Immunotherapy and TKIs: Precision Agonism or Antagonism for Ph+ ALL?

Two decades ago, clinical outcomes of adults and children with BCR-ABL1–rearranged (Philadelphia chromosome–positive [Ph⁺]) B-cell acute lymphoblastic leukemia (ALL) were revolutionized by addition of the first-generation tyrosine kinase inhibitor (TKI) imatinib to chemotherapy.^1-3  These landmark trials established a new paradigm for precision medicine in acute leukemia by markedly improving relapse-free and overall survival, reducing the need for allogeneic hematopoietic stem cell transplantation (HSCT) and setting the stage for subsequent clinical investigation of second- (e.g., dasatinib, nilotinib) and third-generation TKIs (e.g., ponatinib) and ABL1 allosteric inhibitors (e.g., asciminib) with potentially more favorable pharmacologic properties, including improved central nervous system penetration and/or efficacy against ABL1 resistance mutations.^4-7  Current trials are now investigating the potential success of reducing chemotherapy backbone intensity to decrease toxicity, with remarkably good outcomes recently reported in older patients with Ph⁺ ALL treated “only” with glucocorticoids and TKI therapy.⁸ 

In the latest precision medicine efforts, Dr. Robin Foà and colleagues describe early results of 63 adults with newly diagnosed Ph⁺ ALL enrolled on the intent-to-treat GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) LAL2116 D-ALBA single-arm phase II trial from May 2017 to January 2019. Patients were administered a seven-day prednisone prophase followed by one month of prednisone with concurrent dasatinib (through day 31), two months of dasatinib monotherapy (through day 35), and two to five 28-day cycles of the bispecific T cell-engaging antibody blinatumomab with concurrent dasatinib. The investigators report complete hematologic remission in 62 (98%) of 63 patients at day 85 (prior to blinatumomab) and complete molecular responses with BCR-ABL1 negativity by reverse transcription-polymerase chain reaction after two cycles of blinatumomab in 33 (60%) of 55 patients. The latter was the primary study endpoint with data comparison to a 40 percent historic control rate of patients treated with dasatinib and chemotherapy on the predecessor GIMEMA LAL1509 trial. In the current trial, further molecular responses were achieved in up to 81 percent of patients who received one to three additional blinatumomab cycles. Interestingly, focused screening of the 15 subjects with increased minimal residual disease at day 85 and one patient with early medullary relapse revealed ABL1 resistance mutations in seven patients (6 with T315I, 1 with E255K), which were able to be eliminated successfully via subsequent blinatumomab therapy. Twenty-four patients underwent allogeneic HSCT after various treatment phases, 23 of whom were in first remission. Follow-up was relatively short at a median of 18 months at time of study publication. As predicted, patients with Ph⁺ ALL with the concomitant IKZF1^plus genotype⁹  had inferior disease-free survival when compared to those with IKZF1 deletions alone (without CDKN2A/B or PAX5 deletions) or no transcription factor deletions.

Importantly, several groups have recently reported deleterious sequelae of dasatinib upon T-cell receptor signaling attributed to the SRC family kinase–targeting properties of this second-generation TKI. In preclinical studies, dasatinib exposure was observed to interfere with desired cytotoxic functionality of blinatumomab and CD19 chimeric antigen receptor–redirected T cells, which was not detected with imatinib or nilotinib (that have minimal effects upon SRC-mediated signaling).^10-12  It is plausible as such that the lack of molecular response seen in 20 to 40 percent of patients after individual blinatumomab cycles in the D-ALBA trial could potentially be driven by dasatinib-mediated interference with needed endogenous T-cell engagement by blinatumomab. While the study investigators performed limited T-cell immunophenotypic analysis in a subset of patients (n=17) and reported decreased CD4⁺/CD25⁺ regulatory T cell numbers and CD4:CD8 ratios post-blinatumomab, more detailed functional correlative analyses are needed to elucidate potential cooperativity or interference effects of blinatumomab and dasatinib co-treatment upon T cells in this patient population.