Immunotherapy: genetically agnostic in BCP-ALL?

In this issue of Blood, Leahy et al demonstrate that the current cytogenetic risk stratification of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is no longer predictive in patients receiving immunotherapy.¹ Primary response to chimeric antigen receptor (CAR) T-cell infusion (either tisagenlecleucel/CTL019 or a humanized CD19 CAR T cell) and 2-year event-free and overall survival were comparable between the different cytogenetic risk categories. Disease response and relapse rates are comparable to data reported by Pasquini et al in a large cohort of patients receiving tisagenlecleucel outside clinical studies.² Since the treatment of Emily Whitehead in 2010 with CTL019 for refractory BCP-ALL, CAR T-cell treatment has evolved, with Food and Drug Administration/European Medicines Agency approval obtained in 2017-2018. Of interest, other immunotherapy in BCP-ALL, like blinatumomab, has also reported to be genetic risk-group agnostic.³ 

In newly diagnosed BCP-ALL, the Cassiopeia study is evaluating the efficacy of tisagenlecleucel in patients that are minimal residual disease positive at the end of consolidation after National Cancer Institute high risk classification (NCI-HR) induction chemotherapy. Notably, this study excludes patients with hypodiploidy and Philadelphia-chromosome positive disease (NCT03876769). Meanwhile, positioning of CAR T-cell therapy for first relapse BCP-ALL remains controversial given the 2-year relapse free survival of ∼50%, significant production costs, and the time delay involved with production. The ACCELERATE Pediatric Strategy Forum meeting in May 2021 with attendance from patient advocates, regulatory representatives, academic partners, and industry identified dual CAR T and human CAR T constructs as well as decentralized production (eg, NCT03853616) as potential urgent improvement strategies.⁴ Moreover, critical issues that need to be solved include access and eligibility to receive CAR T-cells, and the need for post CAR T-cell consolidation therapy with stem cell transplantation (SCT), despite the fact that replacement of SCT by CAR T-cell therapy was envisioned as a way of avoiding long-term transplant-related morbidity.

Except for KMT2A rearrangements and the Philadelphia chromosome, different cytogenetic abnormalities are not specifically associated with clinical outcome after CAR T-cell therapy. Patients with Philadelphia-chromosome ALL were found to have a significantly higher 2-year relapse-free survival in comparison with all other patients (88% [95% confidence interval, 74-100] vs 57% [95% confidence interval, 49-66]) and show a trend toward a higher overall survival.¹ Philadelphia-like patients showed a similar trend; however, this failed to reach statistical significance. Consolidation with tyrosine kinase inhibitors after successful remission induction with CAR T-cells is controversial, as tyrosine kinase inhibitors may interfere with the ITAM motifs included in the CAR T-cell construct.⁵ In contrast, KMT2A rearrangements identify a subgroup of patients with inferior overall survival, whereas relapse-free survival was not affected. Relapse in patients with KMT2A rearrangements predominately consisted of phenotype switches, resulting in the inability to salvage patients relapsing with lineage switching after CAR T-cell treatment. Complete remission rates are high in patients with KMT2A; therefore, these patients are suitable candidates for CAR T-cell therapy, but consolidation therapy with allogeneic hematopoietic SCT might be considered. Other options include targeted therapies such as menin inhibitors currently in trial for patients with relapsed/refractory disease.⁶ The interaction of menin inhibitors with CAR T-cells have not yet been elucidated, but menin plays an important role in CD8 effector cell function,⁷ and therefore menin inhibitors should be carefully considered in the presence of functioning CAR T-cells. The previously mentioned dual targeting concept against 2 lymphoid antigens, or alternatively against CD19 in combination with a myeloid antigen or FLT3, may better protect against phenotype switches.

(Cyto-)genetic aberrations and/or pathways previously not included in the risk stratification of BCP-ALL might well be predictive for response and outcome in the era of immunotherapy. Next-generation sequencing may provide further insight in these aberrations. As an example, mutations or deletions of TP53 were associated with inferior event-free survival after CAR T-cell therapy.⁸ An in vitro genomewide “loss-of-function” screening led to the identification of the death receptor signaling pathway as a major driver for resistance to CAR T-cell therapy causing exhaustion of CAR T cells.⁹ Other aberrations related to apoptosis pathways, or, for example, different relapse presentations in extramedullary sites may play a role, and might give more insights into the escape mechanisms involved. Next to the characteristics of the leukemic blast, the CAR T-cell product characteristics and the immune response after CAR T-cell infusion including anti-CAR immunity may play an important role in relapse-free survival.

Taken together, the current study demonstrates that CAR T-cell efficacy is not affected by the majority of the currently documented cytogenetic abnormalities in BCP-ALL. This supports the use of CAR T-cells, for example, in very high-risk first relapse, defined as relapse within 18 months from diagnosis, or relapse with hypodiploidy, a TP53 alteration, MLL/AF4, t(17;19), or t(1;19), as currently studied as a separate cohort in the ITCC-059 study in collaboration with IntReALL (EudraCT 2016000227-71).