Current Hematologic Malignancy Reports最新文献

Purpose of review: 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.

Recent findings: 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.

Purpose of review: 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 findings: 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.

Purpose of review: Richter transformation (RT), the progression of chronic lymphocytic leukemia (CLL) to aggressive lymphomas, poses a significant therapeutic challenge with historically poor outcomes. Chemoimmunotherapy (CIT) regimens have demonstrated limited efficacy with short durations of response. This review aims to evaluate the evolving treatment landscape for RT, with a focus on recent advances in targeted therapies, immunotherapies, and cellular therapies that are redefining the current and future standards of care.

Recent findings: The treatment paradigm for RT is rapidly shifting away from cytotoxic chemotherapy. The combination of the B-cell lymphoma 2 inhibitor venetoclax with CIT has emerged as a new first-line benchmark with promising response rates and overall survival. Covalent Bruton tyrosine kinase (BTK) inhibitors had modest activity as monotherapy but showed improved responses when given with an immune checkpoint inhibitor. Pirtobrutinib has demonstrated responses even in heavily pretreated patients. Furthermore, advancement in immunotherapy has expanded treatment options for this patient population with bispecific T-cell engagers achieving high response rates and chimeric antigen receptor T-cell therapy providing deep, durable responses and favorable median overall survival in the relapsed/refractory (R/R) setting. The therapeutic landscape for RT has broadened with the introduction of targeted agents and immunotherapy. Venetoclax-based regimens represent a new standard for chemotherapy-eligible patients, allowing for a more effective bridge to potentially curative consolidation with transplantation. For R/R disease, novel BTK inhibitors, bispecific antibodies, and cellular therapies are demonstrating substantial efficacy. Ongoing trials investigating combinations of these agents are poised to further transform RT management.

Purpose of review: B-cell acute lymphoblastic leukemia (B-ALL) is a highly aggressive hematologic malignancy, with particularly poor outcomes in relapsed or refractory cases. Relapses remain a major challenge, often resulting in short remission durations and limited survival. This review summarizes emerging therapeutic strategies for B-ALL, focusing on novel immunotherapies and targeted approaches beyond the relapsed/refractory setting.

Recent findings: Transformative therapies such as chimeric antigen receptor (CAR) T-cell therapy, antibody-drug conjugates (ADCs), and bispecific antibodies have shown promising efficacy. Beyond the R/R setting, both blinatumomab and inotuzumab ozogamicin demonstrated high rates of eradication of measurable residual disease (MRD) up to 97% and 80%, respectively. Furthermore, the addition of blinatumomab following chemotherapy in the frontline setting in patients with patients with Philadelphia chromosome (Ph)-negative B-ALL who achieved negative MRD was showing to improve outcomes with a 3-year overall survival rate of 85% compared to 68% with chemotherapy alone. Tisagenlecleucel, brexucabtagene autoleucel, and obecabtagene autoleucel, are chimeric antigen receptor (CAR) T-cell therapies that improved survival compared to chemotherapy alone in patients with relapsed/refractory ALL. In newly diagnosed Ph-positive ALL, chemotherapy-free regimens combining blinatumomab with TKIs resulted in high rates of MRD negativity and improved survival. The combination of blinatumomab and ponatinib led to a 98% MRD negativity rates by next-generation sequencing and a 3-year overall survival of 91% without reliance on allogeneic stem cell transplantation. Novel immunotherapies and targeted agents offer new avenues to improve outcomes in B-ALL. Expanding the use of blinatumomab, inotuzumab ozogamicin, and CAR T-cell therapy across treatment phases, together with strategic sequencing, may help overcome relapsed/refractory disease. These approaches provide renewed hope for achieving durable remissions and extending survival in patients with B-ALL.

Purpose of review: Plasmacytoid dendritic cell-expansion in acute myeloid leukemia (pDC-AML) is an uncommon AML subset that differs from conventional AML and from blastic plasmacytoid dendritic cell neoplasm (BPDCN). This review synthesizes the clinicopathologic, immunophenotypic, cytogenetic, and molecular features of pDC-AML, highlights its outcomes, and discusses emerging therapeutic approaches, while underscoring the need for further studies to refine classification and guide therapy.

Recent findings: Published cohorts show that pDC-AML occurs mainly in older male adults, with CD123 and HLA-DR forming a consistent immunophenotypic backbone across both myeloblasts and pDCs. pDC-restricted markers (CD303, CD304, CD4, TCL1) are confined to the pDC compartment, whereas myeloblasts are enriched for CD34, CD117, and TdT. Cytogenetic findings are heterogeneous but often adverse, with recurrent - 7/del7q and trisomy 13. RUNX1 mutations and secondary-type co-mutations (ASXL1, DNMT3A, TET2, splicing factors) are frequent, while activating mutations such as FLT3 or NRAS are variably present. Outcomes are generally inferior compared with other AML subsets, though allogeneic transplantation can achieve durable remissions in a subset. Reports on venetoclax-based therapy show mixed outcomes, while CD123-directed therapies are being explored. pDC-AML is emerging as a potentially higher-risk AML phenotype, with clinicopathologic and biologic features distinct from BPDCN. Early recognition, dual-compartment minimal residual disease assessment, timely transplant consideration, and referral for clinical trials are central to management. Standardized immunophenotypic criteria, integrated genomic profiling, and prospective evaluation of CD123-targeted and rational combination therapies are priorities to improve classification, risk stratification, and patient outcomes.

Purpose of review: Given the high risk of relapse for Philadelphia-negative (Ph-negative) B-cell acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (allo-HCT) is often recommended following first complete remission (CR1) in high-risk patients. However, in the era of measurable residual disease (MRD) testing, allo-HCT may not be indicated for patients with standard-risk disease. Here we review the use of allo-HCT and other consolidative approaches for standard- and high-risk Ph-negative ALL, based on MRD following induction therapy.

Recent findings: Allo-HCT is strongly indicated for patients with high-risk Ph-negative ALL, especially those who are MRD positive at end of induction. Ongoing trials using cellular and immune therapies such as blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapies have shown promising results in deepening response and decreasing relapse. Further, these agents have demonstrated overall manageable safety profiles. The role for allo-HCT following CR1 in patients with standard risk Ph-negative ALL is evolving with advances in therapeutic approaches. MRD is emerging as a critical prognostic factor regardless of treatment strategy, thus questioning the necessity of transplant in MRD-negative patients. With the advances in safety and accessibility of allo-HCT as well as novel therapeutics, overall outcomes in ALL continue to improve.

Purpose of review: Advances in modern molecular and genomic testing have spurred tremendous progress in our understanding of MDS pathogenesis. Here we review common diagnostic methods, the evolving multi-omics landscape of MDS, molecular subtypes, and targeted therapies.

Recent findings: MDS is a heterogeneous disease defined by a wide array of chromosomal abnormalities and > 40 common somatic mutations affecting RNA splicing complex, chromatin modification, DNA methylation, lineage specific transcription, DNA damage, RAS/MAPK signaling, and cohesin complex pathways. This has shaped current WHO/ICC classification criteria with the inclusion of 3 genetically defined subgroups: del(5q), SF3B1, and TP53-mutated. IDH1/2-mutated MDS is a new, emerging subgroup, for which multiple clinical trials are underway. Several recent targeted drug approvals including luspatercept and imetelstat have greatly expanded the treatment arsenal for lower-risk MDS. Standard of care therapy options for high-risk MDS, in particular TP53-mutated, remain limited beyond HMAs and transplant and are an active area of investigation.

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.