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Abstract Core‐binding factor acute myeloid leukemia (CBF‐AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21) and is classified as a favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. The CD33‐targeting antibody‐drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF‐AML. We sought to compare outcomes in patients treated with IC with or without GO in CBF‐AML. We included 200 patients with CBF‐AML treated with IC across seven academic centers. Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin). Median follow‐up for the whole cohort was 2.5 years. Three‐year overall survival (OS) was 70% and 3‐year event‐free survival (EFS) was 51%. Patients treated with IC with GO experienced a 3‐year EFS of 50% compared to those treated with IC alone who experienced a 3‐year EFS of 47%, with no statistically significant difference (p = 0.62). Similarly, those treated with IC with GO did not experience an improved OS compared to those treated with IC alone (p = 0.67). Patients treated with IC with KIT inhibitor experienced a significantly improved 3‐year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF‐AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p

Not available.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P

This case report explains an extraordinary presentation of chronic myeloid leukemia (CML) in a 39-year-old male with a T315I mutation, presenting with acute bilateral hearing loss and imbalance secondary to myeloid blast crisis. Neurological involvement was confirmed through MRI brain and cerebrospinal fluid analysis. Initial treatment with ponatinib and FLAG (fludarabine, cytarabine, G-CSF) regimen showed promise, but complications necessitated discontinuation. The patient's complex clinical trajectory, marked by complications and intolerance to tyrosine kinase inhibitors, highlights the intricate nature of CML blast crisis with T315I mutation management. Recognizing atypical presentations and early mutation analysis are pivotal for tailored treatment strategies.

Abstract We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.

Abstract We surveyed the performance of ponatinib, as salvage therapy, in a real-world setting of chronic phase chronic myeloid leukemia (CML-CP). Among 55 consecutive patients (median age 49 years) with relapsed/refractory CML-CP, 35 (64%) had failed ≥3 tyrosine kinase inhibitors (TKIs), 35 (64%) were pre-treated with nilotinib, and 14 (28%) harbored ABL1T315I. At start of ponatinib (median dose 30 mg/day), 40 patients were already in complete hematologic (CHR), 4 in complete cytogenetic (CCyR), 3 in major molecular (MMR) remission, while 8 had not achieved CHR (NR). Ponatinib improved the depth of response in 13 (33%), 3 (75%), 2 (66%), and 4 (50%) patients with CHR, CCyR, MMR, and NR, respectively (p = 0.02). At a median follow-up of 42 months, 13 (23%) deaths, 5 (9%) blast transformations, and 25 (45%) allogeneic transplants were recorded. Five/10-year post-ponatinib survival was 77%/58% with no significant difference when patients were stratified by allogeneic transplant (p = 0.94), ponatinib-induced deeper response (p = 0.28), or a post-ponatinib ≥CCyR vs CHR remission state (p = 0.25). ABL1T315I was detrimental to survival (p = 0.04) but did not appear to affect response. Prior exposure to nilotinib was associated with higher risk of arterial occlusive events (AOEs; 11% vs 0%; age-adjusted p = 0.04). Ponatinib starting/maintenance dose (45 vs 15 mg/day) did not influence either treatment response or AOEs. Our observations support the use of a lower starting/maintenance dose for ponatinib in relapsed/refractory CML-CP but a survival advantage for deeper responses was not apparent and treatment might not overcome the detrimental impact of ABL1T315I on survival. The association between prior exposure to nilotinib and a higher risk of post-ponatinib AOEs requires further validation.

The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41path and DDX41VUS (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell leukemias, occurring because of abnormal proliferation of non-functional B-lymphocytes. Progressive disease is commonly complicated by anemia, thrombocytopenia, infections as well as secondary malignancies. Bone marrow fibrosis is infrequently co-occurred along with CLL. Although multiple explanations have been proposed for this association, the etiology remains unclear in most cases. Bone marrow fibrosis occurring as a complication of CLL itself, however, is a rare entity. We present an uncommon case of a patient initially diagnosed with primary myelofibrosis but later revealed to have aggressive CLL leading to bone marrow fibrosis upon re-evaluation. Treatment for CLL resolved the bone marrow fibrosis completely, confirming our suspicion of fibrosis being secondary to CLL. This sheds light on the importance of understanding the etiology of bone marrow fibrosis in patients with CLL owing to its therapeutic implications. The utility of bone marrow biopsy in not only helping understand the etiology of the fibrosis but also providing prognostic information merits reconsideration of performing it in all cases of CLL.

Myeloid sarcoma (MS) is a rare extramedullary blast proliferation of immature cells of myeloid origin. It is commonly associated with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN), and may precede, coincide with, or follow the diagnosis of a myeloid disorder. MS treatment is controversial, but AML induction like regimens is usually recommended. We present an unusual case of de novo TP53 mutated MDS/MPN overlap with bladder MS. Due to the high-risk nature of the disease, the patient was induced with decitabine and venetoclax combination therapy, resulting in complete remission. The response was further consolidated by an allogeneic hematopoietic stem cell transplantation.

Abstract: Patients with classic Hodgkin lymphoma (cHL) who relapse after autologous hematopoietic cell transplantation (auto-HCT) historically have had poor outcomes. We hypothesized that, post–auto-HCT relapse, overall survival (PR-OS) has improved in recent years as a result of more widespread use of novel therapies and allogeneic HCT (allo-HCT). We conducted a retrospective study in 4 US academic centers, evaluating 215 patients who underwent auto-HCT from 2005 to 2016 and relapsed thereafter. Patients were divided into 2 cohorts based on timing of auto-HCT, 2005 through 2010 (cohort 1; n = 118) and 2011 to 2016 (cohort 2; n = 97), to compare differences in clinical outcomes. The median age and disease status at auto-HCT were similar in cohorts 1 and 2. The proportions of patients who received brentuximab vedotin (Bv; 55% vs 69%; P = .07), checkpoint inhibitors (CPIs; 3% vs 36%; P ≤ .001), and allogeneic-HCT (22% vs 35%, P = .03) were significantly different between cohorts 1 and 2, respectively. At the 5-year follow-up after auto relapse, 32% and 50% of patients were alive in cohorts 1 and 2, respectively (P = .01). In multivariate analysis for PR-OS, cohort 1 vs 2 (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.14-4.60; P = .01), age at auto-HCT (HR, 1.48; 95% CI, 1.18-1.87; P ≤ .001), and time to relapse from auto-HCT (HR, 0.59; 95% CI, 0.47-74; P ≤ .0001), retained independent prognostic significance for PR-OS. Our study supports the hypothesis that survival of cHL patients after auto-HCT failure has significantly improved in recent years, most likely because of incorporation of novel therapies and more widespread use of allo-HCT.

Immunoglobulin (Ig) light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by misfolded Ig light chain deposition in vital organs of the body, resulting in proteotoxicity and organ dysfunction. Owing to its diverse clinical presentations and a tendency to mimic common medical conditions, AL amyloidosis is often diagnosed late and results in dismal outcomes. Early referral to a specialized center with expertise in management of AL amyloidosis is always recommended. The availability of sensitive biomarkers and novel therapies is reforming our approach to how we manage AL amyloidosis. Treatment for patients with AL amyloidosis should be risk-adapted and customized on the basis of individual patient characteristics. In the future, approaches directed at amyloid fibril clearance in combination with agents that target plasma cells will be needed both to eradicate the malignant clone and to establish organ responses.