Dasatinib-blinatumomab for adult patients with Ph-positive acute lymphoblastic leukemia

 

A chemotherapy-free, dasatinib-based induction therapy followed by consolidation with the CD19-targeting antibody blinatumomab has demonstrated a molecular response in adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to a Phase II study published in the New England Journal of Medicine.1

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) accounts for a quarter of all adult patients with ALL and has historically been associated with poor response to chemotherapy and higher incidences of relapse.2 The outcomes of adult patients with Ph-positive ALL have dramatically improved since the development of tyrosine kinase inhibitors, which mitigate dysregulated BCR-ABL1 expression, a driver of pathogenesis in Ph-positive ALL.

In a clinical trial led by Prof. Robin Foà of the GIMEMA study group and Sapienza University of Rome, Rome, Italy, 63 patients were treated with induction dasatinib, a second-generation tyrosine kinase inhibitor, at a dose of 140 mg once daily for 85 days. This was followed by postinduction consolidation therapy with blinatumomab, a bispecific monoclonal antibody targeting CD19 in B-cells, of a minimum of two cycles. The primary endpoint of the study was the rate of patients obtaining a molecular response following induction with dasatinib and consolidation therapy with two cycles of blinatumomab. Secondary endpoints included a decreased level of minimal residual disease (MRD), overall survival, and safety profile of dasatinib-blinatumomab.


Following induction therapy using dasatinib, 29% (17/59) of patients had a molecular response. After two cycles of blinatumomab, 60% (33/55) of patients demonstrated MRD negativity, meeting the primary endpoint. Furthermore, the incidence of molecular response was found to increase after subsequent cycles of blinatumomab with an 81% molecular response seen after four cycles of consolidation therapy.

Within the cohort of patients, variations in the IKZF1 gene were observed and were reflected as differences in the frequency of molecular response achieved, with patients with IKZF1plus status showing less favorable molecular responses as well as a lower probability of disease-free survival (100% in patients with no IKZF1 genetic lesions, 92% of patients with IKZF1 deletions alone and 64% of patients with IKZF1plus status).

 

“The data of disease-free survival and overall survival at 18 months are extremely good. I would say the best so far seen, with very limited toxicity… This protocol is for all adult patients, again with no upper age limit, from 18 up until whatever age it may be so this is a doable protocol, with limited toxicity”

Robin Foà, lead investigator, Sapienza University of Rome

The median follow-up was 18 months, with the secondary points of overall survival and disease-free survival being 95% (95% CI, 90-100), and 88% (95% CI, 80-97) respectively. Chemotherapy-free induction and consolidation using dasatinib and blinatumomab were shown to be feasible and safe; 28 patients exhibited adverse events, with the most commonly reported grade 3 or higher adverse events being cytomegalovirus reactivation/infection (seen in 6 patients) and neutropenia (seen in 4 patients).

The results of this study have demonstrated that chemotherapy-free strategies may be a feasible approach to some patients with Ph-positive ALL, with further studies using the more potent inhibitor ponatinib and comparing against chemotherapy regimens being investigated to conclusively determine whether chemotherapy-free approaches are beneficial in this patient population.

References

  1. Foà R, Bassan R, Vitale A. et al. Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. NEJM. 2020;383:1613-1623.
  2. Yilmaz M, Kantarjian H, Ravandi-Kashani F. et al. Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia in Adults: Current Treatments and Future Perspectives. Clin Adv Hematol Oncol. 2018;16(3):216-223.

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