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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.

Background: Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for hematological disease however can be complicated by relapse or graft failure (GF), for which second-HCT and donor lymphocyte infusions (DLI) are performed. This study aimed to compare outcomes following the two interventions. Methods: We retrospectively investigated 89 patients with relapse or GF after first-HCT, 50 (56%) underwent second HCT and 39 (44%) received (DLI), from June 2011 to September 2020. Results: Median age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2-year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%) (p=0.03). For DLI patients, 2-year OS was 49% for GF and 45% for relapse patients (p=0.49). For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI (p=0.07). Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95%CI 0.26-0.94%, p=0.03), KPS at time of intervention (HR 2.10, 95%CI 1.14-3.85%, p=0.02) and time from first-HCT to intervention (HR 0.51, 95%CI 0.28-0.93%, p=0.03) as significant variables. Conclusion: Second-HCT may improve outcomes when performed for relapse post-transplant if patients achieve remission again, while DLI may be reserved for patients with active disease.

Increasing survival of patients with multiple myeloma (MM) has resulted in an increased recognition of therapy-related hematological malignancies (t-MDS/AML, t-ALL, and t-CMML). There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HCT) in this patient population.We retrospectively reviewed patients who underwent HCT for t-MDS/AML, t-ALL, and t-CMML developing after receiving treatment for MM at our center. Patients were analyzed for myeloma characteristics and therapy, time to diagnosis of therapy-related hematological neoplasms, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS).Twenty patients underwent HCT for therapy-related hematological malignancies after MM (t-MDS/AML = 13, t-ALL = 6, t-CMML = 1). Median(range) age at time of transplant was 62.5 (49-73) years and 70% (n = 14) were male. The most common cytogenetic abnormality was complex/monosomal karyotype in 30% (n = 6) followed by monosomy/deletion of chromosome 5 or 7 in 15% (n = 3) of patients each. Donors were human leukocyte antigen matched (10/10 or 6/6) siblings in 30% (n = 6), unrelated in 60% (n = 12) and haploidentical in 10% (n = 2) patients. Estimated 2-year OS and RFS for the whole cohort were 53.1% and 47.2% respectively. There was a trend toward better survival in patients with t-ALL when compared to t-MDS/AML; however, the difference was not statistically significant. We did not find any pre-transplant or post-transplant factors that were predictive of survival outcomes after multivariate analysis.Allogeneic HCT provides substantial long-term disease-free survival in a proportion of patients with MM-associated therapy-related hematological malignancies. Multicenter studies with more patients and longer follow-up may provide additional information about factors affecting outcomes.

Donor clonal hematopoiesis may be transferred to the recipient through allogeneic hematopoietic stem cell transplantation (HCT), but the potential for adverse long-term impact on transplant outcomes remains unknown. A total of 744 samples from 372 recipients who received HCT and the corresponding donors were included. Bar-coded error-corrected sequencing using a modified molecular inversion probe capture protocol was performed, which targeted 34 genes covering mutations involved in clonal hematopoiesis with indeterminate potential (CHIP) and other AML-related mutations. A total of 30 mutations were detected from 25 donors (6.7%): the most frequently mutated gene was TET2 (n=7, 28%), followed by DNMT3A (n=4, 16%), SMC3 (n=3, 12%) and SF3B1 (n=3, 12%). With a median follow-up duration of 13 years among survivors, the presence of CHIP in the donor was not associated with recipient overall survival (p=0.969), relapse incidence (p=0.600) or non-relapse mortality (p=0.570). Donor CHIP did not impair neutrophil (p=0.460) or platelet (p=0.250) engraftment, the rates of acute (p=0.490), or chronic graft-vs-host disease (p=0.220). No significant difference was noted for secondary malignancy following HCT between the two groups. The present study suggests that the presence of CHIP in allogeneic stem donors does not adversely affect transplant outcomes after HCT. Accordingly, further study is warranted to reach a clearer conclusion on whether molecular profiling to determine the presence of CHIP mutations is necessary for the pre-transplant evaluation of donors prior to stem cell donation.

Background We evaluated feasibility, safety, and total resource use of subcutaneous immunoglobulin (SCIG) in a pilot study of patients who underwent allogeneic hematopoietic cell transplant (HCT) over a 6-month period. Methods A total of 20 eligible patients were treated with SCIG at 0.1 g/kg/week for up to 6 months. Patients were matched to 20 concurrent intravenous immunoglobulin (IVIG) controls. Clinical outcomes measured included adverse reactions, healthcare resource use, patient satisfaction, and quality of life (QOL). (ClinicalTrials.gov Identifier: NCT03401268.) Results Groups were comparable in terms of age, weight, sex, transplant indication, donor type, and conditioning intensity. All 20 IVIG patients completed 6 consecutive months of therapy compared with 13/20 (65%) SCIG patients. There were no adverse reactions in IVIG patients, compared with six (30%) SCIG patients. All adverse reactions in SCIG patients were grade I, transient, and required no medical intervention. Median overall cost per patient was lower with SCIG than with IVIG ($9,756 vs. $13,780, p = .046). Among patients who completed 6 months of SCIG, median preference and satisfaction scores were 100%. Over the 6-month period, QOL scores remained stable in SCIG patients. Conclusions In a subgroup of patients, SCIG was associated with high patient satisfaction and a reduction in total healthcare costs compared with IVIG in a cohort of HCT patients.

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.

During 2020, the concurrent novel COVID-19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n = 348), patients who received cryopreserved grafts (n = 135) had reduced survival and GRFS, reduced incidence of chronic graft-versus-host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched-related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post-HSCT, possibly due to the combination of ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation.

Refereed/Peer-reviewed Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) is a provisional disease entity in the 2016 WHO classification, while its genetic profile of Ph+ AML remains poorly defined. In addition, the differentiating features of Ph+ AML and chronic myeloid leukemia in myeloid blast crisis (CML-MBC) remain controversial.We conducted a retrospective study of 15 Ph+ AML patients to compare their clinical and laboratory profiles with 27 CML-MBC patients.Compared to CML-MBC, Ph+ AML patients presented with significantly higher peripheral WBC count and bone marrow blast percentage. The immunophenotypic profiles were largely similar between Ph+ AML and CML-MBC, except for CD4 expression, which was significantly enriched in CML-MBC. Ph+ AML patients less frequently harboured co-occurring additional cytogenetic abnormalities (ACA) compared to CML-MBC, and trisomy 19 (23%) and IDH1/2 (46%) were the most common ACA and mutated genes in Ph+ AML, respectively. Overall survival (OS) did not significantly differ between Ph+ AML and CML-MBC. Ph+ AML without CML-like features appeared to have a better outcome compared to Ph+ AML with CML-like features; ACA in Ph+ AML may confer an even worse prognosis.Our results indicate that patients with Ph+ AML share similar genetic profiles and clinical outcomes with those with CML-MBC, thus should be classified as a high-risk entity.

Treatment-free remission is achievable in approximately half of patients with chronic myeloid leukemia who attain a sustained, deep molecular response with tyrosine-kinase inhibitor (TKI) therapy. We aimed to identify potential predictors of future achievement of stable MR4.5, defined as a sustained 4.5-log reduction in BCR-ABL1 transcripts for a minimum of 2 years, in 593 patients treated with imatinib as first-line TKI therapy. In multivariable analyses of patient and disease variables including baseline blood counts, disease phase, additional cytogenetic abnormalities, prior therapy, depth and rapidity of molecular response, the only predictor for future achievement of stable MR4.5 was molecular response at 6 months. In this study, patients failing to attain a molecular response of BCR-ABL1≤ 0.16%IS after 6 months of imatinib therapy were unlikely to subsequently achieve stable MR4.5 with imatinib. Our data suggest that achievement of BCR-ABL1≤ 0.16%IS at 6 months is predictive of future stable MR4.5.

Allogeneic hematopoeitic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post-transplant in MF. Data of 89 consecutive MF patients (primary 47%) who underwent allo-HCT between 2005 and 2018 was evaluated. Fifty-four percent patients had received JAK1/2 inhibitors (JAKi) pre-HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3-4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two-year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2 years were 11% and 46%, respectively. Higher CD34 cell dose (≤5 × 106 cells/kg vs 5-9 or ≥9 × 106 cells/kg) and lower pre-HCT ferritin (

While ruxolitinib is emerging as the treatment of choice for steroid refractory/dependent chronic graft vs host disease (cGVHD) based on randomized control trial data, there is relatively little real world data published on ruxolitninb for this indication.to evaluate the real world efficacy and safety of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD STUDY DESIGN: We retrospectively evaluated the efficacy of ruxolitinib in 115 heavily pre-treated patients with steroid-refractory or dependent chronic GVHD across 5 transplant centres.The majority of the study population had severe chronic GVHD (60%) and received ruxolitinib at the 4Overall, this study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.

INTRODUCTION Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. METHODOLOGY We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. RESULTS Median follow-up was 33 months. Overall survival (OS) for the whole cohort was 55.8% at 2 years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P

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.

Objective/Background: 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). Methods: We retrospectively analyzed all adults undergoing Allo HSCT for AML from January 2011 to August 2019. Patients with any documented cytogenetic abnormalities were excluded. Baseline characteristics and transplant outcomes were compared between patients with normal cytogenetics and those with UC. Results: Overall, 243 AML patients (median age, 55 years; 55.1% female) were included. UC were reported in 79 patients, whereas 164 patients had a normal karyotype. The two groups were similar to each other in terms of baseline demographics, treatment received, and transplant related variables. There was no difference between patients with UC and normal cytogenetics in terms of relapse-free survival (66 months vs. 42 months, p = .53) or overall survival (OS; 77 months vs. 76 months, p = .72). Survival parameters remained similar even in subgroup analysis based on NPM1 and FLT3 mutation status. Significant predictors of OS after Allo HSCT in AML patients with UC were increased age at time of Allo HSCT (hazard ratio [HR] = –1.049; 95% confidence interval [CI], 1.005–1.095), favorable (NPM1Mut/FLT3wt) mutation profile (HR = 0.11; 95% CI, 0.01–0.84), neutrophil engraftment

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

BCR-ABL1 plays a key role in the pathogenesis of chronic myeloid leukemia (CML), and it has been investigated as a druggable target of tyrosine kinase inhibitors (TKIs) over two decades. Since imatinib, the first TKI for anti-cancer therapy, was successfully applied in CML therapy, further generation TKIs and a novel allosteric inhibitor targeting the myristate binding site have been developed as alternative options for CML management. However, significant concerns regarding toxicity profiles, especially in long-term treatment, have emerged from TKI clinical data. Efforts to reduce adverse events and serious complications are warranted not only for survival, but also quality of life in CML patients. A better understanding of the mechanism of action will help to identify on- and off-target effects of TKIs, and guide personalized TKI drug selection in each individual CML patient. Herein, this review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.

The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p

OBJECTIVES Hepatic grading systems for categorizing severity in chronic graft-versus-host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis. METHODS Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non-relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p-values as measures of risk stratification power. RESULTS We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low-RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high-RHS group with score 1-2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1-2 19.6%, P = .1. CONCLUSIONS Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long-term outcomes.

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18–70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69–96%) in the midostaurin arm and 76% (54–88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12–1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

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 MRDpos subgroup 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 MRDneg subgroup. 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.

INTRODUCTION The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors. METHODS Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels. RESULTS Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P

Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co-morbidities. Cardiovascular toxicity post-transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100 days post-transplant.We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100 days, and whether or not transient anthracycline-induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52 years who underwent HSCT from 2009 to 2015.The most frequent CV event in the first 100 days post-HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100 days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome.A history of CV disease, MI, or CAD was the most important predictive of CV events, P-value = .00002. 88.6% survived the first 100 days. Patients with an EF 50% had a significant likelihood of having a CV event compared to patients with an EF 60% (OR = 5.3, 95% CI [1.6-18.1], P = .0219). Cumulative anthracycline dose did not have a significant impact on overall survival.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable (

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 (

Graft-versus-host disease (GVHD) represents a major contributor to morbidity and mortality in recipients of allogeneic hematopoietic cell transplants (HCT). Several strategies exist for GVHD prophylaxis and include post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG). While several groups have described the use of PTCY in younger patients, there is a paucity of data about the efficacy of PTCY in older individuals, particularly when combined with ATG. We investigated the effect of PTCY and ATG combination on transplant outcomes in older patients at Princess Margaret Cancer Centre, Toronto, Canada. Compared to those patients who received other forms of GVHD prophylaxis, individuals who received ATG-PTCY combination had higher 2-year overall survival (OS), 57% (95% confidence interval, 44–69) vs 37% (26–49), P = 0.02; higher 2-year graft-vs-host– and relapse-free survival (GRFS), 27% (17–39) vs 12% (6–21), P = 0.01; lower 2-year non-relapse mortality (NRM), 21% (12–32) vs 45% (33–56), P = 1.00 × 10−3; lower 100-day incidence of grade 2–4 acute GVHD (aGVHD), 11% (5–21) vs 28% (18–39), P = 0.02; and lower 100-day incidence of grade 3–4 aGVHD, 0% vs 7% (3–15), P = 0.02 without an increase in the 2-year cumulative incidence of relapse (CIR), 31% (20–43) vs 21% (12–32), P = 0.14. Therefore, in older HCT recipients, use of PTCY combined with ATG is associated with improved OS, lower NRM, decreased risk of aGVHD, and improved GRFS without a significant increase in relapse risk. Therefore, the PTCY with ATG combination represents an effective strategy for GVHD prophylaxis in older allogeneic HCT recipients.

Introduction Therapy-related acute lymphoblastic leukemia (t-ALL) is an increasingly recognized subset of therapy-related acute leukemia. There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HSCT) in t-ALL. Recent reports suggest comparable outcomes of t-ALL with de novo ALL after HSCT. Patients and methods We retrospectively reviewed all patients of t-ALL who underwent HSCT at our center. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-ALL, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS). Results Eighteen patients (M:F ratio 1:1; Median age 44 years) underwent HSCT for t-ALL. Median latent period from primary malignancy to t-ALL was 44.8 months. 11q23 rearrangement and t(9;22) were present in 33.3% and 22.2% patients, respectively. Stem cell donors were matched related, matched unrelated, and haploidentical in 27.8% (n = 5), 55.6% (n = 10), and 16.7% (n = 3) patients, respectively. Five patients died before D+ 100 (27.8%). Estimated 2-year RFS and OS were 47.1% and 51.8%, respectively. We did not find any pretransplant and post-transplant risk factors that were predictive of improved OS or RFS after multivariate analysis. Conclusions Allogeneic HSCT outcomes in t-ALL were comparable to HSCT outcomes in de novo ALL. Multicenter studies with more patients and longer follow-up may provide factors affecting outcome and survival.

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

Key Points 5-hydroxymethylcytosine and TET2 messenger RNA (mRNA) downregulation are common in myelodysplastic syndromes irrespective of TET2 mutations.TET3 mRNA expression levels are associated with distinct clinical outcomes in myelodysplastic syndromes with and without TET2 mutations., 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.

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.

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HCT) is currently the only curative treatment for patients with chronic lymphocytic leukemia (CLL). METHODS We analyzed the outcomes of 93 patients (median age: 52 years) who underwent allo-HCT at our center between 1989 and 2019. RESULTS After a median follow-up of 35 months, relapse was observed in 15.1% (n = 14) patients. The estimated 2-year non-relapse mortality, relapse-free survival, and overall survival (OS) were 38.1%, 54.2%, and 58.7%, respectively. The ECOG performance status ≥ 2 (hazard ratio [HR]: 4.1; p = .001) and use of total body irradiation (in a myeloablative conditioning regimen; HR: 2.64; p = .005) were predictive of poor OS after multivariable analysis. The occurrence of sinusoidal obstruction syndrome/veno-occlusive disease post-transplant was associated with poor survival (p = .001). CONCLUSION Although the use of kinase and bcl2 inhibitors may result in a decrease in the number and need of transplants, allo-HCT remains a viable option in selected patients with high-risk CLL and good performance status.

This study compares the outcomes before and after reducing the ATG dose from 4.5 to 2 mg/kg, in a combination of PTCy and CsA for GVHD prevention, in 250 patients treated with HLA matched RIC PB-alloHCT (70% received 4.5 mg/kg and 30% received 2 mg/kg). The incidences of grade II-IV and III-IV aGVHD at day +100, and moderate/severe cGVHD at 1-year were 12.6% vs. 20% (

This study investigated the single-center incidence and risk factors for bloodstream infections (BSIs) in 651 adults who underwent allogeneic hematopoietic cell transplantation (alloHCT) between 2015 and 2019 and explored the impact of these BSIs on post-transplantation outcomes. Antibiotic prophylaxis with ciprofloxacin was given during the aplastic phase. Overall, the median patient age was 57 years, 79.7% of patients received an alternative donor graft, and 68.7% received post-transplantation cyclophosphamide (PTCy) as part of their graft-versus-host disease (GVHD) prophylaxis. Of the 651 patients, 358 (55.0%) had at least 1 episode of BSI, and the overall mortality rate secondary to this complication was 7.5% (12.6% among those diagnosed with at least 1 episode of BSI). BSI was more often diagnosed during the first 30 days (58.7%), and gram-positive bacteria were the most prevalent microorganisms isolated during the entire post-transplantation follow-up (62%). A high Disease Risk Index (hazard ratio [HR], 1.47; P < .029) and receipt of PTCy-based GVHD prophylaxis (HR, 3.33; P < .001) were identified as risk factors for BSI. Additionally, univariate analysis showed that patients diagnosed with a BSI during post-transplantation follow-up had worse overall survival (HR, 2.48; P < .001) and higher nonrelapse mortality (HR, 2.68; P < .001) than those without BSI. In conclusion, alloHCT recipients with a BSI had a higher risk of mortality compared with those who did not develop BSI. The inclusion of PTCy as part of GVHD prophylaxis was identified as an independent risk factor for BSI during early post-transplantation follow-up. Single-center analyses focused on reporting the incidence and risk factors for BSI highlight the need for active implementation of preemptive strategies to decrease BSI incidence in the alloHCT setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT12·75 days but0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

Background Several agents have been investigated for beyond second-line treatment of chronic graft-versus-host disease (GVHD). Ruxolitinib has been recently approved for steroid-refractory acute GVHD, while a prospective randomized study is ongoing to examine its efficacy in steroid-resistant chronic GVHD (cGVHD). The present study evaluated the efficacy of Ruxolitinib in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of corticosteroid exposure, 4) failure-free survival (FFS) and 5) overall survival (OS), in patients heavily pretreated for steroid-resistant cGVHD. Patients and methods A total of 47 patients who developed cGVHD after HCT and treated with Ruxolitinib for cGVHD from March 2016 to April 2020, at three different sites (Princess Margaret Cancer Center, Canada; Vancouver General Hospital, Canada and Saint Vincent Hospital, Australia), were evaluated in the retrospective study. Patients and disease characteristics are as follows: median age 52 years; classical 35 (71%), overlap syndrome 14 (29%). Of note, 27 patients (57.4%) had a previous history of acute GVHD. The ORR and CB were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting Ruxolitinib therapy for cGVHD treatment. Results A total of 47 patients had moderate (11/47, 24.4%) to severe (33/47, 73.3%) cGVHD except one who had mild grade cGVHD with a high-risk feature (thrombocytopenia at the time of Ruxolitinib start). The median number of organ involvement was 3 (range 1-7). Over half of patients (63.8%) received Ruxolitinib as 4th line or beyond for cGVHD treatment, while median number of previous lines of therapy was 3 (range 1-9). All 47 patients (100%) had been previously treated with systemic steroids; other previous treatments included ECP therapy (53.2%), Imatinib (29.8%), Ibrutinib (23.4%), Rituximab (21.3%). Ruxolitinib was started at 10-15 mg daily as initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12.With a median follow-up duration of 12 months, ORR was attained in 35.7%, 36.0% and 35.0% at 3, 6 and 12 months, respectively (Figure A). Of note, ORR in patients with sclerotic changes was 56%, and 61.5% in those with lung involvement. Patients resistant to TKI (i.e. Imatinib or Ibrutinib) for cGVHD treatment showed similar ORR compared to those naïve to TKI therapy.The CB was observed in 53.5%, 66.7% and 72.2% at months 3, 6 and 12, respectively (Figure B). Patients resistant to TKI for cGVHD treatment did not show any difference in CB compared to those naïve to TKI therapy.In terms of prednisone dose reduction, by 12 months , half of patients (50.0%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of patients on prednisone dose below 0.1mg/kg/day was 9.3%, 20.0%, 17.4%, and 50.0% at month 0, 3, 6 and 12, respectively (Figure C). The group who achieved CB at 3 months showed a significantly lower dose of prednisone at 12 months (0.078mg/kg/day) compared to those without clinical benefit at 3 months (0.197mg/kg/day; p=0.033; Figure D).Out of 37 patients evaluated, 11 failures (29.7%) were noted, including resistance requiring a switch to other therapy (n=7), NRM (n=2) and intolerance (n=2). The FFS rate at 1 year in the overall population was 68.5% (Figure E). The FFS at 1 year in those having CB at 3 months vs not was 86.5% vs 51.4% (p=0.025).The OS at 1 year was 90.9% (Figure F). The OS at 1 year in those having a CB at 3 months vs not was 100% vs 78.8% (p=0.053). Conclusion: This multicenter retrospective study revealed that Ruxolitinib is an effective treatment option for patients with cGVHD, with good ORR and CB. The achievement of CB in the first 3 months correlated well with steroid dose reduction. It suggests that Ruxolitinib is a feasible GVHD treatment option, even for patients who were heavily pretreated for cGVHD or failed previous TKI drug. Figure 1 Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. OffLabel Disclosure: Ruxolitinib treatment for steroid resistant chronic GVHD

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 =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.