Current Hematologic Malignancy Reports最新文献

Purpose of review: This review will summarize recent research into the diverse biological consequences of splicing factor mutations, and possible therapeutic vulnerabilities uncovered by such mutations, with a dedicated focus on chronic myelomonocytic leukemia.

Recent findings: Splicing factor mutations dysregulate alternative splicing transcriptome-wide. The global nature of such dysregulation has pleiotropic effects on cellular function. Splicing factor mutations can alter NF-κβ and IFN-γ signaling, alter malignant hematopoietic cell differentiation, degrade the function of epigenetic complexes, and predispose cells to DNA replicative stress. Therapeutic strategies to target the altered biology of clones harboring splicing mutations have had varying degrees of success. Because splicing factor mutations are highly prevalent in chronic myelomonocytic leukemia and many other hematologic malignancies, an understanding of their downstream effects and therapeutic vulnerabilities is of key interest in the field. This review highlights recent developments and opportunities for targeted therapies.

Purpose of review: Management of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has improved patient survival. However, patient quality of life (QOL) continues to be impacted by disease symptoms and treatment-related adverse events. Patient-reported outcome measures (PROMs) provide evidence of the patient experience. A scoping literature review was conducted to identify and summarize the evidence on PROMs used for patients with CML.

Recent findings: Embase and MEDLINE databases were searched for publications from 2001 to 2023 that reported PROMs. Ongoing and completed trials listed on ClinicalTrials.gov were also reviewed. Results were summarized according to the PROMs used and the information collected in these PROMs. After screening 6337 records, 208 unique studies were identified with published PRO evidence reporting data from 92 unique PROMs. The most commonly reported PROMs (in ≥5% of publications) were used in 115 studies, of which 45 were exclusively in the frontline setting. The most commonly used PROMs in studies in the frontline setting were variations of European Organisation for Research and Treatment of Cancer QLQ, Functional Assessment of Chronic Illness Therapy Measurement System/Functional Assessment of Cancer Therapy, and 36-Item Short Form Survey. This scoping literature review highlighted that a variety of PROMs are used in CML studies, including studies in the frontline setting. Different QOL aspects are measured by commonly used PROMs, and the choice of PROM is dependent on the study setting and objectives. A more comprehensive understanding of QOL gained by using appropriate PROMs will help optimize patient-centered treatment selection in CML.

Purpose of review: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by monocytosis and dysplasia. While mutations in genes like TET2 and SRSF2 have helped us understand its molecular foundations, the role of inflammation in driving disease behavior is becoming increasingly evident. This review explores the role of inflammation in the biology and clinical progression of CMML, with a focus on its impact on disease initiation, progression, and potential therapeutic strategies.

Recent findings: Recent studies have shown that inflammatory cytokines, especially IL-6, TNF-α, and IL-8, are not just bystanders but active participants in promoting clonal hematopoiesis, immune dysregulation, and bone marrow dysfunction in CMML. Patients with systemic inflammation or autoimmune conditions are at a higher risk of developing CMML, suggesting a potential causal relationship. On the therapeutic front, drugs targeting cytokine pathways, such as ruxolitinib (a JAK inhibitor) and lenzilumab (an anti-GM-CSF antibody), have shown early promise in modifying disease activity and improving symptoms. Inflammation plays a central role in CMML, from disease onset to transformation into acute leukemia. Understanding and targeting these inflammatory circuits may not only help slow disease progression but also improve quality of life for patients. As our knowledge grows, incorporating inflammation into both our diagnostic frameworks and treatment approaches will likely become standard in the care of CMML.

Purpose of review: Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) caused by a somatic gain-of-function mutation of the Janus kinase2 (JAK2) gene in hematopoietic stem and peripheral blood cells, leading to erythrocytosis which is often accompanied by leukocytosis and thrombocytosis. Historically, PV management has mainly focused on maintaining hematocrit (HCT) levels below 45% to reduce major thrombotic risk, improving symptoms and monitoring disease progression. Phlebotomy alone or in combination with cytoreductive therapy, where indicated, form the current standard of care. This review explores the potential correlation between the depletion of neoplastic clones in patients with PV with the achievement of durable complete molecular remission (CMR), and long-term treatment effects on thrombotic events and survival, as well as implications for re-defining treatment goals.  RECENT FINDINGS: Past management practices do not ideally optimize outcomes for patients with PV. Specifically, these approaches do not adequately address the underlying risk of disease progression driven by the neoplastic cells carrying mutated JAK2 and additional mutations. Patients with PV who are treated with interferon-based therapies can achieve complete hematologic response, together with a significant reduction of JAK2V617F Variant Allele Frequency (VAF). Continued reduction of the JAK2VAF may lead to CMR and is correlated with in vivo drug exposures and durable improvement of thrombotic risk, as well as increased probability of event-free survival (EFS). The results indicate that reduction in JAK2V617F VAF, and by extension depletion of neoplastic cells, is essential for favorable long term clinical outcomes in patients with PV. Emerging data suggest a direct correlation between deep reduction in JAK2V617F VAF as a measure of suppressing neoplastic cells and improved probability of EFS and delayed disease progression. These observations suggest a treatment paradigm shift from solely managing symptoms and preventing thrombotic events, toward achieving durable clonal depletion with potential for remission and preventing transformation to myelofibrosis or acute myeloid leukemia. Integration of molecular biomarkers into risk-adapted treatment algorithms may enable personalized approaches to achieve deep molecular responses and durable disease modification in PV. Clonal molecular response, therefore, deserves attention as a biomarker of response that should be evaluated in clinical trials, as well as for treatment monitoring.

Purpose of review: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm that is characterized by sustained monocytic proliferation, bone marrow dysplasia, and progression to acute myeloid leukemia (AML). Somatic mutations are observed in most patients, with mutations in epigenetic regulatory genes being frequent and often impacting survival outcomes. Deeper understanding of the biological impacts of these mutations has resulted in rationally derived precision therapeutics. Here, we discuss two classes of epigenetic regulator genes and describe the prevalence and impact of somatic mutations in these genes on CMML outcomes.

Recent findings: The increased use and availability of sequencing techniques in the clinical setting has demonstrated the prevalence of mutations in epigenetic regulator genes in CMML. This has provided additional cases to study the impact of these mutations on survival outcomes, leading to the incorporation of some of these mutations in contemporary molecular CMML prognostic models (ASXL1, TET2). Furthermore, advances in understanding epigenetic dysregulation in CMML have led to the development of emerging targeted therapies for select patients. Studying the prevalence of these mutations and their biological implications in CMML may offer an opportunity to identify genotypes likely to respond to treatment or to develop targeted mutation-specific therapies.

Purpose of the review: To summarize evidence and provide an overview of the microenvironment and myeloid-immune cell interactions within the chronic myelomonocytic leukemia (CMML) microenvironment that drive mutation-agnostic pathways of disease progression.

Recent findings: Recent work has demonstrated the importance of myeloid-immune cell interactions in CMML and related myeloid neoplasms. In particular, we focus on the bone marrow microenvironment of CMML, highlighting the role of clonal dendritic cell aggregates and their interaction with other myeloid cells such as monocytes and their precursors, and adaptive immune cells. Several drugs are currently under investigation that target the inflammasome, specific immune cell populations, and immune checkpoint inhibitors with limited success as monotherapy. Immune microenvironment plays a critical role in CMML disease biology and can be targeted for therapeutic benefit. Future research should focus on identifying pathways that are indispensable for progression.

Purpose of review: Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy at the intersection of myelodysplastic (MDS) and myeloproliferative neoplasms, predominantly affecting older adults. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option, yet its application is limited by the advanced age and comorbidities of most patients. Recent classification updates and refined prognostic tools, particularly molecularly integrated models like CPSS-Mol have enhanced patient stratification and informed transplant timing. The aim of this review is to highlight the evolving landscape of CMML management, with a focus on the role of allo-HCT.

Recent findings: Novel studies patients demonstrated that individualized transplant timing significantly improved life expectancy. Optimizing transplant outcomes hinges on several factors:managing pretransplant splenomegaly, choosing appropriate debulking strategies, selecting optimal donors, and tailoring conditioning regimens. New data favor treosulfan-based and thiotepa-busulfan regimens for their favorable toxicity and relapse profiles. Post-transplant, strategies like post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis and emerging approaches to minimal residual disease (MRD) monitoring offer additional refinements in patient management. While no MRD studies are CMML-specific, extrapolation from MDS supports its role in relapse prediction. Innovative therapies, including hypomethylating agent combinations, venetoclax, targeted inhibitors, and immunotherapies are under active investigation, with potential to improve pre- and post-transplant outcomes. Advancements in molecular classification, dynamic prognostic tools, and therapeutic strategies are reshaping the CMML treatment paradigm. Personalized approaches that integrate genetic risk, patient fitness, and disease characteristics are enabling more effective transplant strategies, with the ultimate goal of extending survival and improving quality of life in this complex and historically difficult-to-treat malignancy.

Purpose of review: This report summarizes key insights from the 8th Annual International Symposium on Myeloproliferative Neoplasms (MPN Asia 2025). The symposium brought together global experts to discuss advancements in MPN biology, diagnostics, and therapeutics, with a focus on emerging molecular understanding, novel treatment strategies and real-world data.

Recent findings: Molecular profiling has become essential in MPN risk stratification and therapeutic decision-making. High-risk mutations (e.g., ASXL1, TP53) and inflammatory pathways (e.g., IL-17, NF-κB) were shown to correlate with disease progression and transformation. Interferon-based therapy is increasingly used in younger, low-risk, or treatment-naïve patients, and is also being investigated in myelofibrosis and essential thrombocythemia. Ropeginterferon alfa-2b, a novel interferon-based therapy, demonstrated durable clinical efficacy in polycythemia vera. Its high initial-dose and accelerated titration (HIDAT) regimen led to fast achievement of complete hematologic response, rapid reductions in JAK2V617F allele burden, and high complete molecular response rate. Combination regimens involving ruxolitinib and agents such as pelabresib, selinexor, and interferon showed potential for enhanced efficacy. Population-based studies from Asia contributed regional epidemiological and treatment data, reinforcing the role of real-world evidence. Modern prognostic models such as MIPSS70+ v2.0 and GIPSS were discussed for more precise risk prediction. Preliminary findings also suggest ropeginterferon alfa-2b may be a safe option during pregnancy. MPN Asia 2025 highlighted the growing role of molecular diagnostics and targeted therapeutics in the management of MPNs. Ropeginterferon alfa-2b has emerged as a therapeutic potential across the MPN spectrum. Its early use and personalized strategies are increasingly recognized. Real-world data and regional insights are shaping a more nuanced, globally informed approach to MPN care.

Purpose of review: Chronic myelomonocytic leukemia (CMML), a rare myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, poses diagnostic and therapeutic challenges due to its heterogeneity and rarity. This review highlights updates to CMML diagnostic criteria, examines risk stratification models and their clinical implications, and outlines both established and emerging therapies for this rare and likely underrecognized hematologic malignancy.

Recent findings: Updated diagnostic criteria from 2022 reduce the monocyte threshold to 0.5 × 10⁹/L for CMML diagnosis, which will reclassify many cases previously diagnosed as MDS. Risk stratification models continue to be refined allowing for improved prediction and may help select appropriate patients for allogeneic stem cell transplantation, the only curative therapeutic modality in CMML. Although trials in CMML were long relegated to subpopulation of MDS studies, there has recently been a flourishing of novel therapies being tested specifically in CMML. These include lenzilumab (anti-GM-CSF) and IO-202 (anti-LILRB4), which have demonstrated promising early efficacy signals but require further study. Established treatments, which include hypomethylating agents and hydroxyurea as well as the JAK1/2 inhibitor ruxolitinib, provide limited survival benefits in CMML, underscoring the urgent need for novel therapeutic development. Coordinated dedicated research efforts have started to evaluate new agents in CMML. Along with further diagnostic and prognostic refinement, these advances are welcomed for this rare and heterogenous disease.

Purpose of review: In this review, we highlight conventional agents and novel emerging therapeutic strategies to treat anemia in MF.

Recent findings: Anemia is a common and challenging feature of myelofibrosis (MF). The pathobiology of anemia is multifactorial, including progressive bone marrow fibrosis, decreased erythropoiesis due to high hepcidin levels leading to iron sequestration in the reticuloendothelial system, hypersplenism, erythropoiesis inhibition by myelosuppressive JAK inhibitors (ruxolitinib, fedratinib), and others. MF-associated anemia has a negative impact on survival. Conventional agents to manage anemia include erythropoiesis-stimulating agents, danazol, corticosteroids, and immunomodulatory agents, but responses are infrequent and lack durability. Notable advancements have emerged in developing novel treatments for anemia in MF, including the regulatory approval of momelotinib (ACVR1/JAK1/2 inhibitor) in 2023 and development of novel promising agents targeting hemojuvelin and activins. Momelotinib and pacritinib (ACVR1/JAK2 inhibitor) are the preferred JAK inhibitors for patients with cytopenias (anemia, thrombocytopenia). Luspatercept and elritercept are activin receptor ligand traps, promoting erythroid maturation and late-stage erythropoiesis. Currently, luspatercept is being evaluated in a phase 3 trial (INDEPENDENCE™) for anemia in MF patients who are on a JAK2 inhibitor and require transfusions, and in a phase 2 trial (ODYSSEY) in combination with momelotinib in MF patients who are transfusion dependent, whether or not on a JAK inhibitor. Interim results of the RESTORE trial demonstrated that elritercept significantly decreased transfusions in MF patients. DISC-0974 is a first-in-class anti-hemojuvelin (positive hepcidin regulator) monoclonal antibody that decreased hepcidin expression, increased serum iron, and enhanced erythropoiesis in anemic patients with MF in a phase 1b/2 study. Burgeoning studies of novel anemia-targeted agents and combinations are significantly improving the quality of life and outcomes of patients with MF. The recent approval of momelotinib to treat MF with anemia and the emerging novel anemia-directed strategies in early and advanced clinical development have ushered in a new era in the treatment of MF-related anemia.