Current Hematologic Malignancy Reports最新文献

Purpose of review: JAK inhibition is an effective means of controlling symptom burden and improving splenomegaly in patients with myeloproliferative neoplasms (MPNs). However, a majority of patients treated with JAK inhibition will have disease progression with long-term use. In In this review, we focus on the investigation of novel targeted agents beyond JAK inhibitors both in the chronic phase of disease and in the accelerated/blast phase of disease.

Recent findings: Relevant targeted therapies in MPNs include BET inhibitors, BCL inhibitors, LSD1 inhibitors, PI3K inhibitors, IDH inhibitors, telomerase inhibitors, and MDM2 inhibitor. Agents within these classes have been investigated either as monotherapy or in combination with a JAK inhibitor. We summarize the prospective data for these agents along with detailing the ongoing phase III trials incorporating these agents. While JAK inhibition has been a mainstay of therapy in MPNs, a majority of patients will have disease of progression. JAK inhibitors also have limited anti-clonal effect and do not impact the rate of progression to the blast phase of disease. The novel therapies detailed in this review not only show promise in ameliorating the symptom burden of MPNs but may be able to alter the natural history of disease.

Purpose of review: With improvement in survival after hematopoietic cell transplantation (HCT), it has become important to focus on the late complications experienced by the survivors that may lead to late mortality and morbidity to be able to provide patient-centered care across the transplant continuum. The goals of this article are to describe the status of literature on late complications in HCT survivors; offer a brief overview of the status of the screening, prevention, and management of these complications; and identify opportunities for future practice and research.

Recent findings: This is an exciting time for the field with increasing awareness about survivorship issues. Studies are moving beyond description to examining pathogenesis of these late complications and identifying biomarkers. The eventual goal is to promote changes in our transplant techniques to decrease the incidence of these complications as well as help develop interventions targeting these late effects. There is also an emphasis on improving health care delivery models to provide optimal post-HCT management for medical and psychosocial complications through close coordination between multiple stakeholders and leveraging technology to help address the barriers in delivery of care to fulfill the unmet needs in this area. The increasing population of HCT survivors with their burden of late effects underscores the need for concerted efforts to improve long-term medical and psychosocial outcomes for this group.

Purpose of review: Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH + ALL, fewer advancements have been for older adults with PH-negative B-cell ALL. Treatment of this population is mired by higher incidence of poor risk biologic features, increased incidence of medical comorbidities, and higher rates of treatment-related mortality (TRM). Here, we review the difficulties in managing elderly patients with PH-negative ALL.

Recent findings: The development of novel agents has brought additional tools to the armamentarium of drugs and has changed the landscape of treatment. More recent clinical trials and future clinical trials focus on blinatumomab, inotuzomab ozogamicin (IO), and/or chimeric antigen receptor T-cell (CAR-T) either alone or integrated with dose-reduced chemotherapy regimens. The introduction of novel agents/therapies and incorporation into our current treatment paradigms may finally offer an avenue to improve the dismal outcomes seen in this population.

Purpose of review: Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME).

Recent findings: There is increasing evidence challenging the model of T_CM:mycosis fungoides (MF) and T_EM:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway. Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.

Purpose of review: Tyrosine kinase inhibitors (TKIs) are very successful for the treatment of chronic myeloid leukaemia (CML) but are not curative in most patients due to persistence of TKI-resistant leukaemia stem cells (LSCs). The bone marrow immune microenvironment (BME) provides protection to the LSC through multidimensional interactions, driving therapy resistance, and highlighting the need to circumvent these protective niches therapeutically. This review updates the evidence for interactions between CML cells and the immune microenvironment with a view to identifying targetable therapeutic vulnerabilities and describes what is known about the role of immune regulation in treatment-free remission (TFR).

Recent findings: Intracellular signalling downstream of the chemotactic CXCL12-CXCR4 axis, responsible for disrupted homing in CML, has been elucidated in LSCs, highlighting novel therapeutic opportunities. In addition, LSCs expressing CXCL12-cleaving surface protein CD26 were highly correlated with CML burden, building on existing evidence. Newer findings implicate the adhesion molecule CD44 in TKI resistance, while JAK/STAT-mediated resistance to TKIs may occur downstream of extrinsic signalling in the BME. Exosomal BME-LSC cross-communication has also been explored. Finally, further detail on the phenotypes of natural killer (NK) cells putatively involved in maintaining successful TFR has been published, and NK-based immunotherapies are discussed. Recent studies highlight and build on our understanding of the BME in CML persistence and TKI resistance, pinpointing therapeutically vulnerable interactions. Repurposing existing drugs and/or the development of novel inhibitors targeting these relationships may help to overcome these issues in TKI-resistant CML and be used as adjuvant therapy for sustained TFR.

Purpose of review: Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy.

Recent findings: Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.

Purpose of review: The goal of this review is to summarize what is known about pregnancy in women with chronic myeloid leukemia (CML): there are very few guidelines regarding how to treat women who are pregnant at the time of CML diagnosis, and similarly, few guidelines regarding family planning for women already on tyrosine kinase inhibitor therapy who might want to start family planning.

Recent findings: Most patients with CML achieve excellent control with first line tyrosine kinase inhibitor therapy that includes either imatinib, dasatinib, nilotinib, or bosutinib. For men, tyrosine kinase inhibitor (TKI) therapy does not affect sperm number or function, and female partners of men on therapy who become pregnant do not have an increased risk of miscarriage or babies with fetal malformation. However, for women, all TKIs are teratogenic and should be avoided at least in the first trimester of pregnancy. However, a small study suggests that women who have achieved a stable deep response therapy can safely stop therapy prior to a planned pregnancy and may not need any intervention during the pregnancy. Another small study suggests that nilotinib and imatinib have the lowest rate of transfer across the placenta. Providing well-documented guidelines for women with CML is challenging as TKI therapy is teratogenic. However, valuable information can be gained from small series of patients as summarized here.

Purpose of review: The study aims to evaluate the impact of COVID-19 on the delivery of health care and services to patients with chronic myeloid leukemia in low- and middle-income countries (LMICs) accessing treatment through The Max Foundation.

Recent findings: An online survey was developed and sent via email to 527 partner physicians who had active patients under their care in July 2020, asking about the disruption of health services with multiple-choice answers or a five-point ordinal scale. Data from The Max Foundation's Patient Access Tracking System (PATS®) was analyzed to evaluate program performance in 2020 compared with 2019. PATS® is used to track key patient information and supply chain data to ensure robust reporting, quality assurance, and safety. Among the 111 physicians who responded (20% response rate), 48% reported that someone on their team had contracted COVID-19. A total of 95 (85%) physicians reported at least some disruption of services to patients due to COVID-19, with 29 (26%) reporting frequent or complete disruption. Almost all physicians in the South Asia and Asia Pacific regions reported disruption (96% and 95%, respectively), compared with three quarters of physicians in Latin America. Institutions overcame challenges using a variety of solutions including telemedicine (60%), electronic prescriptions (45%), home delivery via courier services (31%), government workers (9%), and dispensation coordination with regional hospitals (14%). The COVID-19 pandemic has disrupted services for CML physicians and patients worldwide. Overall, these disruptions did not appear to significantly affect The Max Foundation's ability to provide patients with access to treatment, as novel approaches in telemedicine, supply chain, and dispensing, as well as provision of guidance and support for physicians were utilized to overcame disruption of services.

Purpose of review: We review how understanding the fitness and comorbidity burden of patients, and molecular landscape of underlying acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) at the time of diagnosis is now integral to treatment.

Recent findings: The upfront identification of patients' fitness and molecular profile facilitates selection of targeted and novel agents, enables risk stratification, allows consideration of allogeneic hematopoietic cell transplantation in high-risk patients, and provides treatment selection for older (age ≥ 75) or otherwise unfit patients who may not tolerate conventional treatment. The use of measurable residual disease (MRD) assessment improves outcome prediction and can also guide therapeutic strategies such as chemotherapy maintenance and transplant. In recent years, several novel drugs have received FDA approval for treating patients with AML with or without specific mutations. A doublet and triplet combination of molecular targeted and other novel treatments have resulted in high response rates in early trials. Following the initial success in AML, novel drugs are undergoing clinical trials in MDS. Unprecedented advances have been made in precision medicine approaches in AML and MDS. However, lack of durable responses and long-term disease control in many patients still present significant challenges, which can only be met, to some extent, with innovative combination strategies throughout the course of treatment from induction to consolidation and maintenance.

Purpose of review: Recent advances have been made in circulating tumor DNA (ctDNA), the method to minimally invasive detect lymphoma sensitively with tumor-derived DNA in the blood of patients with lymphomas. This article discusses these various methods of ctDNA detection and the clinical context in which they have been applied to for a variety of lymphoma subtypes.

Recent findings: ctDNA has been applied to a variety of subtypes of lymphoma and has been used in the context of genotyping somatic mutations and classification of disease, monitoring of response during treatment, detecting minimal residual disease even with radiographic remission, and predicting relapse and long-term survival outcomes. There are a variety of techniques used to measure ctDNA including digital polymerase chain reaction and next-generation sequencing techniques including high-throughput variable-diversity-joining rearrangement sequencing, high-throughput sequencing of somatic mutations, and Cancer Personalized Profiling by deep sequencing. While the greatest data has been generated in diffuse large B cell lymphoma, there have been studies utilizing application of ctDNA in follicular lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, peripheral T cell lymphoma, and primary CNS lymphoma among others. ctDNA is an emerging biomarker in lymphoma that can minimally invasively provide further genotypic information, diagnostic clarification, and treatment prognostication by detection of minimal residual disease even without radiographic evidence of disease. Future studies are needed to standardize the use of ctDNA and translate its use clinically for the management of lymphoma patients.