Current Hematologic Malignancy Reports最新文献

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.

Purpose of review: Hematologic malignancies were previously thought to be primarily sporadic cancers without germline predispositions. However, over the last two decades, with the widespread use of next generation sequencing (NGS), there have been several genes have been identified that carry a risk of inheriting hematologic malignancies. Identification of individuals with hereditary hematologic malignancies (HHM) involves a high index of suspicion and careful attention to family history, clinical features, and variant allele frequency on somatic NGS panels.

Recent findings: Over the last several years, many genetic predisposition syndromes have been recognized to have unique features with both hematologic and non-hematologic co-morbidities. Multidisciplinary evaluation, including genetic counseling, is critical to optimizing diagnostic testing of individuals and at-risk family members. Prompt recognition of affected patients is imperative not only for personalized surveillance strategies but also for proper donor selection for those undergoing stem cell transplantation to avoid familial donors who also may share the same germline mutation. Herein, we describe our approach to recognizing patients suspected to carry a germline predisposition to hematologic malignancies and evaluation within a hereditary hematologic malignancies clinic (HHMC).

Purpose of review: Myeloproliferative neoplasms (MPNs) are chronic hematological malignancies characterized by increased proliferation of MPN stem and myeloid progenitor cells with or without bone marrow fibrosis that typically lead to increased peripheral blood cell counts. The genetic and cytogenetic alterations that initiate and drive the development of MPNs have largely been defined, and we summarize these here.

Recent findings: In recent years, advances in understanding the pathogenesis of MPNs have defined a long-preclinical phase in JAK2-mutant MPN, identified genetic loci associated with MPN predisposition and uncovered mechanistic insights in CALR-mutant MPN. The integration of molecular genetics into prognostic risk models is well-established in myelofibrosis and ongoing studies are interrogating the prognostic implications of concomitant mutations in ET and PV. Despite all these advances, the field is deficient in clonally selective therapies to effectively target the MPN clone at any stage of disease, from pre-clinical to advanced. Although the biological understanding of the pathogenesis of MPNs has progressed quickly, substantial knowledge gaps remain, including in the molecular mechanisms underlying MPN progression and myelofibrotic transformation. An ongoing goal for the MPN field is to translate advances in biological understanding to improved treatments for patients.

Purpose of review: Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition.

Recent findings: Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition. t-MN remains a disease with poor prognosis. Studies are needed to better define an individual's inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy.

Purpose of review: Acute myeloid leukemia (AML) survivors face unique challenges affecting long-term outcomes and quality of life. There is scant literature on the long-term impact of AML treatment in physical and mental health, disease recurrence, and financial burden in survivors.

Recent findings: Fatigue, mental health concerns, infections, sexual dysfunction, and increase cancer recurrence occur after AML treatment. Chronic graft-versus-host disease (GVHD) and infections are common concerns in AML after hematopoietic stem cell transplantation (HCT). Survivorship guidelines encompass symptoms and complications but fail to provide an individualized care plan for AML survivors. Studies in patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are sparse. Here we discuss the most common aspects pertaining to AML survivorship, late complications, care delivery, prevention of disease recurrence, and potential areas for implementation.

Purpose of review: The chronic myeloid leukemia (CML) treatment success story is incomplete as some patients still fail therapy, leading to end-stage disease and death. Here we discuss recent research into CML incidence, the role of comorbidities on survival and detecting patients at risk of failing therapy.

Recent findings: The incidence of CML has fallen markedly in high social-demographic index (SDI) regions of the world but there is disturbing evidence that this is not the case in low and low-middle SDI countries. Now that CML patients more frequently die from their co-morbid conditions than from CML the Adult Comorbidity Evaluation-27 score can assist in risk assessment at diagnosis. Non-adherence to therapy contributes greatly to treatment failure. A good doctor-patient relationship and social support promote good adherence, but patient age, gender, and financial burden have negative effects, suggesting avenues for intervention. Mutations in cancer-associated genes adversely affect outcome and their detection at diagnosis may guide therapeutic choice and offer non-BCR::ABL1 targeted therapies. A differential gene expression signature to assist risk detection is a highly sought-after diagnostic tool being actively researched on several fronts. Detecting patients at risk of failing therapy is being assisted by recent technological advances enabling highly sensitive genomic and expression analysis of insensitive cells. However, patient lifestyle, adherence to therapy, and comorbidities are critical risk factors that need to be addressed by interventions such as social and financial support.

Purpose of review: Despite the adoption of tyrosine kinases inhibitors (TKIs) as molecular targeted therapy in chronic myeloid leukemia, some patients do not respond to treatment and even experience disease progression. This review aims to give a broad summary of advances in understanding of the mechanisms of therapy resistance, as well as management strategies that may overcome or prevent the emergence of drug resistance. Ultimately, the goal of therapy is the cure of CML, which will also require an increased understanding of the leukemia stem cell (LSC).

Recent findings: Resistance to tyrosine kinase inhibitors stems from a range of possible causes. Mutations of the BCR-ABL1 fusion oncoprotein have been well-studied. Other causes range from cell-intrinsic factors, such as the inherent resistance of primitive stem cells to drug treatment, to mechanisms extrinsic to the leukemic compartment that help CML cells evade apoptosis. There exists heterogeneity in TKI response among different hematopoietic populations in CML. The abundances of these TKI-sensitive and TKI-insensitive populations differ from patient to patient and contribute to response heterogeneity. It is becoming clear that targeting the BCR-ABL1 kinase through TKIs is only one part of the equation, and TKI usage alone may not cure the majority of patients with CML. Considerable effort should be devoted to targeting the BCR-ABL1-independent mechanisms of resistance and persistence of CML LSCs.

Purpose of review: Employment is an important indicator of health and functional recovery for hematopoietic cell transplantation (HCT) survivors and has significant social and economic impacts. Cancer survivors treated with conventional non-HCT therapy are known to be at a higher risk of unemployment or not returning to work after completion of therapy compared with the control population. However, the literature on return-to-work challenges among HCT survivors remains limited.

Recent findings: Here we summarize the evidence on prevalence and determinants of return-to-work challenges among HCT survivors using previously published literature. Findings from previously published research show that return to work or unemployment is a major concern among HCT survivors, especially for allogeneic HCT recipients, and prior studies have identified several modifiable risk factors associated with it. Survivors' post-HCT employment status is significantly associated with quality of life, impacting physical, emotional, social, and financial aspects of their lives. We also highlight the gaps in current knowledge such as limited information on employment outcomes of childhood, adolescent, and young adult HCT survivors; work-related challenges among employed HCT survivors; consequences of work-related challenges; and interventions to improve return to work among HCT survivors. Findings highlighted in this review make a strong case of a multidisciplinary return-to-work support for HCT survivors to properly address their needs.

Purpose of review: Advances in the understanding of germline predisposition to pediatric cancers, particularly myeloid neoplasms, have increased rapidly over the last 20 years. Here, we highlight the most up-to-date knowledge regarding known pathogenic germline variants that contribute to the development of myeloid neoplasms in children.

Recent findings: This discussion enumerates the most notable myeloid neoplasm-causing germline mutations. These mutations may be organized based on their molecular underpinnings-transcriptional control, splicing and signal transduction control, and a group of heterogeneous bone marrow failure syndromes. We review recent findings related to the biochemical mechanisms that predispose to malignant transformation in each condition. Key genetic discoveries such as novel mutations, degrees of penetrance, principles of the two-hit hypothesis, and co-occurrence of multiple mutations are shared. Clinical pearls, such as information regarding epidemiology, natural history, or prognosis, are also discussed. Germline mutations predisposing to pediatric myeloid neoplasms are frequent, but underrecognized. They hold major clinical implications regarding prognosis, treatment strategies, and screening for other malignancies. Further research is warranted to better characterize each of these conditions, as well as identify additional novel germline pathogenic variants of interest.