The field of plasma cell dyscrasias has undergone dramatic evolution in recent yeast due to rapid therapeutic advances. While exciting, the growth of novel therapeutic strategies has created significant evidence gaps which cannot all be feasibly addressed with dedicated prospective trials. The role of real-world data (RWD) and real-world evidence (RWE) in informing management has thus also expanded. We aim to review the use of RWD and RWE in PCD management. RWD has been used significantly to assess short- and long-term toxicities associated with rapidly expanding treatment modalities such as cellular therapies that were not explored in RCTs. Other RWE has shown that clinical efficacy of newer treatment options is maintained in patient populations that would be excluded from RCT participation. RWE has also lent greater support for and generated new ideas for optimal therapeutic sequencing in PCD. Furthermore, RWE has allowed for the development of treatment ideas for less common PCD that have not been studied in RCTs. The use of RWD and RWE in the field of PCDs has effectively supplemented the use of RCTs in expanding the treatment options available to combat PCDs. As this field continues to expand at a rapid pace, RWD and RWE will continue to be needed as a source of data to support new treatments.
Outdoor air pollution (OAP) is a major global environmental health threat associated with respiratory disease and solid tumors, with growing evidence linking it to hematologic malignancies. This review summarizes the molecular mechanisms and epidemiologic evidence connecting OAP exposure to acute and chronic leukemias, lymphomas, myelodysplastic syndromes (MDS), clonal hematopoiesis of indeterminate potential (CHIP), and multiple myeloma (MM). Pollutants implicated in hematologic carcinogenesis include particulate matter (PM), benzene, nitrogen dioxide (NO₂), sulfur dioxide (SO₂), arsenic, and ethylene oxide. Molecular mechanisms include oxidative stress, DNA damage, epigenetic dysregulation, chronic inflammation, and hematopoietic stem cell dysfunction. Epidemiologic evidence is strongest for acute myeloid leukemia (AML), particularly with benzene exposure. Acute lymphoblastic leukemia (ALL) has also been associated with traffic-related pollution, NO₂, and PM exposure, though findings are less consistent. Certain lymphoma subtypes demonstrate pollutant-specific associations, while emerging evidence suggests possible links between OAP exposure and MDS and CHIP. In contrast, evidence for chronic leukemias and MM remains limited. Despite limitations, including exposure misclassification and residual confounding, cumulative molecular and epidemiologic evidence supports OAP as an important and potentially modifiable risk factor for hematologic malignancies. OAP exposure disproportionately affects racial and ethnic minorities, low-income communities, and rapidly industrializing regions, magnifying existing health disparities. Further research, environmental policy reform, and public health interventions are needed to reduce exposure and disease burden. HSC: hematopoietic stem cell. Created in BioRender. Murli, H. (2026) https://BioRender.com/tkhy5k7
Targeted immunotherapies have transformed the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), yet their efficacy depends on sustained expression of lineage-associated surface antigens. This review examines how antigen-directed pressure reshapes the biology of resistance, distinguishes canonical antigen escape from lineage plasticity, and clarifies the genomic contexts, diagnostic challenges, and therapeutic implications of these distinct escape routes. Under antigen-directed pressure, leukemia may escape through antigen downregulation, alternative splicing, acquired genetic alteration, or epitope disruption — mechanisms that generally preserve B-lineage identity and often remain addressable with alternative lineage-directed therapy. A biologically distinct route is lineage plasticity, in which cells destabilize lineage commitment or undergo overt lineage switch; clinical outcomes are poor, with a median overall survival of approximately 4.8 months in the largest reported series. Lineage switch is enriched within permissive genomic contexts, most notably KMT2A-rearranged leukemia, which accounted for the majority of B-ALL-to-acute myeloid leukemia or mixed-phenotype switches in a large international cohort. By contrast, CD19-negative antigen escape is more strongly associated with TP53 mutations and preserves B-lineage identity. Whether switching reflects selection of pre-existing subclones, active epigenetic reprogramming, or both remains unresolved. As antigen-directed therapies move into frontline use, distinguishing antigen escape from true lineage transformation is becoming essential for relapse surveillance, disease classification, therapeutic sequencing, and the design of strategies to prevent resistance.
Immunotherapeutic strategies for the treatment of lymphomas are rapidly expanding and can deliver durable remissions to patients with historically limited treatment options. Patient-reported outcomes (PROs) provide direct measurement of symptoms, functioning, and health-related quality of life (HRQoL), complementing physician-assessed toxicities and enabling a more comprehensive assessment of “treatment tolerability,” defined as the willingness of patients to adhere to treatment dose and schedule based on symptom burden and functioning. In this review, we demonstrate that when PROs are incorporated into clinical research, we gain a better understanding of treatment tolerability, particularly of novel immunotherapies, which confer distinct toxicity profiles compared with traditional chemoimmunotherapy. As survival improves, we argue that PROs should be incorporated as a primary or co-primary endpoint in most modern clinical trials, rather than as a point of interest in exploratory analyses. In patients with lymphoma, baseline and longitudinal HRQoL are prognostic of progression-free and overall survival. However, persistent discordance between clinician-graded adverse events (AEs) and patient-reported symptomatic AEs suggests that current trial endpoints focused primarily on safety and survival incompletely capture the patient experience, particularly in the context of novel immunotherapy-related toxicities. PROs are essential for interpreting modern lymphoma immunotherapies, where acute and chronic toxicities coexist with the promise of long-term remissions. Despite broad consensus of their utility, PRO analysis from seminal lymphoma immunotherapy trials remains inconsistent, and there remain significant gaps in the literature regarding the true patient-reported tolerability of emerging therapeutic regimens. Future trials should adopt harmonized PRO strategies (including symptom and functional domains), define meaningful thresholds for minimally important differences, and integrate real-world PRO data prospectively to better align clinical trial data with patient-centered treatment tolerability.
Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic/myeloproliferative neoplasm characterized by sustained monocytosis, recurrent gene mutations, and a risk of transformation to acute myeloid leukemia (AML). This review examines the historical evolution of CMML as a diagnostic entity, its genetic landscape, fundamental controversies in definition, including the contentious boundaries of oligomonocytic CMML (OM-CMML), and the spectrum of associated phenomena, such as plasmacytoid dendritic cell proliferations, systemic mastocytosis, extramedullary disease, and autoimmune manifestations. Since the publication of the most recent myeloid classification systems, genomic studies in large CMML cohorts have clarified that cases with borderline monocyte counts are biologically heterogeneous: a subset with bi-allelic TET2 inactivation or TET2 + SRSF2 co-mutation bears the greatest similarity to true CMML, while cases harboring SF3B1, bi-allelic TP53 inactivation (biTP53), or del(5q) may be better classified as myelodysplastic syndrome/neoplasm (MDS), irrespective of the presence of borderline monocytosis. Molecular evolution from clonal hematopoiesis through OM-CMML to overt CMML, and ultimately to acute myeloid leukemia (AML), follows a defined clonal trajectory characterized by the stepwise acquisition of spliceosome, epigenetic, and signaling mutations. Plasmacytoid dendritic cell proliferations, particularly blastic forms, arising in association with or following CMML, share clonal origin and represent a distinct spectrum of monocyte/plasmacytoid dendritic cell lineage dysregulation. In future classification systems, better biologic homogeneity of CMML may be achieved by incorporating specific molecular signatures in the diagnostic criteria and by excluding cases with biTP53 or AML-defining alterations. CMML is defined by its combination of proliferative (monocytic) and dysplastic features, but exhibits considerable genetic heterogeneity. Optimal diagnosis and distinction from related entities require integration of morphology, immunophenotype, and comprehensive genomic profiling.
Central nervous system (CNS) involvement in adult acute lymphoblastic leukemia (ALL) remains a critical determinant of treatment failure and long-term survival. This review provides a comprehensive, evidence-based framework for the diagnosis, risk stratification, prophylaxis, and treatment of CNS disease in adult ALL, with emphasis on the evolving challenges introduced by immunotherapy-based and chemotherapy-sparing regimens and presents our institutional approach to CNS-directed therapy. Modern CNS prophylaxis combining intrathecal chemotherapy with CNS-penetrating systemic agents has dramatically reduced CNS relapse rates, yet diagnostic and therapeutic limitations persist. The increasing use of immunotherapies, such as blinatumomab and inotuzumab ozogamicin, has improved systemic disease control, while CNS relapse is increasingly recognized in this context, particularly among heavily pretreated patients. This pattern likely reflects multiple factors, including limited CNS penetration, improved disease control that unmasks previously subclinical CNS involvement, and the high-risk biology of relapsed/refractory disease. In contrast, CD19-directed CAR T-cell therapies have demonstrated meaningful activity in CNS disease, while investigational strategies targeting leukemic trafficking pathways and IL-15 signaling offer additional preclinical promise. As adult ALL treatment has shifted toward chemotherapy-sparing regimens, new concerns have emerged regarding disease control within the CNS compartment. Durable remission will require integration of rigorous intrathecal prophylaxis, risk-adapted systemic therapy, and novel agents capable of penetrating the CNS microenvironment into every treatment algorithm.
BRAF alterations are uncommon in chronic lymphocytic leukemia (CLL), yet increasing use of broad genomic profiling has identified them as a recurrent component of MAPK-pathway dysregulation. This revised review summarizes the reported frequency, mutation spectrum, co-mutation patterns, treatment-era associations, and clinical implications of BRAF alterations in adult CLL, with explicit separation of chemoimmunotherapy-dominant cohorts from targeted-therapy-era cohorts. Across published studies, BRAF mutations are usually detected in approximately 2–6
Despite the success of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), resistance and disease progression remain significant challenges. In this review, we summarize current understanding of BCR::ABL1 dependent and independent mechanisms of resistance, including BCR::ABL1 mutations and additional genetic abnormalities. We also discuss the current and emerging therapeutic strategies aimed at overcoming treatment failure. Recent findings have highlighted the heterogeneity of resistance in CML, suggesting that distinct BCR::ABL1 mutations confer variable sensitivity to TKIs, including mutations affecting the myristoyl binding pocket. In parallel, the acquisition of additional genetic abnormalities such as ASXL1 and RUNX1 has been increasingly linked to disease progression and poor outcomes. Together, these findings have driven the development of novel therapeutic agents such as TERN-701, ELVN-001 and Olverembatinib, as well as growing interest in combination therapy such as asciminib plus ATP-binding site TKIs. Early studies indicate that these novel agents and combination approaches show promising activity against resistant CML. Resistance in CML can be BCR::ABL1 dependent or independent, emphasising the need for molecular profiling to guide treatment decisions. Continued development of mutation-specific therapies, and combination BCR::ABL1-targeted approaches may improve outcomes for patients who develop resistance or experience disease progression. This represents an important focus for future investigations.
To sumarize, provide an overview, and critically assess the currently available literature pertaining to the detection, management, and prognosis of DDX41 germline predisposition syndrome and related myeloid neoplasms. DDX41-germline predisposition syndrome is associated with an increased risk of cytopenias, myelodysplastic syndrome, and acute leukemia. Its association with other hematologic and solid malignancies is evolving. Prognosis needs to be further refined in the context of co-mutations and variant location, especially since conventional prognostic models are not accurate in predicting risk. Management strategies can range from active surveillance to allogeneic hematopoietic stem cell transplantation. DDX41 germline predisposition syndrome represent a distinct biological and clinical entity. Future research should focus on better understanding the patterns of disease progression and timing of therapeutic strategies to optimize clinical outcomes.
In inherited bone marrow failure syndromes (IBMFS), clonal hematopoiesis (CH) has been increasingly recognized as a molecular fingerprint of the underlying pathophysiology. A specific clonal profile has been reported in telomere biology disorders (TBDs), an IBMFS caused by pathogenic germline variants (PGV) in genes related to telomere maintenance and characterized by short/dysfunctional telomeres and increased risk of cancer. This review summarizes current data on specific somatic mutational profiles seen in TBDs and their associations with clinical features and cancer risk. Recent studies have reported a specific CH landscape in TBDs that is associated with patients’ age, genotype, and phenotype. CH often involves the affected germline gene, with reversion or compensation of the PGV, or mutations in PPM1D, TERT promoter, or POT1—none of which are associated with increased risk of cancer. In contrast, a distinct group of recurrent CH that modulates TP53 pathway has been associated with cancer development in TBDs. These differing patterns of CH in TBDs have important implications for patients’ diagnosis, risk stratification, and surveillance. Characterization of clonal profiles across TBDs cohorts has helped identify potential molecular markers that can aid in diagnosis and guide future adapted surveillance and early intervention strategies. Although opportunities exist to incorporate CH into clinical care of patients with TBDs, multicenter longitudinal studies are still needed for validation and to allow for wide-scale adoption of CH into clinical care protocols.
This review examines the rapidly evolving landscape of myeloproliferative hypereosinophilic syndromes (HES) and related neoplasms. We aim to synthesize current understanding of their diverse molecular drivers, evaluate the efficacy of established and novel targeted therapies, and identify critical research gaps. The goal is to provide a clinically relevant update on how molecular precision is reshaping the diagnosis and management of these rare, often aggressive hematologic malignancies beyond the established standard of imatinib. The field has moved beyond generic HES diagnoses to a molecularly defined classification. While imatinib remains the standard for PDGFRA/B-rearranged disease, resistance has spurred the development of next-generation inhibitors like avapritinib, which effectively targets the highly resistant PDGFRA D842V mutation. A major recent advance is the approval of pemigatinib for FGFR1-rearranged neoplasms, a historically chemo-refractory subgroup with a dismal prognosis. Clinical trials are also defining the roles of JAK inhibitors for JAK2-driven disease and exploring monoclonal antibodies like mepolizumab and benralizumab for symptom control in broader eosinophilic populations. The management of myeloproliferative HES has transitioned from empirical therapy to a precision medicine paradigm. Early comprehensive molecular profiling is essential to guide therapy selection. While imatinib remains a cornerstone for select patients, novel agents like pemigatinib and avapritinib have filled critical therapeutic gaps. Future progress depends on the routine integration of comprehensive next-generation sequencing, the validation of minimal residual disease monitoring to guide therapy de-escalation, and international collaboration to conduct innovative trials for these rare patient populations.
Myeloproliferative neoplasms (MPNs) lie at the intersection of malignancy and chronic inflammatory disease. This review summarizes current understanding of how inflammation drives MPN pathogenesis, from clonal initiation to progression and symptom burden, and explores how emerging therapies modulate the inflammatory microenvironment. Evidence from human genetics, epidemiology, and experimental models shows that chronic inflammatory stress promotes the expansion of JAK2- and other MPN-associated clones. Inflammatory cytokine networks sustain myeloproliferation, reshape the bone marrow niche, and contribute to fibrosis. JAK inhibitors remain the cornerstone of therapy and exert much of their clinical benefit through suppression of cytokine signaling. Newer agents also mitigate inflammation through complementary mechanisms. Inflammation is inseparable from MPN biology and represents both a driver and a therapeutic target. Reframing MPN as a disorder of maladaptive immune and stromal interactions highlights opportunities to restore balance within this ecosystem and potentially alter disease course.
Targeted therapies have revolutionized the treatment of chronic lymphocytic leukemia (CLL), however the disease remains incurable. This is largely due to somatic mutations in proteins targeted by these therapies, like Bruton’s tyrosine kinase (BTK) and B cell lymphoma-2 (Bcl-2), or transcriptional rewiring of CLL cells. Here we review recent findings regarding mechanisms of resistance to targeted agents in CLL. BTK inhibitor (BTKi) resistant CLL is potentiated by mutations disrupting covalent and non-covalent BTKi binding or those conferring loss of BTK’s kinase activity. Point mutations in Bcl-2 impact the efficacy of Bcl-2 inhibitor venetoclax, however cells employ a diverse variety of mechanisms to escape venetoclax-induced apoptosis. These mechanisms function through AKT and result in increased dependency on and stabilization of other antiapoptotic Bcl-2 family members as well as disruption of BAK/BAX pore formation. Recent work in CLL has pinpointed mechanisms hijacked by cells to abrogate treatment efficacy. Ongoing research efforts are focused on the advent of next-generation inhibitors and protein degraders to circumvent resistance. Such studies will prove invaluable in providing CLL patients with a diverse repertoire of therapeutic options following relapse.
Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy with a bimodal distribution of incidence in both pediatric/young adult and elderly patient populations. Despite the high complete remission rate, there is a high rate of relapse necessitating a need for therapy options in the relapsed/refractory setting. Given this, treatment paradigms for ALL have shifted towards targeted therapies and away from high-intensity chemotherapy. The efficacy of inotuzumab ozogamicin (InO) in the relapsed/refractory setting for pediatric and adult populations has led to incorporation of this targeted therapy into frontline regimens. In this review, the role of InO in the frontline, measurable residual disease (MRD) positive and relapsed/refractory settings is highlighted. InO is a directed antibody-drug conjugate that binds to CD22 on the surface of leukemic blasts. The cell internalizes InO, prompting enzymatic cleavage in the lysosome that releases calicheamicin, inducing double-strand DNA breaks and causing apoptosis. However, off-target effects can lead to severe adverse events such as hepatotoxicity, including veno-occlusive disease, and myelosuppression. Prior studies have supported its use in the relapsed or refractory treatment setting; however, newer studies incorporating InO in the frontline have shown promising results. Newer studies have also shown evidence of utilization of InO in specific sub-populations of B-cell ALL, including those with MRD-positive disease and Philadelphia-positive (Ph +) disease, and as bridging therapy with CAR T-cell therapy, and in the post-transplant maintenance setting. This review evaluated the effectiveness of InO in clinical practice, associated adverse events, future directions in specific patient populations. Despite recent advancements, patients with B-cell ALL tend to have poorer outcomes, especially in the adult population. Future research and larger scale prospective studies are indicated to evaluate the efficacy of InO in different lines of therapy.
Measurable residual disease (MRD) has emerged as the strongest prognostic biomarker in multiple myeloma (MM), providing a deeper assessment of treatment response than conventional serological tests. Sensitive MRD detection is helpful in risk stratification, prognostication, and early relapse prediction and is increasingly being used as an important clinical trial endpoint in MM. Moreover, MRD has emerged as a useful tool in guiding treatment intensity and duration. MRD can be assessed using bone marrow-based, peripheral blood-based, or imaging-based techniques. Bone marrow-based next-generation flow cytometry and next-generation sequencing, with a minimum sensitivity of 10− 5, remain the current standard for MRD testing in MM. However, limitations like the need for frequent bone marrow aspirations and false negative results in patchy marrow involvement or isolated extramedullary disease have accelerated the interest in peripheral blood-based MRD tools. Mass spectrometry-based approaches, including intact protein mass spectrometry (MALDI-TOF assays like ‘MASS-FIX’ and ‘EXENT’) and clonotypic peptide mass spectrometry (such as ‘EasyM’ and ‘M-Insight’), have evolved as highly sensitive peripheral blood-based MRD detection tools for relatively non-invasive dynamic MRD monitoring. Newer technologies like droplet digital PCR, circulating tumor cell analysis using enriched flow cytometry, cell-free DNA sequencing, and emerging epigenetic and fragmentomic profiling are in various phases of research and have the potential to revolutionize the way we monitor and treat MM. Finally, numerous active clinical trials worldwide are exploring the role of MRD in guiding treatment and are expected to shed light on the optimal approach to MRD assessments in routine clinical practice.
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis and potential progression to a blast phase. This review provides a comprehensive overview of the current molecular landscape of MF beyond canonical driver mutations (JAK2, MPL or CALR), emphasizing insights gained from murine models that served as valuable tools for understanding disease mechanisms. High-throughput next-generation sequencing (NGS) has markedly enhanced our understanding of the molecular basis of MF, identifying numerous mutations beyond the canonical driver genes JAK2, MPL, and CALR, which are present in about 80
The goal of this review is to provide an updated synthesis of therapeutic advances and remaining controversies in the management of Philadelphia chromosome–positive (Ph +) B-cell acute lymphoblastic leukemia (ALL). We sought to examine how modern tyrosine kinase inhibitors (TKIs), immunotherapies, and response-adapted strategies have reshaped treatment paradigms, including the role of allogeneic hematopoietic stem cell transplantation (allo-HCT), central nervous system (CNS) prophylaxis, and emerging chemotherapy-free approaches. Successive generations of TKIs have transformed Ph + ALL from a uniformly fatal leukemia into a highly treatable disease, with dasatinib or ponatinib-based and TKI–blinatumomab regimens achieving high rates of complete molecular remission. Achieving early measurable residual disease (MRD) negativity predicts long-term survival and identifies patients who may safely defer allo-HCT. Genomic profiling has uncovered prognostic subgroups, notably IKZF1^plus, T315I mutated, and multilineage disease, which remain resistant or challenging to current therapy. Novel agents, including asciminib and olverembatinib, are expanding options for resistant or relapsed disease, while CAR-T cell therapy and next-generation bispecific T-cell engagers are emerging as promising tools for refractory and post-TKI settings. Ph + ALL exemplifies the paradigm shift toward precision, MRD-directed, and chemotherapy-sparing treatment. Integrating potent TKIs with immunotherapy enables deep and durable remissions, potentially eliminating the need for upfront transplantation in selected patients. Future research should define molecular predictors of treatment-free remission, optimize CNS prophylaxis in targeted regimens, and establish standardized monitoring for safe TKI discontinuation.
Triple-negative (TN) myeloproliferative neoplasms (MPNs), defined by the absence of canonical driver JAK2, CALR and MPL mutations, represent a heterogeneous and still poorly understood subgroup of chronic myeloid neoplasms. This review summarizes current knowledge on characteristics and molecular landscape of TN MPNs. Although TN MPNs share clinical and morphological features with classic forms of primary myelofibrosis and essential thrombocythemia, their clinical behavior varies widely, from indolent in TN essential thrombocythemia to aggressive in TN myelofibrosis. Recent next-generation sequencing analyses have identified mutations affecting epigenetic regulation, RNA splicing, and various signaling pathways (e.g., TET2, ASXL1, SRSF2, EZH2, SETBP1), thereby underscoring the substantial biological complexity within these subgroups. This review provides an updated overview of the molecular landscape, clinicopathological features, and prognostic implications of TN MPNs, with a focus on the molecular mechanisms that have been uncovered through recent advances in diagnostic and genomic profiling techniques. Understanding the underlying disease mechanisms may lead to personalized treatments and better risk assessment for these patients.
Clonal hematopoiesis (CH) arises from the expansion of a single hematopoietic stem cell harboring somatic mutations that confer growth advantage. Recent studies highlight a substantial heritable component to CH, implicating germline mutations in DNA damage repair (DDR) genes. These genes are essential for maintaining genomic integrity and pathogenic variants in key DDR genes are well-established genetic underpinnings of several hereditary cancer syndromes. This review synthesizes current data linking germline DDR mutations – including ATM, CHEK2, TP53, PPM1D, BRCA1/2, and PARP1 – to CH and the development of myeloid malignancies. Emerging evidence suggests that germline perturbations in DDR pathway contribute to CH, though mechanisms remain incompletely defined. Large scale genome-wide association studies (GWAS) have identified strong associations between ATM and CHEK2 variants and CH. Assessing prevalence and CH risk in individuals with germline TP53 variants presents unique challenges, as distinguishing between somatic and constitutional lesions is often complex and requires careful tissue evaluation. The link between germline BRCA1/2 and CH remains inconclusive, confounded by concurrent diagnosis of solid malignancy and prior exposure to chemoradiation therapy in studied patient populations. Although germline mutations in PPM1D and PARP1 are rare, a potential germline predisposition to CH cannot be excluded. The totality of current evidence suggests that germline DDR pathway mutations not only predispose to well-established solid malignancy syndromes but also to CH, which independently increases the risk of hematologic malignancies. Recognizing germline contributions to CH has broad implications for risk assessment, surveillance strategies, and development of preventive strategies in myeloid neoplasia.
Despite increased recognition of FPDMM and advancements in genetic technologies that have improved carrier identification and our understanding of RUNX1 function, the mechanisms driving hematologic malignancy (HM) development in this disorder remain incompletely understood. Currently, there are no FPDMM-specific therapeutic strategies, and clinical management is largely confined to surveillance and supportive measures. This review aims to summarise emerging therapeutic strategies across all stages of disease progression, from early preventive interventions to treatments post-malignant transformation. Recent studies have explored multiple experimental strategies addressing distinct aspects of RUNX1-FPDMM pathobiology. These include CRISPR/Cas9-mediated correction of pathogenic germline RUNX1 variants, approaches that stabilize or enhance RUNX1 protein function by preventing its degradation or inhibition, and modulation of deregulated signaling pathways downstream of RUNX1 dysfunction. In addition, emerging therapies aim to target high-risk somatic variants that arise during disease progression. Interventions directed at hyperactivated inflammatory pathways, including JAK1/2 and mTOR, have also shown potential in mitigating the proinflammatory environment that contributes to hematologic malignancy development in FPDMM. Therapeutic approaches for FPDMM are multi-modal with approaches including; correcting pathogenic RUNX1 gene variants, enhancing RUNX1 protein stability and protection, and modulating signaling pathways disrupted by its dysfunction to normalise the underlying hematological disturbances. Although several agents are in clinical studies, all approaches are at an early stage and there remains much work to be done to translate treatments for clinical benefit.
