Although adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high complete remission (CR) rates following treatment with intensive multi-agent chemotherapy regimens, up to two-thirds of these patients eventually relapse. Unfortunately, adults with relapsed or refractory (R/R) B-ALL have a poor prognosis, with variable responses to salvage chemotherapy regimens and allogeneic stem cell transplant. As such, the need to develop effective and well-tolerated treatments for this patient population has been of paramount importance over the past decade. In this regard, treatment options for R/R B-ALL patients have expanded considerably over a relatively short period of time, with the approvals of blinatumomab, inotuzumab ozogamicin and tisagenlecleucel occurring within only the past six years. Blinatumomab, a CD19 x CD3 bispecific T-cell engager (BiTE) was the first of these immune therapies to receive approval, and for many patients, is used as first-line salvage therapy. A number of large clinical trials have demonstrated improved progression-free survival and overall survival for R/R B-ALL patients receiving blinatumomab as compared to those receiving conventional salvage chemotherapy. In addition to being approved for both Philadelphia chromosome-negative and Philadelphia chromosome-positive R/R B-ALL, blinatumomab is also the only ALL therapy that carries approval for the treatment of measurable residual disease (MRD). Although blinatumomab has changed the therapeutic landscape for adults with R/R B-ALL, a number of important clinical considerations and questions remain, including the potential role of blinatumomab in the frontline setting, mechanisms of resistance, optimal goal MRD level, the role of transplant following MRD clearance, the optimal place for blinatumomab in the context of other recently approved immune-mediated therapies, and real world outcomes for patients treated outside the context of clinical trials. These issues are the focus of ongoing studies, which will hopefully inform future clinical practice regarding the utility of blinatumomab in the treatment of B-ALL patients.
Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25–34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9–12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin–cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group.
Allogeneic hematopoietic stem cell transplantation is a curative option for patients with a variety of diseases. Transplantation from a related haploidentical donor is being increasingly utilized for patients who lack an available human leukocyte antigen matched related or unrelated donor. One of the strategies used for haploidentical transplants involves selective depletion of T cells expressing the αβ T cell receptor and CD19+ B cells prior to transplant. This allows for the removal of cells responsible for graft-versus-host disease and post-transplant lymphoproliferative disorder but maintains hematopoietic progenitor and stem cells for engraftment (CD34+ cells), as well as cells to elicit graft-versus-tumor effect and provide anti-infective activity (such as gamma-delta T cells and natural killer cells). The aim of this review article is to present and discuss the data available to date from studies utilizing this method of transplantation.
The treatment landscape in acute myeloid leukemia (AML) is rapidly evolving, with multiple new therapies approved in recent years. However, the prognosis for patients with high-risk genetic subsets of AML remains poor, and the development of more effective treatment options for these patients is ongoing. Three of these high-risk AML patient subsets include TP53-mutated AML, FLT3-internal tandem duplication (ITD)-mutated AML, and AML harboring rearrangements affecting the KMT2A locus (KMT2A-r AML). The prognosis for TP53-mutated AML remains poor with both intensive and targeted regimens, including those incorporating the BCL-2 inhibitor, venetoclax. Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for these patients, but posttransplant relapse rates remain high. Patients with FLT3-ITD-mutated AML continue to have suboptimal outcomes with standard therapies and experience high rates of relapse following transplant. KMT2A-r AML is also associated with poor outcomes with current treatment approaches, and effective standards of care are lacking for patients with relapsed/refractory disease. This article discusses current treatment approaches, along with the investigational agents being explored for the treatment of these 3 AML subsets, focusing primarily on agents that are further along in development.
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