The impact of cytotoxic therapy on the risk of progression and death in clonal cytopenia(s) of undetermined significance.

Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified CCUS patients by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs. 44.8%, P=0.002) but had higher median bone marrow blast percentages. After a median follow up of 2.2 years, t-CCUS had significantly shorter PFS (1.8 vs. 6.3 years, HR 2.1, P=0.007) and median OS (3.6 years vs. not reached, HR 2.3, P=0.007) compared to CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk-factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

IDH Mutant Myeloid Neoplasms are Associated with Seronegative Rheumatoid Arthritis and Innate Immune Activation.

High prevalence of IDH-mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity and pro-inflammatory microenvironment, suggests causative association between IDH-mutations and seronegative RA. Our findings merit investigation of IDH-inhibitors as therapeutics for seronegative IDH-mutated RA.

Genetic Testing Goes Beyond Imaging and Histological Evaluation in Pleuroparenchymal Fibroelastosis.

BACKGROUND: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes. METHODS: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis. RESULTS: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations. CONCLUSION: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD.

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent.

Not available.

Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management.

DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, characterized by prominent monocytosis and an inherent risk for leukemic transformation (~15%-20% over 3-5 years). DIAGNOSIS: Newly revised diagnostic criteria include sustained (>3 months) peripheral blood (PB) monocytosis (≥0.5 × 109 /L; monocytes ≥10% of leukocyte count), consistent bone marrow (BM) morphology, <20% BM or PB blasts (including promonocytes), and cytogenetic or molecular evidence of clonality. Cytogenetic abnormalities occur in ~30% of patients, while >95% harbor somatic mutations: TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), RAS pathway (~30%), and others. The presence of ASXL1 and DNMT3A mutations and absence of TET2 mutations negatively impact overall survival (ASXL1WT /TET2MT genotype being favorable). RISK STRATIFICATION: Several risk models serve similar purposes in identifying high-risk patients that are considered for allogeneic stem cell transplant (ASCT) earlier than later. Risk factors in the Mayo Molecular Model (MMM) include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 109 /L, hemoglobin <10 g/dL, platelet count <100 × 109 /L, and the presence of circulating immature myeloid cells; the resulting 4-tiered risk categorization includes high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors); the corresponding median survivals were 16, 31, 59, and 97 months. CMML is also classified as being "myeloproliferative (MP-CMML)" or "myelodysplastic (MD-CMML)," based on the presence or absence of leukocyte count of ≥13 × 109 /L. TREATMENT: ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease. Drug therapy is currently not disease-modifying and includes hydroxyurea and hypomethylating agents; a recent phase-3 study (DACOTA) comparing hydroxyurea and decitabine, in high-risk MP-CMML, showed similar overall survival at 23.1 versus 18.4 months, respectively, despite response rates being higher for decitabine (56% vs. 31%). UNIQUE DISEASE ASSOCIATIONS: These include systemic inflammatory autoimmune diseases, leukemia cutis and lysozyme-induced nephropathy; the latter requires close monitoring of renal function during leukocytosis and is a potential indication for cytoreductive therapy.

Venous and Arterial Thrombosis in Patients with VEXAS Syndrome.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS. The risks factors and frequency of thrombosis in VEXAS are not well described, due to the disease's new discovery and paucity of large databases. We evaluated 119 VEXAS patients for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two thirds of VTE were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence (CI) of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism (PE) by univariate (OR: 4.58, CI 1.28-16.21; p=0.02) and multivariate (OR: 16.94, CI 1.99-144.3; p=0.01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival (OS) of the entire patient cohort at median follow up time of 4.8 years was 88% and there was no difference in survival between patients with or without thrombosis (p=0.8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.

Inherited bone marrow failure syndromes and germline predisposition syndromes (IBMFS/GPS) are associated with increased risk for hematologic malignancies, particularly myeloid neoplasms, such as myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The diagnosis of MDS in these syndromes poses difficulty due to frequent bone marrow hypocellularity and the presence of some degree of dysplastic features related to the underlying germline defect causing abnormal maturation of one or more cell lines. Yet, the diagnosis of MDS is usually associated with a worse outcome in several IBMFS/GPS. Criteria for the diagnosis of MDS in IBMFS/GPS have not been standardized with some authors suggesting a mixture of morphologic, cytogenetic, and genetic criteria. This review highlights these challenges and suggests a more standardized approach to nomenclature and diagnostic criteria.

Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data is 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 comutations. 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 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 < 0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P = 0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P = 0.02), whereas melphalan-based conditioning was associated with a decreased relapse-risk (HR 0.02, P = 0.01). We conclude that mBCOR is a high-risk feature across MDS/AML and that alloSCT improves survival in this population.

Fifth Edition of the World Health Classification of Tumors of the Hematopoietic and Lymphoid Tissue: Myeloid Neoplasms.

In this manuscript, we review myeloid neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5), focusing on changes from the revised fourth edition (WHO-HEM4R). Disease types and subtypes have expanded compared with WHO-HEM4R, mainly because of the expansion in genomic knowledge of these diseases. The revised classification is based on a multidisciplinary approach including input from a large body of pathologists, clinicians, and geneticists. The revised classification follows a hierarchical structure allowing usage of family (class)-level definitions where the defining diagnostic criteria are partially met or a complete investigational workup has not been possible. Overall, the WHO-HEM5 revisions to the classification of myeloid neoplasms include major updates and revisions with increased emphasis on genetic and molecular drivers of disease. The most notable changes have been applied to the sections of acute myeloid leukemia and myelodysplastic neoplasms (previously referred to as myelodysplastic syndrome) with incorporation of novel, disease-defining genetic changes. In this review we focus on highlighting the updates in the classification of myeloid neoplasms, providing a comparison with WHO-HEM4R, and offering guidance on how the new classification can be applied to the diagnosis of myeloid neoplasms in routine practice.

VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly identified disease caused by somatic alterations in UBA1 which produce a recalcitrant inflammatory state along with hematologic disturbances. Patients with VEXAS can have a wide spectrum of clinical symptoms and providers should be familiar with the heterogeneity of associated clinical features. While hematologic parameters may be generally non-specific, peripheral blood features of macrocytosis, monocytopenia, and/or thrombocytopenia coupled with bone marrow vacuolization of erythroid or myeloid precursors should raise suspicion for this condition. Due to an increased mortality, prompt recognition and accurate diagnosis is paramount. Access to testing for confirmation of UBA1 variants is not yet universally available but clinicians should understand the current available options for genetic confirmation of this disease. Treatment options are limited due to lack of prospective clinical trials but cytokine directed therapies such as interleukin-6 inhibitors and JAK-STAT inhibitors as well as hypomethylating agents such as azacitidine have shown evidence of partial effect. Though cases are limited, allogeneic stem cell transplantation holds promise for durable response and potential cure. The intent of this review is to outline the pathophysiology of VEXAS syndrome and to provide a practical approach to diagnosis and treatment.

Prognostic relevance of clonal hematopoiesis in myeloid neoplastic transformation in patients with follicular lymphoma treated with radioimmunotherapy.

While novel radioisotope therapies continue to advance cancer care, reports of therapy-related myeloid neoplasms (t-MN) have generated concern. The prevalence and role of clonal hematopoiesis (CH) in this process remain to be defined. We hypothesized that: (i) CH is prevalent in relapsed follicular lymphoma and is associated with t-MN transformation, and (ii) radiation in the form of radioimmunotherapy (RIT) plays a role in clonal progression. In this retrospective cohort study, we evaluated the prevalence and prognostic impact of CH on clinical outcomes in 58 heavily pre-treated follicular lymphoma patients who received RIT. Patients had been given a median of four lines of therapy before RIT. The prevalence of CH prior to RIT was 46%, while it was 67% (P=0.15) during the course of RIT and subsequent therapies in the paired samples. Fourteen (24%) patients developed t-MN. Patients with t-MN had a higher variant allele fraction (38% vs. 15%; P=0.02) and clonal complexity (P=0.03) than those without. The spectrum of CH differed from that in age-related CH, with a high prevalence of DNA damage repair and response pathway mutations, absence of spliceosome mutations, and a paucity of signaling mutations. While there were no clear clinical associations between RIT and t-MN, or overall survival, patients with t-MN had a higher mutant clonal burden, along with extensive chromosomal abnormalities (median survival, afer t-MN diagnosis, 0.9 months). The baseline prevalence of CH was high, with an increase in prevalence on exposure to RIT and subsequent therapies. The high rates of t-MN with marked clonal complexities and extensive chromosomal damage underscore the importance of better identifying and studying genotoxic stressors accentuated by therapeutic modalities.

Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders.

PURPOSE OF REVIEW: Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive. RECENT FINDINGS: Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis. TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.

Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.

Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).