Current Hematologic Malignancy Reports最新文献

Purpose of review: The development of potent novel agents has improved outcomes for patients with multiple myeloma (MM). Heterogeneity of response to therapy, an expanding arsenal of treatment options, and cost are however major challenges for physicians making treatment decisions. Response-adapted therapy is hence an attractive strategy for sequencing of therapy in MM. Despite its successful application in other haematologic malignancies, response-adapted therapy is yet to become a standard of care for MM. We provide our perspective on response-adapted therapeutic strategies evaluated thus far and how they may be implemented and improved on in treatment algorithms of the future.

Recent findings: While older studies suggested that early response based on International Myeloma Working Group response criteria could impact long-term outcomes, recent data have contradicted these findings. The advent of minimal residual disease (MRD) as a powerful prognostic factor in MM has raised the promise of MRD-adapted treatment strategies. The development of more sensitive techniques for paraprotein quantification as well as imaging modalities to detect extramedullary disease is likely to change response assessment in MM. These techniques combined with MRD assessment may provide sensitive and holistic response assessments which could be evaluated in clinical trials. Response-adapted treatment algorithms have the potential to allow an individualised treatment strategy, maximising efficacy, while minimising toxicities and cost. Standardisation of MRD methodology, incorporation of imaging into response assessment, and the optimal management of MRD positive patients are key questions to be addressed in future trials.

Purpose of review: Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML.

Recent findings: Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Purpose of review: There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.

Recent findings: Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

Purpose of review: CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic and familial AML.

Recent findings: Due to the recent advances in molecular testing and the prognostic role of CEBPA mutation in AML, the definition for AML with CEBPA mutation (AML-CEBPA) has significantly changed. This review provides the rationale for the updates on classifications, and the impacts on laboratory evaluation and clinical management for sporadic and familial AML-CEBPA patients. In addition, minimal residual disease assessment post therapy to stratify disease risk and stem cell transplant in selected AML-CEBPA patients are discussed. Taken together, the recent progresses have shifted the definition, identification, and management of patients with AML-CEBPA.

Purpose of review: The treatment landscape of multiple myeloma (MM) has evolved resulting in MM becoming a chronic condition. The costs of MM therapies are substantial and compound as patients remain on long-term maintenance therapies and progress through multiple lines of high-cost therapies. MM predominantly impacts the elderly population insured by Medicare; here, we analyze how these costs impact patients and the Medicare trust fund.

Recent findings: With the recent passing of the Inflation Reduction Act (IRA), we postulate how costs may be impacted and debate future policy initiatives that may result in sustainability. The IRA will impact drug pricing and likely reduce the costs of some treatments used in MM; there is still a lot of room for policy reform to reduce financial toxicity to patients and prevent depletion of the Medicare trust fund.

Purpose of review: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF.

Recent findings: BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Purpose of review: This review focuses on vascular complications associated with chronic myeloproliferative neoplasms (MPN) and more specifically aims to discuss the clinical and biological evidence supporting the existence of a link between clonal hematopoiesis, cardiovascular events (CVE), and solid cancer (SC).

Recent findings: The MPN natural history is driven by uncontrolled clonal myeloproliferation sustained by acquired somatic mutations in driver (JAK2, CALR, and MPL) and non-driver genes, involving epigenetic (e.g., TET2, DNMT3A) regulators, chromatin regulator genes (e.g., ASXL1, EZH2), and splicing machinery genes (e.g., SF3B1). The genomic alterations and additional thrombosis acquired risk factors are determinants for CVE. There is evidence that clonal hematopoiesis can elicit a chronic and systemic inflammation status that acts as driving force for the development of thrombosis, MPN evolution, and second cancer (SC). This notion may explain the mechanism that links arterial thrombosis in MPN patients and subsequent solid tumors. In the last decade, clonal hematopoiesis of indeterminate potential (CHIP) has been detected in the general population particularly in the elderly and initially found in myocardial infarction and stroke, rising the hypothesis that the inflammatory status CHIP-associated could confer predisposition to both cardiovascular diseases and cancer. In summary, clonal hematopoiesis in MPN and CHIP confer a predisposition to cardiovascular events and cancer through chronic and systemic inflammation. This acquisition could open new avenues for antithrombotic therapy both in MPNs and in general population by targeting both clonal hematopoiesis and inflammation.

Purpose of review: Long-term outcomes have significantly improved with treatment of chronic myeloid leukemia. With proper treatment, most patients will achieve similar survival rates compared to an age-matched population. Treatment-free remission is not attainable for over half of patients and chronic treatment carries with it unique challenges. We provide a pragmatic approach to the monitoring and management of chronic adverse effects (AEs).

Recent findings: In the presence of severe or intolerable AEs, switching tyrosine kinase inhibitors (TKIs) is reasonable but is not without risk. Dose reductions can be attempted when response is stable to reduce AE intensity. More frequent molecular monitoring with any change is essential. Treatment strategies must adapt to the personalized treatment goal of each patient. Long-term survival remains good even when response is less than a complete molecular response. Consider risks of new AEs when changing therapy and evaluate for dose reductions when appropriate.

Purpose of review: GATA2 deficiency is a haploinsufficiency syndrome associated with a wide spectrum of disease, including severe monocytopenia and B and NK lymphopenia, predisposition to myeloid malignancies, human papillomavirus infections, and infections with opportunistic organisms, particularly nontuberculous mycobacteria, herpes virus, and certain fungi. GATA2 mutations have variable penetrance and expressivity with imperfect genotype-phenotype correlations. However, approximately 75% of patients will develop a myeloid neoplasm at some point. Allogeneic hematopoietic cell transplantation (HCT) is the only currently available curative therapy. Here, we review the clinical manifestations of GATA2 deficiency, characterization of the hematologic abnormalities and progression to myeloid malignancy, and current HCT practices and outcomes.

Recent findings: Cytogenetic abnormalities are common with high rates of trisomy 8, monosomy 7, and unbalanced translocation der(1;7) and may suggest an underlying GATA2 deficiency in patients presenting with myelodysplastic syndrome (MDS). Mutations in ASXL1 and STAG2 are the most frequently encountered somatic mutations and are associated with lower survival probability. A recent report of 59 patients with GATA2 deficiency who underwent allogenic HCT with myeloablative, busulfan-based conditioning and post-transplant cyclophosphamide reported excellent overall and event-free survival of 85% and 82% with reversal of disease phenotype and low rates of graft versus host disease. Allogeneic HCT with myeloablative conditioning results in disease correction and should be considered for patients with a history of recurrent, disfiguring and/or severe infections, organ dysfunction, MDS with cytogenetic abnormalities, high-risk somatic mutations or transfusion dependence, or myeloid progression. Improved genotype/phenotype correlations are needed to allow for greater predictive capabilities.

Purpose of review: To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS).

Recent findings: Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy. Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.