Current Hematologic Malignancy Reports最新文献

Purpose of review: The management of myelofibrosis is risk-adapted when considering transplant eligibility and symptom-directed, prioritizing the most burdensome symptoms for the patient. Unfortunately, myelofibrosis-anemia is common, multifactorial in its origin, and impactful regarding prognosis. While clinical trials are advised, not all patients have convenient access, and therefore, hematologists should be aware of the data supporting the use of conventional agents such as erythropoietin-stimulating agents, steroid treatments (danazol and prednisone), and immunomodulatory drugs (thalidomide and lenalidomide). This review summarizes the conventional approach to treating myelofibrosis-anemia and highlights recent data from 3 novel agents that are under phase 3 evaluation.

Recent findings: Momelotonib is a JAK1/2 and ACVR1 inhibitor that has demonstrated not only improvements in splenomegaly and symptoms, but also amelioration of anemia on the SIMPLIFY 1 and 2 clinical trial program. This may occur through suppression of hepcidin production. Luspatercept promotes late-stage hematopoiesis, and the phase 2 study has shown promise in ameliorating anemia as a monotherapy, and especially in combination with ruxolitinib. Finally, CP-0160, a BET inhibitor, has shown efficacy as an anemia-directed agent, when used as monotherapy and in combination. This agent reduces cytokine production and promotes erythroid differentiation. Results have been presented for patients previously treated with JAK inhibitors, as well as those who were naïve to JAK inhibitor therapy. Safety and effectiveness are reviewed for both conventional and selected novel agents used in the treatment of MF-anemia. A practical approach to treatment is presented, and data from ASH 2020 are presented.

Purpose of review: Coronavirus disease 2019 (COVID-19) is associated with a high rate of respiratory failure, thromboembolism, bleeding, and death. Patients with myeloproliferative neoplasms (MPNs) are prone to both thrombosis and bleeding, calling for special care during COVID-19. We reviewed the clinical features of MPN patients with COVID-19, suggesting guidance for treatment.

Recent findings: One study by the European LeukemiaNet collected 175 MPN patients with COVID-19 during the first wave of the pandemic, from February to May 2020. Patients with primary myelofibrosis (PMF) were at higher risk of mortality (48%) in comparison with essential thrombocythemia (ET) (25%) and polycythemia vera (19%); the risk of death was higher in those patients who abruptly discontinued ruxolitinib. In patients followed at home, in regular wards, or in ICU, the thrombosis rate was 1.0%, 2.8%, and 18.4%, respectively. Independent risk factors for thrombosis were ET phenotype, transfer to ICU, and neutrophil/lymphocyte ratio; major bleeding occurred in 4.3% of patients, particularly those with PMF. MPN patients with non-severe COVID-19 treated at home should continue their primary or secondary antithrombotic prophylaxis with aspirin or oral anticoagulants. In the case of hospitalization, patients assuming aspirin should add low molecular weight heparin (LMWH) at standard doses. In contrast, LMWH at intermediate/therapeutic doses should replace oral anticoagulants prescribed for atrial fibrillation or previous venous thromboembolism. Intermediate/high doses of LMWH can also be considered in ICU patients with ET, particularly in the case of a rapid decline in the number of platelets and progressive respiratory failure.

Purpose of review: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by uncontrolled proliferation of mature and maturing granulocytes. The disease is characterized by the presence of translocation t(9;22) leading to the abnormal BCR-ABL fusion. Historically, treatment options included hydroxyurea, busulfan, and interferon-α (IFN-α), with allogeneic stem cell transplant being the only potential curative therapy. More recently, the development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of CML and turned a once fatal disease into a chronic and manageable disorder. This review aims to discuss the frontline treatment options in chronic-phase CML, provide recommendations for tailoring frontline treatment to the patient, and explore emerging therapies in the field.

Recent findings: The first-generation TKI, imatinib, was FDA approved in 2001 for use in CML. Following the approval and success of imatinib, second- and third-generation TKIs have been developed providing deeper responses, faster responses, and different toxicity profiles. With numerous options available in the frontline setting, choosing the best initial treatment for each individual patient has become a more complex decision. When choosing a frontline therapy for patients with chronic-phase CML, one should consider disease risk, comorbid conditions, and the goal of therapy.

Purpose of review: Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a significant number of patients still progress on current available therapies. Here, we review treatment modalities used to target BCMA in the treatment of MM, specifically antibody-drug conjugates (ADC), bispecific antibody constructs, and chimeric antibody receptor (CAR) modified T-cell therapies. We will provide an overview of therapies from these classes that have presented or published clinical data, as well as data on mechanisms of resistance to these novel agents.

Recent findings: Clinical trials exploring different BCMA-targeting modalities to treat multiple myeloma are underway and demonstrate promising results. In relapsed/refractory multiple myeloma, anti-BCMA ADCs and bispecific antibody constructs are showing impressive efficacy with manageable side effect profiles. In parallel, adoptive cellular therapy has induced dramatic durable responses in multiply relapsed and refractory myeloma patients. Therapeutic approaches targeting BCMA hold significant potential in the management of multiple myeloma and will soon be incorporated in combination with current standard therapies to improve outcomes for patients with multiple myeloma. In addition, novel approaches are being evaluated to overcome resistance mechanisms to anti-BCMA therapies.

Purpose of review: Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with CML. Our goal in this paper is to review the current data on TFR, and discuss future directions.

Recent findings: Multiple studies have demonstrated that attempting a treatment-free remission is safe and effective in a select group of patients. More recent data suggested that undetectable BCR-ABL1 by digital PCR prior to discontinuation is highly predictive of successful TFR. However, some patients have a successful TFR with no evidence of clinical disease despite persistent detectable BCR-ABL1. Some recent studies have shed some more light on possible mechanisms for this phenomena. Some possible mechanisms include immune mechanism, BCR-ABL1 detected in the lymphoid component only, or stem cell exhaustion. TFR should be discussed with patients with CML. Patients who achieve a sustained deep molecular response may be eligible to attempt TFR, however, setting expectations that overall only 20% of patients with newly diagnosed CML will achieve a successful TFR. The importance of compliance to treatment early on cannot be overemphasized. Further studies using other drugs to get patients to a deeper remission in order to be eligible for TFR attempt, or attempting a second TFR in patients who had disease recurrence after first TFR attempt, are currently underway.

Purpose of review: Despite recent advances in the treatment of de novo acute myeloid leukemia (AML), AML arising from antecedent chronic myelomonocytic leukemia (CMML) continues to have dismal outcomes. While the unique biological drivers of CMML and subsequent leukemic transformation (LT) have been revealed with advances in molecular characterization, this has not yet translated to the bedside. Here, we review these biologic drivers, outcomes with current therapies, and rationale avenues of future investigation specifically in blast phase CMML (CMML-BP).

Recent findings: CMML-BP outcomes are studied as an aggregate with more common categories of AML with myelodysplasia-related changes (AML-MRCs) or the even broader category of secondary AML (sAML), which illustrates the crux of the problem. While a modest survival advantage with allogeneic hematopoietic stem cell transplant exists, the difficulty is bridging patients to transplant and managing patients that require an allograft-sparing approach. Limited data suggest that short-lived remissions can be obtained employing CPX-351 or venetoclax-based lower intensity combination therapy. Promising future strategies include repurposing cladribine, exploiting the supportive role of dendritic cell subsets with anti-CD123 therapies, MCL-1 inhibition, dual MEK/PLK1 inhibition, FLT3 inhibition in RAS-mutated and CBL-mutated subsets, and immune therapies targeting novel immune checkpoint molecules such as the leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune-modulatory transmembrane protein restrictively expressed on monocytic cells. The successful management of an entity as unique as CMML-BP will require a cooperative, concerted effort to design and conduct clinical trials dedicated to this rare form of sAML.

Purpose of review: The treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed over the last few years with the introduction of novel targeted agents. Physicians are now faced with several equally effective therapy options when treating patients with CLL. Here, we review the role of Bruton tyrosine kinase (BTK) inhibitors in treating patients with treatment-naïve and relapsed or refractory CLL. We review recent approvals of BTK inhibitors as well as reported and ongoing clinical trial data.

Recent findings: The approval of ibrutinib rapidly led to a paradigm shift in the management of CLL. Randomized trials have now compared ibrutinib to several chemoimmunotherapy approaches, which were in favor of ibrutinib. Second-generation more selective BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed, and recent data have led to the approval of acalabrutinib in CLL. Ongoing and future studies focus on either combining BTK inhibitors with other novel agents (e.g., venetoclax, obinutuzumab, or ublituximab) or developing next-generation non-covalent reversible BTK inhibitors that may be effective in treating patients with CLL harboring BTK-resistant mutations. The field of CLL continues to evolve rapidly with new and evolving combination treatments and novel BTK agents, which will continue to change the standard of care for CLL.

Purpose of review: Recent efforts to characterize hematologic cancers with genetic and molecular detail have largely relied on mutational profiling via next-generation sequencing (NGS). The application of NGS-guided disease prognostication and clinical decision making requires a basic understanding of sequencing advantages, pitfalls, and areas where clinical care might be enhanced by the knowledge generated. This article identifies avenues within the landscape of adult acute lymphoblastic leukemia (ALL) where mutational data hold the opportunity to enhance understanding of disease biology and patient care.

Recent findings: NGS-based assessment of measurable residual disease (MRD) after ALL treatment allows for a sensitive and specific molecular survey that is at least comparable, if not superior, to existing techniques. Mutational assessment by NGS has unraveled complex signaling networks that drive pathogenesis of T-cell ALL. Sequencing of patients with familial clustering of ALL has also identified novel germline mutations whose inheritance predisposes to disease development in successive generations. While NGS-based assessment of hematopoietic malignancies often provides actionable information to clinicians, patients with acute lymphoblastic leukemia are left underserved due to a lack of disease classification and prognostication schema that integrate molecular data. Ongoing research is positioned to enrich the molecular toolbox available to clinicians caring for adult ALL patients and deliver new insights to guide therapeutic selection, monitor clinical response, and detect relapse.

Purpose of review: The chimeric antigen receptor (CAR) T-cell therapy is currently changing the landscape of hematologic malignancies with multiple FDA-approved cell therapy products in the USA. The current administration process of the CAR T-cell therapy is complicated, labor-intensive, and expensive.

Recent findings: The chimeric antigen receptor (CAR) T-cell therapy is currently changing the landscape of hematologic malignancies with multiple FDA-approved cell therapy products in the USA. The current administration process of the CAR T-cell therapy is complicated, labor-intensive, and expensive. This review article addresses the present-day challenges and discusses opportunities to optimize the access and affordability of the CAR T-cell therapy. The field of cellular immunotherapy is going to change the future of solid tumors and non-oncological diseases. However, this promising therapy poses challenges in the administration and management of quality in the current field of healthcare. We describe various novel approaches to manage challenges in improving access and improving widescale implementation of cellular therapies.

Purpose of review: For decades, the management of chronic myelomonocytic leukemia (CMML) or juvenile myelomonocytic leukemia (JMML) has been largely inextricable from myelodysplastic syndromes (MDS), myeloproliferative neoplasms, and acute myeloid leukemia. Hallmarks of these diseases have been the emergence of unique genomic signatures and discouraging responses to available therapies. Here, we will critically examine the current options for management and review the rapidly developing opportunities based on advances in CMML and JMML disease biology.

Recent findings: Few clinical trials have exclusively been done in CMML, and in JMML, the rarity of the disease limits wide scale participation. Recent case series in JMML suggest that hypomethylating agents (HMAs) are a viable option for bridging to curative intent with allogeneic hematopoietic stem cell transplant or as posttransplant maintenance. Emerging evidence has demonstrated targeting the RAS-pathway via MEK inhibition may also be considered. In CMML, treatment with HMAs is largely derived from data inclusive of MDS patients, including a small number of patients with dysplastic CMML variants. Based on CMML disease biology, additional therapeutic targets being investigated include inhibitors of splicing, CD123/dendritic cell axis, inherent GM-CSF progenitor cell hypersensitivity, and targeting the JAK/STAT pathway. Current evidence is also expanding for oral HMAs. The management of CMML and JMML is rapidly evolving and clinicians must be aware of the genetic landscape and expanding treatment options to ensure these rare populations are afforded therapeutic interventions best suited to their needs.