Advances in cell and gene therapy最新文献

T-cell acute lymphoblastic leukemia (T-ALL) is a rare subtype of ALL which primarily affects older children and young adults, with a male bias. Clinically, T-ALL presents with hyperleukocytosis, mediastinal disease, and/or involvement of the central nervous system. T-ALL is a high-risk subgroup within pediatric cohorts whereas among adults, outcomes are similar or better than that of B-cell acute lymphoblastic leukemia (B-ALL). Most T-ALL patients have mutations in NOTCH or FBXW7 (a NOTCH regulator) which suggests a common pathway of disease pathogenesis. The presence of one of these mutations confers a favorable prognosis in the absence of mutations in RAS and PTEN. Early T-precursor (ETP)-ALL is a high-risk subgroup of T-ALL that is characterized by stem-cell-like features, absence of NOTCH pathway mutations, and resistance to chemotherapy. Patients with T-ALL should be treated with intensive, ideally asparaginase-based, chemotherapy regimens. Allogeneic transplant is considered for consolidation of some adults with high-risk disease, including those with ETP-ALL or poor response to therapy. Relapsed T-ALL can be treated with nelarabine, but outcomes are poor and new therapies are needed.

Although germline predisposition to hematologic malignancy is gaining increasing recognition and more patients with acute myeloid leukemia and myelodysplastic syndrome may have a germline predisposition than previously thought, individuals and families with these mutations often go unrecognized. Nowhere are the potential consequences of missing an underlying germline predisposition more devastating than in the setting of allogeneic hematopoietic cell transplantation, a procedure often necessary to obtain the best chance of cure for patients with myeloid malignancies. In this brief review, we will discuss the importance of upfront screening all transplant recipients and all prospective donors to mitigate potential disastrous complications if such germline predisposition is overlooked. We will also outline features that should strongly arise suspicion and prompt testing for germline predisposition as well as highlight some of the challenges and barriers to genetic testing for patients with hematologic malignancies.

Adult acute lymphoblastic leukemia management has traditionally relied upon pretreatment conventional risk factors for treatment decisions. Despite using intensive multiagent chemotherapy followed by a prolonged maintenance or allogeneic stem cell transplantation, these patients remain at a high risk of relapse. Improved techniques for detection of measurable residual disease (MRD) have tremendously changed the posttreatment disease burden assessment and evolved as a powerful predictor of relapse and survival superseding historical prognostic factors. Moreover, MRD measurement has become an integral part of risk stratification, prognosis assessment, intensification or de-escalation of treatment, monitoring of disease burden, and an endpoint in clinical trials. With existing approaches like allogeneic hematopoietic stem cell transplantation and emergence of novel agents (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor [CAR] T cells) that are highly effective in eradicating residual disease, understanding the role of MRD in treatment decisions is getting more and more important and complex. This review will highlight the advances that have been achieved in MRD monitoring over the years and the practical applications in different time points of treatment to provide a framework for rational management decisions by practicing hematologists and oncologists.

Graft-vs-host Disease (GVHD) is a frequent complication following allogeneic stem cell transplantation (allo-HCT). The National Institute of Health consensus group established new guidelines for the evaluation of chronic GVHD. However, GVHD assessment remains challenging due to its complexity and requirement for laborious evaluation. We, therefore, established a standardized approach for the assessment of chronic GVHD in accordance with the NIH consensus criteria (NCC) guidelines. At a single institution, all allograft recipients were evaluated for GVHD within the first-year post allo-HCT following a three-step workflow (real-time assessment, consensus review, and documentation). A GVHD adjudication committee was created and a dynamic electronic GVHD data capture form was developed guiding the clinician through a comprehensive review of systems following the NCC guidelines. We found that the assessment and reporting of GVHD reached 100% compliance. The establishment of an institutional GVHD adjudication committee enabled standardized assessment of GVHD. Our workflow can be adopted by other centers to create a similar framework for dedicated GVHD evaluation.

The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Although, as a group, these inhibitors have led to one of the most successful targeted therapies in leukemia, Ph+ ALL still remains a formidable disease. Unlike chronic myeloid leukemia (CML) where TKIs lead to dramatic long-lasting responses as single agents, the biology of Ph+ ALL is far more complex and adjunctive therapies are mandatory. These may include corticosteroids, chemotherapy, antibody-based therapies or, even, allogeneic hematopoietic cell transplantation. Clearly, other genes or mutations are in place that affect the outcome of Ph+ ALL. Additional chromosomal abnormalities are common in Ph+ ALL and have a varying impact on prognosis; some adverse, others less so. Genomic alterations have come into their own in the last decade and have increased our understanding of the mechanisms of resistance and differing responses to therapy. In this review, these genetic aberrations will be considered in some detail. In addition, innovations in current practice – including the use of immunological therapies – will be carefully reviewed. For the first time in decades, the long-held imperative requiring an allogeneic transplant for a curative approach in adult Ph+ ALL is now being questioned and clinical trials are underway to resolve this issue. However, despite much progress in the past two decades, both in the biology and therapy of Ph+ ALL, this disease still presents a compelling challenge and much remains to be overcome.

Significant progress has been made toward the development of effective therapies for multiple myeloma. Current treatment strategies include combinations of several different approved medication classes, including alkylating agents, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies. In this review, we highlight currently active clinical trials for patients with multiple myeloma. Additionally, we describe emerging strategies in the design of future trials, which will include new combinations of available therapies, targeted therapies, immune-based therapies such as chimeric antigen receptors T-cells (CAR-Ts), and drugs with novel mechanisms of action.