 1.4 months (Q1-Q3: 0.62 - 2.6) and 0.9 months (Q1-Q3: 0.4 - 2.1) for LOT-1, -2 and -3, respectively. The most frequently used treatment regimens at LOT-1 were the Hyper-CVAD (22.9%), BFM (20.0%) and GRAAL (15.7%). The most reported reasons for patients discontinuing their regimen in LOT-1 were progression of disease (37.5%), followed by adverse events (25%). For LOT-2 discontinuation, adverse events and/or toxicity (33.3%) were most frequently reported, followed by progression of the disease (25%). Of the total number of R/R ALL patients, 26 (36.6%) underwent stem cell transplantation (SCT), with a median time from diagnosis to transplantation of 9.6 months. All those patients (n=26) received allogeneic hematological SCT (100%), and haploidentical donors were most common (42.3%), followed by identical (matched) related (34.6%), mismatched unrelated donor (15.4%), and identical (matched) unrelated donors (7.7%). For R/R ALL patients, the median overall survival (mOS) was 18.96 months, with a probability of survival of 66.6% at 1 year, 32.3% at 3 years, and 16.2% at 5 years. Philadelphia Chromosome (Ph) molecular results were reported in 53 patients: 38 (71.7%) were Ph- and 15 (28.3%) were Ph+. The mOS in Ph+ patients was 31.5 months, numerically longer than the 17.7 months seen in Ph- patients (p = 0.500); however, the Kaplan-Meiers crossed over and separation was not clearly evident within the follow-up period (Figure 1). Conclusions: This study enabled a better understanding of R/R ALL in LA in the real-world. Data from this study demonstrate the high heterogenicity within first salvage (LOT-1) treatment patterns in R/R ALL, likely due to no established single standard of care in the region and highlights that only a fraction of the patients undergo SCT, which should be the treatment goal following induction therapy. In addition, our study reinforces already published data that overall survival on R/R ALL adult patients remain poor. Consistent guidelines and access to new treatments and are needed to remove inequalities in the management of ALL in LA.

Comparing Older Matched Related to Younger Matched Unrelated Donors in Acute Myeloid Leukemia in Remission Using Post-Transplant Cyclophosphamide

Backgroud. Over the past 25 years, the landscape of allogeneic stem cell transplantation (allo-SCT) changed from being rarely performed in patients 50 years or older to accounting for a little less than half of the transplantations reported in USA and Europe. Older patients will on average have older matched related siblings (MRD) being considered as donors with issues such as comorbidities, risk of clonal haematopoiesis of indeterminate potential, and impaired immune and regenerative potential of stem cells. Although younger HLA-matched unrelated donors (MUD) are an important alternative in this context, it remains unclear whether the use of MUD is associated with better outcomes. This is especially true in the context of post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis. Methods. The aim of this study was to compare the graft-relapse-free survival (GRFS) for patients diagnosed with acute myeloid leukemia (AML) in first complete remission (CR1), aged 50y or more, and having received a first allo-SCT from a 10/10 MUD younger than 40y or a MRD older than 50y using PTCy for in-vivo T-cell depletion. All transplants were performed between 2015-2021 at the EBMT centres. Results. A total of 410 consecutive patients were included, 172pts receiving a MRD, 238pts transplanted from a MUD. All patients with detailed conditioning regimen dosages were classified according to the transplant conditioning intensity (TCI) score in low (1-2), intermediate (2.5-3.5), high (4-6). TCI-score was available for 345 patients and was as follows: low in 53pts (36.8%), intermediate in 79pts (54.9%) and high in 12pts (8.3%) for MRD, low in 91pts (45.3%), intermediate in 93pts (46.3%) and high in 17pts (8.5%) for MUD (p=0.26). Only patients with available TCI-score were analysed. In univariate analysis the 2-year GRFS was 58% (49.8-65.3%) for TCI intermediate-high and 43.1% [34.3-51.5] for TCI low (p=0.005). In TCI-score intermediate-high non-relapse mortality (NRM) wasn't higher compared to TCI-score low (12.7% [12.2-24] vs 13.7% [8.4-20.3], p=0.53) but relapse incidence (RI) was lower (17.7% [12.2-24] vs 33.2% [25.1-41.5], p=0.003). As a strong interaction between TCI-score and type of donor was found, we compared transplant outcomes between MRD and MUD separately for TCI-score low and TCI-score intermediate-high. In TCI-score low, 2-year GRFS was 44.4% [33.5-54.8] for MUD and 40.9% [26.4-54.9] for MRD (p=0.83) (Figure 1A). In multivariable analysis (MVA) type of donor was not a risk factors for neither GRFS (HR 0.98, CI: 0.57-1.69; p=0.95) nor for any other transplant outcome. In TCI-score intermediate-high, 2-year GRFS was 67.2% [55.8-76.2] for MUD and 46.1% [34.4-57.1] for MRD (p=0.001) (Figure 1B). In MVA MUD were associated to better GRFS (HR 0.41, CI: 0.24-0.7; p=0.001), lower NRM (HR 0.19, CI: 0.07-0.55; p=0.002) and lower RI (HR 0.32, CI: 0.14-0.73; p=0.007) without advantages in terms of neither aGvHD nor cGvHD. Conclusions. In patients with AML in CR1, aged 50y or more and receiving a conditioning regimen with TCI-score ≥ 2.5 in the PTCy setting, a MUD younger than 40y is associated to longer GRFS, lower NRM and lower RI compared to a MRD older than 50y. For patients receiving regimens with TCI-score low transplant outcomes are independent on the type of HLA-matched donor.

Clinical Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation Using Busulfan/Cyclophosphamide and Melphalan or Thiotepa As Conditioning Regimen in 37 Patients with Acute Megakaryoblastic Leukemia

Background Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of childhood AML and about 1% of adult AML. Patients with non-Down's syndrome AMKL (non-DS-AMKL) are often associated with a poor prognosis with a 3-year overall survival (OS) rate of less than 40%. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative therapy for AMKL. However, the long-term survival post-transplant needs to be improved. Here we conducted a single-center study to evaluate the long-term efficacy and safety of allo-HSCT in 37 non-DS-AMKL patients using an innovative conditioning regimen of Busulfan/Cyclophosphamide (Bu/Cy) and Melphalan (MEL) or Thiotepa (TT). Methods From August 2015 to July 2023, a total of 37 non-DS-AMKL patients (M/F 21:16) were treated consecutively in our hospital (Hebei Yanda Lu Daopei Hospital). The median age was 2 years (range 1-9 years). Chromosomal abnormalities were present in 24 cases, with fusion genes as follows CBFA2T3/GLIS2 (5 cases) 13.5%, NUP98-KDM5A (2 cases) 5.4%, MLL-AF10 (3 cases) 8.1%, MLL-AF9 (1 case) 2.7%. Gene mutations: WT1 (10 cases) 27%, JAK2 (7 cases) 18.9%, EVI1 (6 cases) 16.2%, TET2 (4 cases) 10.8%, ASXL1 (4 cases) 10.8%, PTPN11 (4 cases) 10.8%, NRAS (3 cases) 8.1%, GATA1 (2 cases) 5.4%. Before transplantation, in bone marrow (BM), 29 patients were in complete remission (CR), 3 were in partial remission (PR) and the rest 5 were in non-remission (NR). Thirty-three patients received the haploidentical transplantation (donors from parents n=31, siblings n=2) including 1 with the 3 rd transplant, and 4 received matched-unrelated donor transplantation. The stem cell sources were from BM and peripheral blood stem cells (PBSCs) among the 33 related donors, and PBSCs for the 4 unrelated donors. Patients received a median cell number of total mononuclear cells 20.15×10 8/kg (10.7-32.85), CD34+ cells 12×10 6/kg(4.05-27.14) and CD3+ cells 4.66×10 8/kg(1.81-19.38). The conditioning regimens administered were modified Bu/Cy (fludarabine 30 mg/m 2/d×5d; cytarabine 2g/m 2/d×5d; Bu 3.2 mg/kg/d×4d, Cy 1.8g/m 2/d×2d; etoposide 100mg/m 2/d×2d; antithymocyte globulin 1.5mg/kg/d×5d) in 2 patients, Bu/Cy+MEL (MEL 55mg/m 2/d×2d) in 31 patients, and Bu/Cy+TT (TT 2.5mg/kg/d×2d) in the rest 4 patients. Cyclosporine A (CSA)+ mycophenolate mofetil (MMF)+ short methotrexate (sMTX) were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up time was 24 months (2-84 months), and all 37 cases survived the graft, with a median leukocyte engraftment of +13 days (9-21 days), and a median platelet engraftment of +9 days (4-38 days). BM was assessed one month after transplantation, with all grafts fully donor-type. The 5-year OS was 54.1% (Figure 1). There was a significantly higher OS in the CR group (5-year OS 69%) than the PR or NR groups (P<0.001) (Figure 2). Among the CR patients, no significant difference was observed in the 3 different condition regimen groups with modified BU/CY group OS of 50%, BU/CY+MEL group OS of 69.6% and BU/CY+TT group OS of 75% (P=0.869) (Figure 3). After transplantation, 17 patients died including 11 from relapse, 4 from GVHD, 1 from gastrointestinal bleeding and 1from cerebral hemorrhage. The cumulative recurrence rate (CIR) was 29.7%, among which the CIR of the CR group was 17.2%, the PR group of 66.7% and the NR group of 80% (P<0.001). Post-transplant, the incidence of acute GVHD (aGVHD) was 35.13% (Grade II-IV), and severe aGVHD (Grade III-IV) incidence was 18.91%. And 51.35% of patients developed chronic GVHD. Other complication incidences were cystitis at 16.21%, cytomegalovirus at 5.94%, Epstein-Barr viremia at 13.5% and infections at 21.62%. Conclusions Our study indicates that the use of modified Bu/Cy +MEL or +TT conditioning regimens in allo-HSCT procedures presents a feasible and effective approach, demonstrating an improvement in overall survival for non-Down Syndrome AMKL patients. Crucially, it was observed that achieving CR prior to transplantation significantly contributes to better outcomes. Therefore, it is strongly recommended that allo-HSCT is performed in CR status. However, to corroborate these findings, it is essential to conduct long-term, large-scale clinical research across multiple centers.

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management.

Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options.

Comparison of Stem Cell Transplantation Using Unrelated, Haploidentical, and Sibling Donors for Patients with Acquired Severe Aplastic Anemia: A Single-Center Retrospective Cohort Study

The preferred donor (haploidentical vs. matched unrelated donor) choice in patients with acquired severe aplastic anemia (SAA) who lack a human leukocyte antigen (HLA)-matched sibling donors (MSDs) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n=58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) (87.5% ± 11.7% vs. 98.0% ± 6.5% vs. 83.3% ± 7.6%, respectively, p= 0.926) and 5-year failure-free survival (FFS) (60.0% ± 18.2% vs. 87.0% ± 7.0% vs. 78.3% ± 8.6%, respectively, p= 0.222) were comparable among the unrelated donors (URD; n=8), haploidentical donors (HID; n=25), and MSD cohorts (n=25). Multivariate analysis revealed that primary engraftment failure independently predicted OS, and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, although donor type and age did not predict the outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Summarily, our findings showed that an alternative donor SCT is indicated for eligible SAA patients without MSDs even if these patients are aged ⩾ 40 years.

Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia.

The data on post-transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo-HSCT are limited to case series. The present study aimed to assess the results of PTCy-based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo-HSCT. A retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n=28) for the study group, and calcineurin inhibitor (CNI)±antimetabolite (n=30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n=42, 66.7%) or PTCy+CNI+sirolimus (n=12, 19%). All patients (n=69) in the control group received ATG+CNI+antimetabolite. After MUD allo-HSCT, the incidences of acute GVHD grade III-IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6%vs. 35.0% and 12.7%vs. 47.1%, respectively, p<.0001). Five-year GVHD-free, relapse-free survival (GRFS) after MUD allo-HSCT was higher in the PTCy group compared to control (35.1%vs. 7.3%, p<.0001). At the same time, there was no significant difference between both groups after MSD allo-HSCT. In pediatric acute leukemia, PTCy-based GVHD prophylaxis for MUD allo-HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG-based approach, PTCy provides better control of GVHD in children. In pediatric allo-HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for AML Patients with KMT2A Rearrangement: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Acute myeloid leukemia (AML) patients with KMT2A rearrangement (KMT2Ar, except for t(9;11)(p21.3;q23.3)/MLLT3::KMT2A) are classified as adverse risk in the 2022 European LeukemiaNet (ELN) classification. There is uncertainty on their outcome following allogeneic cell transplantation (allo-HCT). We compared, in an European Society for Blood and Marrow Transplantation (EBMT) global multi-center registry-based analysis, outcomes following an allogeneic stem cell transplantation (allo-HCT) with either a matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAPLO). Methods Data from 586 AML patients with KMT2Ar receiving a first allo-HCT in 183 EBMT centers from 2010-2022 were analyzed. All patients achieved first complete remission (CR1) before transplantation. Patients with t(9;11), without details on translocation, receiving mismatched UD (&amp;lt;10/10), umbilical cord blood, or grafts with ex-vivo manipulation were excluded. Univariant analysis and Cox regression models were used. Results KMT2A rearranged AML patients received allo-HCT from 201 MSD, 256 10/10 MUD, and 129 HAPLOs. For KMT2Ar type, t(6;11), t(11;19), t(10;11) or other translocations account for 27.8%, 37.5%, 23.9% and 10.8%, respectively. Peripheral blood was the major graft source (83.2%), and myeloablative conditioning accounted for the majority (60.2%) of all allo-HCTs. Engraftment rates were comparable in the three cohorts (MSD 99.5%, MUD 98.4% and HAPLO 96.9% p=0.17). AML relapse was the major cause of death in each donor cohort. On univariate analysis, HAPLO was associated with a lower 2-year relapse incidence (RI) (MSD 41.1%, MUD 37.2%, HAPLO 20%) but a higher 2-year non-relapse mortality (NRM) (MSD 6.1%, MUD 19.3%, HAPLO 21.3%) compared with MSD and MUD. The 180-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was lower in MSD (18.8%) than in MUD (31.3%) or HAPLO groups (26.5%), respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were comparable among the three cohorts. Lower RI was observed in patients with t(11;19) compared with t(6;11) or t(10;11). Complex karyotype (CK) (at least 3 abnormalities) or monosomal karyotype (MK) were both associated with higher RI compared with those without. In addition, in-vivo T cell depletion was related to lower intensive chronic GVHD (cGVHD) incidence. On multivariate analysis, HAPLO HCT was associated with lower RI (hazard ratio [HR=0.46], 95% CI 0.28-0.77; p&amp;lt;0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p&amp;lt;0.01) compared with MSD, while HAPLO had no significant impact on LFS, OS and GRFS. MUD HCT was associated with higher incidence of grade II-IV aGVHD (HR=1.82, 95% CI 1.19-2,78; p&amp;lt;0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p&amp;lt;0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p&amp;lt;0.05) compared with MSD (reference). Concerning translocation type, t(11;19) was associated with a lower RI (HR=0.64, 95% CI 0.43-0.94; p=0.022), a better LFS (HR=0.66, 95% CI 0.48-0.91; p=0.012), OS (HR=0.63, 95% CI 0.45-0.89; p=0.008) and GRFS (HR=0.75, 95% CI 0.57-1; p=0.049) compared with t(6;11)(reference). Translocations other than t(6;11), t(11;19) or t(10;11) were related to a lower RI (HR=0.45, 95% CI 0.24-0.87) and better OS (HR=0.57, 95% CI 0.34-0.95) compared to t(6;11). MK was associated with higher RI (HR=1.59, 95% CI 1.04-2.45; p&amp;lt;0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p&amp;lt;0.05). Conclusions For AML patients with KMT2Ar, HAPLO HCT was associated with a lower RI but higher NRM, leading to similar LFS, OS and GRFS compared with MUD and MSD HCTs. In the setting of allo-HCT, t(11;19) seems to be associated with favorable outcomes compared with other KMT2Ar.

ATG or Post-Transplant Cyclophosphamide to Prevent Gvhd in Matched Unrelated Stem Cell Transplantation? - a Registry Analysis By the EBMT Transplant Complications Working Party

T There is a considerable risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when matched unrelated donors (MUD) are used. Prophylaxis with either rabbit anti-thymocyte globulin (rATG, also termed anti-T-lymphocyte globulin) or post-transplantation Cyclophosphamide (PTCy) is in standard clinical use. The unresolved question is whether to prefer PTCy or rATG in this setting. So far, two randomized trials, several retrospective studies and a meta-analysis comparing PTCy to rATG in MUD alloSCT gave contradictory results. Current data from large registry cohorts has not been published. To improve the evidence base, we analyzed outcomes of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen MUD between Jan 2018 and June 2021 in the EBMT database. We performed multivariate analyses using Cox cause-specific hazard models, adjusting for known risk factors, and variables that showed significant difference between the two comparison groups. Overall 8764 patients were included, treatment- and patient characteristics are shown in Table 1. Patients receiving PTCy (n=1039) were younger, had undergone alloSCT more recently, and had a lower disease risk compared to patients receiving rATG (n=7725). Median follow up was 2.1 years in both groups. Outcomes graphs are shown in figure 1. All outcomes are given starting from alloSCT (with 95% CI): NRM (fig 1A) was higher in the rATG arm (2-years NRM: PTCy 12.4% [10.2 - 14.7] vs. rATG 16.1% [15.3 - 17]; HR 0.72, p=0.016), same for Relapse incidence, (2-years RI: PTCy 22.8% [19.9 - 25.8] vs. rATG 26.6% [25.5 - 27.7]; HR 0.87, p=0.046), Overall survival (fig 1B) was better in the PTCy arm (2-years OS: PTCy 73.1% [70 - 76] vs. rATG 65.9% [64.7 - 67.1]; HR 0.82, p=0.001), same for Progression free survival (fig 1C) (2-years PFS: PTCy 64.9% [61.4 - 68.1] vs. rATG 57.2% [56 - 58.5]; HR 0.83, p&amp;lt;0.001), Chronic GVHD was lower in the PTCy arm (2-years cGVHD: PTCy 28.4% [25.2 - 31.7] vs. rATG 31.4% [30.3 - 32.6]; HR 0.77, p=0.012), whereas acute GVHD grades II-IV was not significantly different between the two arms (100-day aGVHD: PTCy 24.1% [21.3 - 27] vs. rATG 26.5% [25.5 - 27.6]; HR 0.85, p=0.11) In conclusion, we found a lower NRM, lower incidence of chronic GVHD as well as higher survival outcomes in adult recipients of peripheral blood alloSCTs from MUD receiving PTCy compared to rATG. The current analysis improves the evidence basis for decision making on GVHD prophylaxis in MUD alloSCT.

Outcomes after Bone Marrow Versus Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Background: Matched unrelated donors (MUD) have become an acceptable alternative donor for patients requiring potentially curative hematopoietic stem cell transplantation (HSCT) and lacking a matched sibling donor. Patients may undergo a bone marrow (BM) or peripheral blood stem cell (PBSC) graft, with previous studies showing similar survival outcomes. However, BM grafts have shown a lower incidence of chronic graft-versus-host disease (GVHD) but a higher relapse rate and slower engraftment. We aimed to compare the outcomes of BM versus PBSC in patients undergoing MUD HSCT. Methods: For this retrospective single-center study, we included all (n=276) adult MUD HSCT recipients at the University of Kansas Medical Center who had at least one year of follow-up (August 2016 to July 2021). We conducted a bivariate analysis using chi-squared and ANOVA tests. The Kaplan-Meier and regression analyses were also performed. Data analyses were conducted using SPSS version 28. Statistical significance was considered at p&amp;lt;0.05. Results: Our study included 276 MUD patients including 110 PBSC (40%) and 166 BM (60%) grafts. The median age was 55 (range 21-77) years, and 158 patients (57%) were males. Eighteen patients (6%) were ethnic minorities, and 89 (32%) patients had a Karnofsky performance status of ≥90%. 118 (43%) patients had a hematopoietic cell transplantation-specific comorbidity index of 3 or higher. Hematologic diseases included acute myeloid leukemia (n=119, 43%), myeloid disorders (n=77, 28%), acute lymphoblastic leukemia (ALL) (n=35, 13%), Lymphoma (n=15, 5%), and others (n=30, 11%). Sixty-two percent of patients were in complete remission at the time of transplantation, and patients not in remission included myelodysplastic syndrome, myelofibrosis, and lymphoma patients. Reduced-intensity conditioning (RIC, n=162, 58%) and myeloablative conditioning (MAC) (n=114, 41%) were used. The median follow-up was 55 (21-73) months. Overall survival (OS) was not reached in either BM or PBSC MUD HSCT group, while a median disease-free survival of 45 and 49 months was noted in PBSC and BM groups respectively (p=0.915). We observed similar rates of relapse (25% vs 27%, p=0.413), one-year overall survival (75% vs 72%, p=0.679), one-year disease-free survival (63% vs 62%, p=1.00), and one-year non-relapsed morality (NRM, 23% vs 21%, p=0.779) after PBSC or BM graft. Bone marrow graft recipients had delayed engraftment of neutrophils (20 days vs 16 days, p&amp;lt;0.001) and platelets (&amp;gt;20 K/uL: 24 days vs 16 days, p&amp;lt;0.001; &amp;gt;50 K/uL: 28 days vs 18 days, p=0.006) compared to PBSC recipients. Bone marrow graft recipients had similar rates of grade II-IV acute GVHD (50% vs 52%, p=0.714) and grade III-IV GVHD (12% vs 11%, p=0.847), but lower rates of 1-year chronic GVHD (39 % vs 55%, p=0.014) compared to PBSC recipients. In the subgroup analysis stratified by conditioning intensity, faster engraftment of neutrophils (median 16 vs 21 days, p&amp;lt;0.001) and platelets (&amp;gt;20 K/uL: 18 days vs 27 days, p&amp;lt;0.001; &amp;gt;50 K/uL: 18 days vs 33 days, p&amp;lt;0.001) was observed with PBSC as compared to BM graft in myeloablative transplant recipients, while there was no statistically significant association with the rates of acute or chronic GVHD, NRM, Relapse, DFS, and OS after a PBSC or BM graft. Among the RIC transplant recipients, faster neutrophil engraftment (mean 17 vs 20 days, p&amp;lt;0.001) and higher 1-year extensive chronic GVHD (52% vs 32%, p=0.015) were observed with PBSC compared to BM graft whereas no statistically significant difference was noted in platelet engraftment, acute GVHD, NRM, Relapse, DFS, and OS after a BM or PBSC graft. Conclusions: Allogeneic matched unrelated donor hematopoietic stem cell transplant recipients had similar rates of overall and disease-free survival, relapse, non-relapse mortality, and acute GVHD after a bone marrow or peripheral blood stem cell graft; however, delayed neutrophil and platelet engraftment with a lower incidence of chronic GVHD was noted after a bone marrow graft compared to peripheral blood stem cell graft.

Role of Polyomavirus BK and Adenovirus in the Development of Urinary Tract Complications in Pediatric Hematopoietic Stem Cell Transplantation

One of the major challenges in pediatric hematopoietic stem cell transplantation (HSCT) is the susceptibility to viral infections and reactivations that can lead to potentially life-threatening complications and increase the transplant-related mortality (TRM). Polyomavirus BK (BKPyV) and Adenovirus (AdV) represent the predominant causes of urinary tract complications, in particular hemorrhagic cystitis (HC), in HSCT recipients. Treatment options for BKPyV and AdV infections are limited and there is no accepted standard of care for the prevention and treatment of these HSCT complications. The aim of our retrospective study was to analyze the incidence of BKPyV and AdV infection in urinary and plasma samples of pediatric patients undergoing HSCT for both malignant and non-malignant disease at a single pediatric Hematology-Oncology unit. Endpoints were the cumulative incidence of infection, measured on blood and urine samples, in the first 100 days after HSCT, prevalence of asymptomatic and symptomatic infection, and correlation between BKPyV and AdV DNAemia and DNAuria and the development of HC. A total of 79 patients were analyzed. Thirty-seven (47%) patients were positive for BKPyV on urine samples and 20 (30%) on blood samples within the first 30 days after transplantation. As for AdV, 11 (9%) patients were positive on urine samples and 18 (15%) on blood samples. In our pediatric cohort, BKPyV DNAuria was a frequent event after HSCT, while BKPyV DNAemia was observed less frequently, and was accompanied by higher viruria values (p-value &amp;lt;0,001, with a median viral load in the urine of 3.8 x 10 9 copies/mL). Conversely, AdV positivity in urine is rare, while AdV DNAemia was more frequent, due to the modality of BKPyV and AdV distribution (urothelium is the main reservoir for BKPyV, while intestinal lymphocytes represents the main reservoir for AdV). Of the 37 patients with BKPyV DNA on urine samples, 11 (30%) developed a symptomatic infection with grade II (5 patients, 40%) and grade III (6 patients, 60%) HC. We did not observe any correlation between BKPyV DNA urinary levels and the development of HC, as higher viral loads have not been shown to be good predictors of occurrence or severity of HC. Cumulative incidence (CI) of BKPyV infection was higher in haploidentical HSCT (51%) and matched unrelated donors (MUD) (48%) than in HSCT from matched familiar donors (31%). Similarly, CI of AdV reactivation was higher in haploidentical HSCT (16%) than MUD (6%) and matched familiar donors (9%). Choice of donor, the type of immunosuppression used and the intensity of conditioning regimen represented predictors of both blood and urine DNA positivity for both viruses. In our cohort, positivity for BKPyV on blood and/or urine did not increase the risk of transplant-related mortality and did not affect the overall survival after HSCT. On the basis of our data, we now perform screening of BKPyV viruria only in symptomatic patients or in transplant recipients with specific risk factors (type of donor, severity of immunosuppression). Similarly, search for BKPyV DNAemia is reserved to subjects with a high viral load on urine. Likewise, search for AdV on urine samples is performed on symptomatic patients with high-load AdV DNAemia.

Comparable Outcome after Busulfan- or Treosulfan-Based Conditioning Regimen in Children Above 4 Years of Age with ALL Undergoing Allogeneic HSCT. Results from the Prospective International Forum-Trial

Purpose: Total body irradiation (TBI) has proved to be the “gold standard” as part of the conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL). Its superiority over chemo-based conditioning was recently demonstrated in the prospective, international, randomized phase III study, which enrolled 417 patients beyond the age of 4 years transplanted for ALL in complete morphological remission (CR) from either matched sibling (MSD) or matched unrelated donor (MD) (Peters et al, JCO 2021, FORUM study; EudraCT: 2012-003032-22;ClinicalTrials.gov: NCT01949129). The use of either of the two protocol-prespecified chemo-conditioning regimens resulted in significantly worse EFS. Given the unavailability of TBI in some regions/centres and contraindications to TBI in individual patients, we here compare the outcomes of patients who received busulfan (BU) - based regimen vs of those who were given a treosulfan (TREO) - based conditioning in FORUM centres in both randomizing and non-randomizing countries in the years 2013-2018. Patients and methods: Patients ≤ 18 years at diagnosis (median age at HSCT 9.9 years, range 4-19.5), in CR pre-HSCT and with an MSD or MUD were assigned to myeloablative conditioning with fludarabine (FLU), thiotepa (THIO) and either BU or TREO according to country preference. Children transplanted from MSDs received cyclosporine A only as graft-versus-host disease (GvHD) prophylaxis, whereas recipients of MUD HSCT also received short-term methotrexate and anti-thymocyte globulin (ATG). Further details of the transplant procedure have been previously described (Peters C, et al. J Clin Oncol 2021). Results:In addition to the 193 patients from the randomizing countries, the FORUM trial included 115 additional children enrolled in countries where randomization could not occur (for legal or technical reasons). Overall, 180 vs. 128 patients received BU/THIO/FLU vs TREO/THIO/FLU, respectively. There were no differences about the patients' gender, age, and remission status and slight differences regarding donor, stem cell source and MRD status pre-transplant between the two cohorts of patients (see Table 1 for details). Patient's outcomes were updated as of February 20 th, 2023, and median follow-up was 4.2 years (range 0.3 - 9.1). There were neither differences between the 3-year overall survival (OS) (0.71±0.03 for BU/THIO/FLU vs 0.72±0.04 for TREO/THIO/FLU) nor event-free survival (EFS) (0.61±0.04 for BU/THIO/FLU vs 0.55±0.04 for TREO/THIO/FLU, p=NS). Three-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 0.31±0.03 and 0.08±0.02 following BU/THIO/FLU and 0.36±0.04 and 0.09±0.03 following TREO/THIO/FLU, respectively (p=NS). Only one case of secondary malignancy was observed in the TREO cohort and one case of fatal liver veno-occlusive disease (VOD) in the BU group. No statistical differences were observed regarding the cumulative incidence of both aGvHD and cGvHD between the two groups; 3-year GFRS was almost identical (0.42± 0.04 in the BU/THIO/FLU group and 0.43±0.04 in the TREO/THIO/FLU cohort). There were no differences in OS, EFS, CIR, NRM and GFRS in either CR1 or CR2 patients between the two conditioning regimens. Furthermore, there were no differences in outcomes between countries. Patients given BU/THIO/FLU had a faster leucocyte, neutrophil and platelet recovery as compared to those prepared with TREO/THIO/FLU. Conclusion: Comparable long-term outcomes were observed after BU/THIO/FLU or TREO/THIO/FLU in children with ALL undergoing allogeneic HSCT included in the FORUM trial. Therefore, either of the 2 regimens may be effectively and safely used worldwide in patients &amp;gt; 4 years having a contraindication to or treated in centres/countries unable to deliver TBI.

Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia - Retrospective Dual-Center Study

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are treated with various chemotherapy regimens. Some patients undergo allogeneic hematopoietic stem cell transplantation (HCT) due to high-risk genetic characteristics, chemo-resistant disease (failure to achieve timely measurable residual disease (MRD) negative remissions, or relapse or refractory disease. There is paucity of data on outcomes of AYA ALL patients receiving HCT. Methods: We performed a dual-center analysis of data from MD Anderson Cancer Center (MDACC) and Dana-Farber Cancer Institute (DFCI) to evaluate outcomes of AYA patients who received HCT for Philadelphia-negative (Ph neg) ALL and examined variables that might have an impact on these outcomes. We included all patients who received their first HCT between the ages of 15-40 years between the years 2010-2022. MRD status was evaluated using flow cytometry with a sensitivity of 0.01%. Acute and chronic graft versus host disease (GvHD) were classified according to consensus criteria. The primary endpoint was overall survival (OS), and secondary endpoints included progression rate and non-relapse mortality (NRM). Cox proportional hazards regression analysis was used to evaluate predictors of OS, and Fine and Gray regression for predictors of relapse and NRM. Competing risks were accounted for in analyses pertaining to progression and NRM. Results: A total of 376 Ph neg ALL AYA patients were included in the analysis, 247 from MDACC and 129 from DFCI. The median age at transplant was 25 (range 15-40) years, 39 patients (10%) were aged ≤18 years at time of HCT and 251 (67%) were males.The majority had B-ALL (n=282, 75%), 42 (11%) had complex karyotype and 28 patients (7%) had translocation (4:11). Most patients received either pediatric-inspired (48%) or hyper- cyclophosphamide, vincristine sulfate, doxorubicin, dexamethasone (CVAD) based (42%) frontline induction regimens, and the median time from diagnosis to HCT was 11 (range 2-283) months. At transplant, most patients were in CR1 or CR2 (44% each); 63% of patients achieved MRD negativity prior to HCT. Most patients received an HCT from a matched unrelated donor (MUD) (33%) or a matched sibling donor (MSD) (32%), and most patients received myeloablative conditioning (MAC) (79%) ( Table 1). The cumulative incidence of grade 2-4 acute GvHD and grade 3-4 acute GvHD at 6 months was 37% (95% CI 33%-42%) and 13% (95% CI 10%-17%), respectively. The cumulative incidence of chronic GvHD at 3 years was 28% (95% CI 23%-33%), with most patients experiencing either mild (39%) or moderate (36%) chronic GvHD, and 25% had severe chronic GvHD. For patients transplanted in CR1, CR2 and CR3/PD the estimated 3-year OS was 69% (95% CI 61%-77%), 53% (95% CI 44%-61%) and 29% (95% CI 16%-43%), respectively; the 3-year NRM rate was 9% (95% CI 5%-15%), 18% (95% CI 13%-25%) and 27% (95% CI 16%-43%), respectively; and the 3-year progression rate was 27% (95% CI 20%-35%), 36% (95% CI 29%-45%) and 48% (95% CI 36%-65%), respectively. In multivariate analysis, HCT in CR3/PD was associated with inferior OS (HR 4.3, p&amp;lt;0.001) and higher NRM (HR 2.3, p=0.04, Table 2), however there was no difference in survival between HCT at CR1 vs. CR2 (p=0.3); &amp;gt;2 lines of therapy prior to HCT was associated with inferior OS (HR 1.8, p=0.004) and higher rate of progression (HR 1.9, p=0.008); HCT-CI&amp;gt;3 was associated with inferior OS (HR 1.6, p=0.01) and higher NRM (2.3, p=0.004); positive MRD status prior to HCT was associated with inferior OS (HR 1.9, p=0.004) and higher rate of progression (HR 3.3, p&amp;lt;0.001); use of bone marrow graft was associated with lower rate of progression (HR 0.6, p=0.02) and use of a matched donor (MSD/MUD) was associated with lower NRM (HR 0.5, p=0.01). Conclusions: In this analysis of a large dual-center cohort of AYA Ph -ALL patients that received HCT, we found that patients transplanted in CR1 had the most favorable outcomes with 69% 3-year OS. Patients not in CR1/CR2, patients who received HCT after &amp;gt;2 lines of therapy and those with positive MRD pre-HCT had inferior OS on MVA. Although patients who received HCT at CR3/PD had inferior OS, an estimated one-third of patients were still alive at 3 years after HCT.

Graft Versus Host Disease Prophylaxis with Tacrolimus, Sirolimus and MMF in Patients Undergoing Reduced Intensity Conditioning Allogeneic Transplantation

I ntroduction GvHD remains the leading cause of toxic morbidity and mortality (NRM) after allo-HSCT. Different prophylaxis schemes have been developed in the context of reduced intensity conditioning (RIC). In 2019, the multicenter phase 3 trial NCT01231412 compared GvHD prophylaxis based on the calcineurin inhibitor (CNI) CSA plus MMF with (experimental arm) or without (control arm) sirolimus. The triple combination was associated with a lower risk of aGvHD and longer survival and, in the authors' opinion, could constitute a new standard (Sandmaier, Lancet Oncol 2019). We present the largest real-world experience to date with the triple prophylaxis scheme in the context of allo-HSCT with RIC from matched-related (MRD), matched-unrelated (MUD) and mismatched URD (mmURD). Material and Methods Prospective study of 159 consecutive patients receiving an allo-HSCT after RIC between 09/2019 and 12/2022 at two centers using the tacro/siro/MMF as GvHD prophylaxis. The primary endpoint was the cumulative incidence of aGvHD grades 2-4. As secondary variables: cGvHD at 1 and 3 years, NRM at +100, +1 year and overall NRM, OS at 1 and 3 years, PFS at 1 and 3 years and GRFS at 1 and 3 years. Results Baseline characteristics are shown in Table 1. Note the high percentage of patients with high/very high rDRI or HCT-CI of 3+. In 38.4% an URD was used as source of progenitor cells and in 20.8% it was a MMURD. The median follow-up was 20 months (3-40). There were 4 (2.5%) graft failures (2 of them secondary). Median neutrophil and platelet engraftment was 16 days (3-175) and 12 days (7-210). The risk of relapse was 31% and 35% at 1 and 3 years. NRM at day +100, + 1 year and overall NRM was 4.4%, 8.17% and 9.4%. The causes of NRM were GvHD +/- infection in 73%, with other causes being TMA (n=1) and SOS (n=1). The cumulative incidence (CI) of grades 2-4 aGvHD 2-4 at day +100 and +180 was 29.7% and 32.3%, including 40% of upper gastrointestinal tract involvement which resolved with topical treatment. The CI of grades 3-4 aGvHD at day +100 and +180 was 12.8% and 16% (3.14% grade 4). The CI of cGvHD at 1 and 3 years was 21.5% and 51.2% and for moderate/severe it was 13.9% and 36.6%. OS at 1 and 3 years was 70.3% and 61%. Median PFS was 35 months, with 1- and 3-year PFS of 60% and 49%. The GRFS at 1 and 3 years was 44% and 32%. The risk of grades 2-4 aGvHD was significantly higher among patients receiving allo-HSCT from MMURD (at d+100 and +180, 35.4% and 39.9%) vs matched donors (at d+100 and +180, 55.5% and 61%, p=0.04). The same variable also influenced on OS (at 1 and 3 years 73.3% vs 64.6% and 57.6% vs 37.8% for matched vs mismatched donors, respectively; p=0.013) (Figure 1). On the other hand, low and intermediate DRI patients had a significantly better OS as compared to high/very high rDRI patients (at 1 and 3 years 80.8% and 80.8% for low vs 86.7% and 78.3% for intermediate vs 56.9% and 55.1% for high and very high; p=0.013) (Figure 1). Conclusions Triple prophylaxis with Tacro-Siro-MMF shows excelent results in terms of NRM, GvHD and survival in a high-risk and elderly population in the context of allo-HSCT from matched-related (MRD) and matched-unrelated (MUD) donors. The subgroup of patients receiving allo-HSCT from MMURD showed a high incidence of overall and grade 3-4 aGvHD with impact on OS, being a group that will probably benefit from other prophylaxis strategies.