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Acute graft versus host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplant (HCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in a phase 3 trial; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD. We included 59 patients treated with ruxolitinib for SR-aGVHD between 2015 and 2022. Of these 59 patients, 36 patients (61.0%) achieved a complete (CR) or partial response (PR) at 28 days, while 31 patients (52.5%) obtained a CR/PR at day 56. Patients that achieved a CR or PR at day 28 had a higher rate of overall survival (OS; 69.2%), compared with patients that did not (31.6%; p= 0.037). OS at 12 months was 41.5%, with a median OS duration of 5.3 months. Failure free survival (FFS) at 12 months was 29.1%, with a median FFS of 2.6 months. Overall, this real-world experience data support ruxolitinib as the standard of care for SR-aGVHD in a non-controlled trial population.

The ideal immunosuppressive agents to complement post-transplant cyclophosphamide (PTCy) in PBSC-based haploidentical hematopoietic cell transplantation (haplo-HCT) remain debated. This study looks at our experience with ATG-PTCy-Cyclosporine (CsA) prophylaxis in PB haplo-HCT since 2015. Between October 2015 and December 2021, 157 adults underwent haploidentical hematopoietic cell transplantation (haplo-HCT) using a GVHD prophylaxis regimen comprising rabbit-ATG, PTCy, and CsA. Among these patients, 76.4% received a total ATG dose of 4.5 mg/kg, and 23.5% received 2 mg/kg. T-cell replete peripheral blood stem cell (PBSC) grafts were infused on day 0. The study reported a median follow-up of 32 months (range 0.3–61.64) for survivors. The cumulative incidence of grade II–IV and grade III–IV acute GVHD at day +100 was 26.3% and 9.5%, respectively. Moderate/severe chronic GVHD at 1 year was 19.9%. The 2-year overall survival (OS) was 49.4%, with a relapse-free survival (RFS) of 44.6%. In multivariate analysis, older patients, and those with high/very-high disease risk indices (DRI) were at higher risk for worse OS and higher non-relapse mortality (NRM). The study confirms that using PTCy and ATG (4.5 mg/kg), alongside CsA is safe and effective in preventing GVHD when using peripheral blood as the stem cell source in haploidentical hematopoietic cell transplantation (haplo-HCT).

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.

Established first-line therapy for chronic graft-versus-host disease (cGvHD) comprises corticosteroids with/without calcineurin inhibitors, but about half of cGvHD patients are refractory to corticosteroid therapy. The present study retrospectively analyzed treatment outcomes in 426 patients and undertook a propensity-score matching (PSM) analysis between ruxolitinib (RUX) treated group and a historical group of cGvHD patients treated with best available treatment (BAT). PSM process adjusted unbalanced risk factors between the 2 groups, including GvHD severity, HCT-CI score, and treatment line, extracting 88 patients (44 in BAT/RUX groups each) for final analysis. In PSM subgroup, RUX group showed 74.7% 12 months’ FFS rate vs 19.1% for BAT group (p< 0.001), whereas 12 months’ OS rates were 89.2% and 77.7%, respectively. Multivariate analysis for FFS confirmed RUX superiority over BAT together with HCT-CI score 0–2 vs ≥3. For OS, RUX was superior to BAT, while age ≥60 years and severe grade cGvHD adversely impacted OS. In PSM subgroup, at months 0, 3, and 6, 4.5%, 12.2% and 22.2% more patients in RUX group could discontinue prednisone compared to BAT group, respectively. In conclusion, the current study showed that for FFS, RUX was superior to BAT as second-line therapy or beyond in cGvHD patients after therapy failure.

This prospective study designs an HCT Frailty Scale to classify alloHCT candidates into groups of frail, pre-frail, and fit, and to be implemented in the first consultation at no additional cost. The present scale is composed of the following eight variables: Clinical Frailty Scale, Instrumental Activities of Daily Living, Timed Up and Go Test, Grip Strength, Self-Health Rated, Falls, Albumin, and C-Reactive Protein. The Frailty score of a patient is the weighted sum of scores for each item, with weights assigned according to the hazard ratios of a multivariable Cox proportional hazards model estimated and validated with data on OS as the dependent variable, and the scores of the eight variables as explanatory ones, from 298 adults split into training (n= 200) and validation (n= 98) sets. For clinical use, the scale scores were transformed into three categories: scale score ≤1: fit; 15.5 frail. The estimated probabilities of 1-year OS in each group of frailty, were, respectively: 83.7%, 48.5%, and 16.5% (p< 0.001). In the validation cohort, the respective values were 90.3%, 69.5%, and 46.2% (p< 0.001). Pending further external validations, the HCT Frailty Scale is a low cost-highly informative prognostic signal of outcomes at the pre-transplant stage.

Although ruxolitinib is emerging as the treatment of choice for steroid-refractory or -dependent chronic graft versus host disease (cGVHD) based on randomized control trial data, there is relatively little real-world data published on ruxolitinib for this indication. We wanted to evaluate the real-world efficacy and safety of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD. We retrospectively evaluated the efficacy of ruxolitinib in 115 heavily pretreated patients with steroid-refractory or -dependent chronic GVHD across 5 transplantation centers. The majority of the study population had severe cGVHD (60%) and received ruxolitinib at the fourth treatment line or beyond (82%, n = 96). The median duration of follow-up in this study population was 13 months. The overall response rate (ORR) was 48.6%, 54.9%, and 48.5% at 3, 6, and 12 months, respectively. Clinical benefit (an outcome metric combining ORR with steroid reduction) was observed in 58.7%, 64.8%, and 60.6% of patients at 3, 6, and 12 months, respectively. Approximately one third of patients (37.9%) were able to discontinue prednisone at 12 months, and 63.8% were able to taper prednisone to a daily dose <0.1 mg/kg at 12 months. Failure-free survival at 12 months was 64.6% (54.1%-73.2%). Multivariate analysis identified that patients with severe cGVHD were at a higher risk of failure because of a therapy switch, whereas a pretransplantation hematopoietic stem cell transplantation–comorbidity index score ≥ 3 was associated with a high risk of failure because of increasing risk of non-relapse mortality. Overall, this study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.

The HCT Frailty Scale is an easy prognostic tool composed of (a) Clinical Frailty Scale; (b) Instrumental Activities of Daily Living; (c) Timed-up-and-Go test; (d) Grip Strength; (e) Self-Health Rated Questionnaire; (f) Falls tests; (g) Albumin and C-reactive protein levels. This scale was designed to classify allogeneic hematopoietic cell transplant (alloHCT) candidates into fit, pre-frail and frail groups, irrespective of age. This study evaluates the ability of this frailty classification to predict overall survival (OS) and non-relapse mortality (NRM) in adult patients of all ages, in a prospective sample of 298 patients transplanted between 2018 and 2020. At first consultation, 103 (34.6%) patients were fit, 148 (49.7%) pre-frail, and 47 (15.8%) were frail. The 2-year OS and NRM of the three groups were 82.9%, 67.4%, and 48.3% (P< 0.001), and 5.4%, 19.2%, and 37.7% (P< 0.001). For patients younger than 60 years (n= 174), the 2-year OS and NRM of fit, pre-frail, and frail groups were 88.4%, 69.3% and 53.1% (P= 0.002), and 5.8%, 22.8%, and 34.8% (P= 0.005), respectively; and in patients older than 60 (n= 124), OS and NRM were 75.5%, 63.8% and 41.4% (P= 0.006), and 4.9%, 16.4%, and 42.1% (P= 0.001). In conclusion, frailty predicted worse transplant outcomes in both younger and older adults.

Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p= 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

There is an increased need for allogeneic hematopoietic stem-cell transplantation (allo-HCT) globally and this causes more pressure on transplant units. This study aims to identify predictors of prolonged LOS for patients (pts) who underwent allo-HCT at Princess Margret Cancer Centre (PMCC).

The utilization of Eltrombopag (EPAG) in the management of Post Allogenic Hematopoietic Stem Cell Transplant (HSCT) cytopenia has exhibited promising outcomes. Isolated thrombocytopenia and Poor Graft Function (PGF) are factors that adversely influence transplant outcomes and patient well-being. This study aims to assess EPAG efficacy in this context as a primary outcome, and evaluate early EPAG tapering post complete response (CR) for cost-efficiency and response durability.

Central nervous system (CNS) involvement of graft versus host disease (GvHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). CNS GvHD symptoms are heterogeneous and include cerebrovascular manifestations, demyelinating disease and immune-mediated encephalitis. The 2010 consensus conference on GVHD provided a framework to diagnose this syndrome (1)

Donor-recipient weight difference may be an important consideration in selection of suitable donors in allogeneic hematopoietic cell transplantation (HCT), as it can affect stem cell yield during harvesting. However, the impact of donor-patient weight difference on transplant outcomes remains largely unknown. We retrospectively analyzed 841 consecutive patients transplanted at Princess Margaret Hospital 2018-2023. The majority of patients received HCT for acute myeloid leukaemia (48.3%) or myelodysplastic syndrome (16.9%) using matched unrelated (48.5%) or matched related (23.3%) donors. The median donor/recipient weight difference was 1.3 kg (range: -82-128). Weight difference was positively correlated with CD34+ cell dose (P<0.001). A Cox proportional hazard model including weight as a continuous variable demonstrated no impact of weight difference on survival, relapse, relapse-free survival (RFS), or non-relapse mortality (NRM). In contrast, the use of heavier donors was associated with a small but significant increase in the risk of cytomegalovirus (CMV) reactivation in univariate analysis (HR 1.06, P=0.02) and chronic graft-vs-host disease (GVHD) in univariate (HR 1.07, P=0.03) and multivariate (HR 1.07, P=0.04) analyses. Patients were then divided into three groups based on the donor-recipient weight difference: <-20kg (16.2%), -20-20kg (62.8%) and >20kg (21.1%). Weight difference was positively correlated with CD34+ cell dose (P<0.001). The use of heavier donors was associated with faster absolute neutrophil count (P=0.03) but not platelet (P=0.18) engraftment. There was no effect of donor-recipient weight difference on survival, relapse, RFS, NRM, grade 2-4 and 3-4 acute GVHD, chronic GVHD, moderate-severe cGVHD, incidence of blood stream infections at day 30, or Epstein-Barr virus reactivation at 1-y (Figure 1). The use of heavier donors remained associated with the incidence of CMV reactivation at 1-y. Our data suggest that donor-recipient weight discrepancy, although associated with risk of CMV reactivation and chronic GVHD, has little impact on other major outcomes post allogeneic HCT. Therefore, donor-recipient weight difference should be given limited consideration on donor selection in allogeneic HCT.

The implementation of dual T-cell depletion comprising 4.5 mg/kg of antithymocyte globulin (ATG), post-transplantation cyclophosphamide, and cyclosporine A for reduced-intensity allogeneic hematopoietic cell transplantation (HCT) independent of donor source in 2015 significantly improved graft-versus-host disease (GVHD) control at our Institution. Further advances were made between 2017 to 2020 in supportive care of allogeneic HCT recipients and were the subject of this study, with 651 adults included. Transplant outcomes were compared between patients who underwent transplantation during Period 1 (2017–2018) and Period 2 (2019–2020). Main changes implemented during the study period were reduction of ATG dose from 4.5 to 2 mg/kg in matched unrelated donor transplants, abandoning of dual T-cell depletion in matched related donor transplants, combining dual T-cell depletion with myeloablative conditioning for selected patients, and reduction of the target therapeutic cyclosporine level from 200 to 400 ng/L to 150 to 250 ng/L. Other improvements included addition of ursodiol until day 100, implementation of a double responsible physician model, and personalized patient supportive care plan focused on activity and calorie intake. The reduction in intensity of GVHD prophylaxis provided comparable acute GVHD and moderate-severe chronic GVHD between both time periods. Altogether the described improvements in transplant methodology and supportive care showed that compared to Period 1, patients transplanted in Period 2 had superior 1-year overall survival, relapse-free survival, and non-relapse mortality and showed a trend toward better GVHD- and relapse-free survival, without an increase in relapse risk. This study reports the results of outcomes-directed improvements in transplantation design, GVHD prophylaxis, and supportive care, highlighting how transplantation outcomes can be improved through careful modifications in response to meticulously monitored outcomes.

Decrease in DNA dioxygenase activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general downregulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, whereas 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was upregulated in MDS and inversely correlated with TET2 expression in wild-type cases. Although TET2 was reduced across all age groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2 deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.

Secondary-type mutations (STMs), namely SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, are more frequently detected in secondary acute myeloid leukemia (AML) than in de novo AML. Whether de novo AML with STMs should be differently managed is, however, unclear. In 394 patients diagnosed with de novo AML who had a normal karyotype, the genetic profiling via targeted deep sequencing of 45 genes revealed 59 patients carrying STMs (STM+). The STM+group showed shorter overall survival (OS) than the STM−group (5-year OS, 15.3 vs. 31.0%) (hazard ratio [HR]: 1.975, 95% confidence interval [CI]: 1.446–2.699, p< 0.001). Among the 40 STM+patients who achieved CR, those who received allogeneic HCT (n= 15) showed better OS (5-year OS, 40.0 vs. 12.0%) (HR: 0.423, 95% CI: 0.184–0.975, p= 0.043) and relapse-free survival (5-year, 40.0 vs. 8.0%) (HR: 0.438, 95% CI: 0.189–1.015, p= 0.054) than those who received consolidation chemotherapy only. The cumulative incidence of relapse was lower in the patients who received allogeneic HCT (5-year, 33.3 vs. 60.0%) (HR: 0.288, 95% CI: 0.111–0.746, p= 0.011), and non-relapse mortality was similar between the two groups (p= 0.935). In conclusion, STM is an independent prognostic factor for adverse outcomes in AML that can be overcome by allogeneic HCT.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

Eltrombopag has shown efficacy in the treatment of thrombocytopenia and poor graft function (PGF) after allogeneic hematopoietic cell transplantation (HCT) in retrospective observational studies, but is not approved for this indication. The cost of this drug is also a major concern in publicly funded health care systems. We collected data about patients who received eltrombopag for thrombocytopenia or PGF after HCT. Post-HCT thrombocytopenia, PGF, and eltrombopag response were defined as per previously published criteria. Primary outcome was treatment efficacy and secondary outcome was cost comparison between estimated treatment cost prior to and after initiation of eltrombopag. Seventeen patients (males 70.6%; median age = 58) received eltrombopag. Isolated thrombocytopenia was present in 11.8% (n= 2) patients while PGF was present in 88.2% (n= 15) of patients. After 8 weeks of treatment at the maximum dose of 150 mg orally daily, overall response rate (ORR) was seen in 76.5% (13/17) of patients: complete response (CR) in 10/13 patients and partial response (PR) in 3/13 patients. The use of eltrombopag was associated with an overall decrease in the total weekly care costs (5021 vs 2,524 CA$; P= 0.04). Thus, Eltrombopag is an efficacious and possibly cost-effective therapy for thrombocytopenia and PGF after allogeneic HCT.

Unsuccessful cytogenetic (US) analysis at baseline has been reported to be a poor prognostic feature in patients with acute myeloid leukemia (AML). We conducted this study to examine the prognostic impact of UC/inconclusive cytogenetic analysis on outcomes in patients with AML undergoing allogeneic hematopoietic stem cell transplantation (Allo HSCT).

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRDpossubgroup with respect to overall survival (HR 0.294, p= 0.003), relapse-free survival (HR 0.376, p= 0.015) and cumulative incidence of relapse (HR 0.279, p= 0.004) in multivariate analysis, but not in the MRDnegsubgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.

Cytomegalovirus (CMV) serostatus remains an independent adverse risk factor for increased transplant related morbidity and mortality (TRM) in CMV seropositive (CMV+) recipients versus CMV seronegative recipients1,2. Letermovir (LET) is a novel anti-CMV agent that prevents CMV replication through inhibition of the viral terminase complex3and is routinely given as primary prophylaxis for CMV seropositive transplant recipients as it results in a lower risk of clinically significant CMV infections4. At our institution we serve a diverse ethnic population and utilize a heterogenous mixture of donor sources and graft-versus-host-disease (GVHD) prophylaxis. We conducted this study to evaluate the impact of LET in our diverse population to evaluate for LET impact on major outcomes and evaluate for efficacy variations by ethnicity.

In allogeneic hematopoietic stem cell transplantation (HCT) genetic and non-genetic factors are implicated in clinical outcomes 1,2,3. Studies have noted ethnic disparities in transplantation are affected by various factors like stem cell sources, conditioning therapies, and immunosuppressive regimens, resulting in discrepancies in mortality4. Specifically, there are observed inequities in mortality risk post HCT in the unrelated donor setting stratified by ethnicity {e.g., Asian (low risk), White (intermediate risk), and Black (high risk)}4. Outcomes have improved with the use of post-transplant cyclophosphamide (PTCY) for graft-versus-host-disease (GVHD) prophylaxis5and the approval of Letermovir (LET) for cytomegalovirus (CMV) prevention in CMV seropositive patients6. Our study aimed to identify if disparities in outcomes are present by ethnicity as an avenue to identify future research targeting an equitable HCT experience.

The objective of this meta-analysis (MA) was to evaluate the clinical efficacy and safety of extracorporeal photopheresis (ECP) for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGvHD).

•Treo-based conditioning shows better overall survival versus busulfan in MDS patients.•Treosulfan recipients had better relapse free survival and event free survival.•Study reveals treosulfan's efficacy and safety in stem cell transplantation.•First study to evaluate treosulfan with ATG and PTCY, supporting its growing evidence.

•In MUD allo-HCT, the use of 2 mg/kg ATG combined with PTCy and CsA [ATG(2)/PTCy] effectively prevents GVHD and results in comparable relapse risk and OS to the use of ATG(4.5)/PTCy and ATG-based prophylaxis, but with lower NRM.•In patients who received ATG(2)/PTCy, the incidences of grade II-IV and grade III-IV aGVHD at day +100 and moderate/severe cGVHD at 1 year were 23.3%, 8.0%, and 14.1%, respectively.

•Blinatumomab is associated with improved post-transplant survival in B-ALL patients.•Blinatumomab is not associated with increased relapse post-transplant.•Blinatumomab is safe in the setting of post-transplant cyclophosphamide.

A Frailty and Functionality evaluation for alloHCT was implemented using existing resources. We describe the implementation of this evaluation across all ages and at first consultation, and correlate results with posttransplant outcomes in 168 patients. The evaluation consists of: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), grip strength (GS), timed up and go test (TUGT), self-rated health question (SRH), Single question of Falls, albumin and C-Reactive Protein (CRP) levels. Median time to perform the evaluation was 5–6?min. Median age was 58 years (range: 19–77) and median follow-up was 5.3 months. TUGT?>?10?s (HR 2.92; p?=?0.003), raised CRP (HR 4.40; p??10?s (HR 3.47; p?=?0.003), GS (HR 2.56; p?=?0.029), SRH (?10?s and raised CRP were significant predictors for worse OS and NRM. SRH (

The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II–IV and III–IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.

Certain subgroups of patients may be particularly vulnerable to cognitive decline after treatment with allogeneic hematopoietic stem cell transplant (HCT). The objective of this study was to identify predictors of cognitive functioning changes within the first 6 months after HCT. Fifty-eight adults treated with allogeneic HCT (53% male, mean 48 years of age) completed neuropsychological tests of learning/memory, psychomotor efficiency/processing speed, and executive functioning/working memory at three time points: pre-HCT and day 100 and 6 months post transplant. On average, there was significant improvement in learning/memory (p= 0.002), psychomotor efficiency/processing speed (p< 0.0001), and executive functioning/working memory (p< 0.0001), at 6 months. Multilevel modeling identified predictors of divergence from this trajectory; Karnofsky performance status <80 was associated with worsening learning/memory over time; peak severity of acute graft-versus-host disease >=Grade 2 was associated with worsening psychomotor efficiency/processing speed; and greater years of education predicted a faster improvement in psychomotor efficiency/processing speed. Other factors were associated with cognitive functioning over time: higher intelligence quotient (IQ) was associated with better cognitive functioning, and older age, being male, and greater pretransplant comorbidities were associated with worse cognitive functioning. Overall, cognitive performance appears to improve over the first 6 months after transplant. However, pretransplant and posttransplant factors may influence this trajectory.

Post allogenic hematopoietic cell transplant (HCT) hemophagocytic lymphohistiocytosis (HLH) is an aggressive disease with unknown etiology. It has a poorly understood pathophysiology and poor outcome if untreated early. It’s a state of hypercytokinemia. There are many proposed diagnostic criteria for Post HCT HLH. It usually occurs early in the first 2–6 weeks after allogeneic HCT but can present late. The incidence is highest among cord blood transplant compared with other sources of stem cells with a higher incidence in HLA mismatch donors. Post HCT HLH has a marked low survival rate, when compared with Non-HLH post HCT patients and specifically poor outcome is associated in patients with liver dysfunction, graft failure, and those with endothelial complications. Steroid is the mainstay treatment which can be followed up by cyclosporine and etoposide though an optimal therapy is not known. Intravenous immunoglobulin (IVIg) has been tried in virus associated HLH. Second bone marrow transplant is a rescue procedure in patient with HLH due to graft failure, though a very careful selection of individual patients is mandatory. It has been recently found that etoposide based conditioning regimen may reduce HLH post HCT. A prospective study on post HCT HLH are needed to evaluate this unrecognized condition.

Background

Introduction

Introduction:

Introduction:

Introduction

Introduction

CML requires chronic therapy, emphasizing the need for Txs that are characterized by high, durable efficacy and a low adverse event (AE) burden. ASC, the first BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), demonstrated significantly superior efficacy and better safety/tolerability compared with BOS in pts with CML-CP who received ≥2 prior TKIs in the phase 3 ASCEMBL study. Major molecular response (MMR) rate was 25.5% with ASC vs 13.2% with BOS at wk 24, meeting the primary objective, and 37.6% vs 15.8% at wk 96, meeting the key secondary objective. Despite the longer duration of exposure to ASC, safety/tolerability remained consistently better with ASC vs BOS, with fewer all-grade and grade ≥3 AEs and AEs leading to Tx discontinuation observed.

Introduction

Introduction:

Introduction:Acute myeloid leukemia (AML) involves somatic mutations in hematopoietic stem cells (HSCs). Recent evidence suggests the bone marrow microenvironment, particularly mesenchymal stromal cells (MSCs), also influences AML development. Abnormalities in MSCs from AML patients have been observed (von der Heide et al., 2016), potentially impacting leukemia progression. This study aims to identify MSC somatic mutations and their consequences, further exploring their role in AML. Understanding MSCs' impact on the leukemic microenvironment may shed light on AML pathophysiology and guide targeted therapies, particularly benefiting patients with adverse risk disease.

Background: We demonstrated that impaired functionality and frailty have a negative impact on survival after allogeneic hematopoietic cell transplantation (HCT) (Salas et al., 2019). This impact is independent of other predictive models including HCT comorbidity index (HCT-CI) and disease risk index (DRI). Cognitive changes are frequently reported among survivors of autologous and allogeneic HCT. However, impact of the presence of cognitive impairment prior to allogeneic HCT has not been studied. We hypothesized that the presence of cognitive impairment before transplantation could have a negative effect on the outcomes of allogeneic HCT.

Background

Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1variant in a discovery set of CML patients (n= 201) and successfully replicated it in a validation set (n= 270). We also investigated the functional relevance of HMGCLL1blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.

Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF0.2%-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF0.2%-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P = .003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.