CAR T cells vs allogeneic HSCT for poor-risk ALL

Abstract

For subgroups of children with B-cell acute lymphoblastic leukemia (B-ALL) at very high risk of relapse, intensive multiagent chemotherapy has failed. Traditionally, the field has turned to allogeneic hematopoietic stem cell transplantation (HSCT) for patients with poor outcomes. While HSCT confers a survival benefit for several B-ALL populations, often HSCT becomes standard-of-care in subsets of de novo ALL with poor risk features despite limited or no data showing a survival benefit in these populations, yet the additive morbidity and mortality can be substantial. With the advent of targeted immunotherapies and the transformative impact of CD19-directed chimeric antigen receptor (CAR)–modified T cells on relapsed or refractory B-ALL, this approach is currently under investigation in frontline therapy for a subset of patients with poor-risk B-ALL: high-risk B-ALL with persistent minimal residual disease at the end of consolidation, which has been designated very high risk. Comparisons of these 2 approaches are fraught with issues, including single-arm trials, differing eligibility criteria, comparisons to historical control populations, and vastly different toxicity profiles. Nevertheless, much can be learned from available data and ongoing trials. We will review data for HSCT for pediatric B-ALL in first remission and the efficacy of CD19 CAR T-cell therapy in relapsed or refractory B-ALL, and we will discuss an ongoing international phase 2 clinical trial of CD19 CAR T cells for very-high-risk B-ALL in first remission.

The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia

“…In addition, incorporation of MRD data in risk stratification models before allo-HSCT may allow better identifying which patients should be offered an allograft and possibly inform how to transplant these subjects [241]. In the last few years, successes obtained by combination chemotherapy and the development of highly effective immunotherapy agents have raised the question of whether HSCT will continue to play a role in modern therapy of childhood AL, particularly in B-ALL [13]. Although the answer to this question should necessarily come from the results of well-designed and randomized clinical trials, the number of variables that may influence transplant outcome and the quantity of innovative approaches that have entered, or are about to enter, into the clinical arena, makes the design and conduction of such studies anything but trivial.…”

“…Despite the criteria used to assess this indication may vary between different cooperative groups, most studies/protocols consider eligible children with an estimated EFS probability lower than 50%, according to response to induction treatment and specific biologic features. Advances in biological characterization, improved MRD measurement capacity and its incorporation in treatment protocols to optimize risk stratification, and the upfront introduction of new biological agents (e.g., blinatumomab in AIEOP-BFM (EUDRACT 2016-001935-12) and COG protocols (AALL1731) and inotuzumab (AALL1732) and tisagenlecleucel (AALL1721/CASSIOPEIA) in COG protocol) have changed (and will continue to shape) the indications for HSCT over time [13]. Current HSCT indications in childhood ALL are summarized in Table 1.…”

“…Current HSCT indications in childhood ALL are summarized in Table 1. For example, criteria that were considered in past studies, such as a high white blood cell (WBC) count at presentation, Philadelphia chromosome positivity (Ph+), or poor-prednisone response, are no longer considered strict indications for transplantation [13]. The strongest criterion for HSCT indication is the response of the disease to induction therapy, this being a surrogate marker of leukemia sensitivity to chemotherapy.…”

“…One possible toxicity concern, regarding the use of InO before HSCT, is related to the risk of sinusoidal obstruction syndrome (SOS), especially in heavily pretreated patients [141,142]. While blinatumomab and InO are mainly recognized as bridge-to-transplant (or, at least, bridge-to-consolidation) strategies in children, the benefit of a consolidative HSCT after chimeric antigen receptor T-cell (CAR T) therapy is currently the object of considerable debate [13]. Anti-CD19 CAR T-cell therapy has produced impressive MRD-negative CR rates, ranging from 56% to 93%.…”

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

“…Some of these cases have shown a promising response to CAR T-cell therapy, including an adult patient with low-hypodiploidy B-ALL in first relapse who received CD19-specific CAR T-cell therapy consolidated with HSCT [ 76 ]. Trials with CAR T-cell therapies as frontline approaches remain scarce and in some of them patients with hypodiploidy <40 chromosomes were excluded, such as the AALL1721/Cassiopeia trial (NCT03876769), a phase II single-arm trial of tisagenlecleucel (CD19-specific CAR T) in children and young adults with high risk B-ALL and persistent MRD at end of consolidation [ 77 ]. Blinatumomab, a BiTE antibody that directs T-cells to CD19-positive cells, has proven to be effective in adult patients with low-hypodiploid B-ALL, with 2 of the 4 patients reaching a complete response in one study [ 78 ].…”