Use of BCR1/ABL receptor tyrosine kinase inhibitor (TKI)-based induction therapy followed by consolidation therapy with the bispecific T-cell engager (BiTE), blinatumomab, without addition of chemotherapeutic agents, in the treatment of adults with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (ALL), was associated with a high survival rate and very low treatment toxicity, according to results of a phase 2 study published in the New England Journal of Medicine.1
Multiagent intensive chemotherapy has traditionally formed the backbone of initial therapy for patients with newly diagnosed ALL, although previous research has shown that the benefits of this approach decreased with increasing patient age.2
While a long-term cure rate of approximately 90% has been achieved in children with ALL who have undergone aggressive chemotherapy-based induction/consolidation therapy, only 70% of adolescents and young adults aged 40 years or younger with newly diagnosed ALL who received this type of treatment were cured. Furthermore, the 5-year survival rates for middle-aged adults over the age of 40 years and elderly patients with ALL treated with induction/consolidation regimens including intensive chemotherapy have been estimated at only 50% and 30%, respectively.2
A major cause of this difference in survival according to patient age had been attributed to chemotherapy-related myelotoxicity during the induction/consolidation phases of treatment. Although use of BCR1-ABL–targeted TKIs in induction therapy with or without the addition of intensive chemotherapy has dramatically improved the outcomes of patients with Philadelphia chromosome-positive ALL, treatment-related mortality rates following allogeneic hematopoietic stem cell transplantation (HSCT) following achievement of a complete hematologic response have been reported to be as high as 20% in this subgroup of patients. Hence, alternative, less toxic treatment approaches are actively being sought.2
In this single-arm, open-label, phase 2 trial (GIMEMA LAL2116; D-ALBA; ClinicalTrials.gov Identifier: NCT02744768), patients with Philadelphia-positive B-cell precursor ALL aged 18 years or older were treated with the BCR1-ABL receptor TKI, dasatinib, plus a glucocorticoid as induction therapy followed by consolidation therapy with blinatumomab immunotherapy, a monoclonal antibody-based treatment that binds CD19 on leukemic cells as well as CD3 on endogenous cytotoxic T cells. Dasatinib was continued during and after consolidation therapy for most patients.
The primary study endpoint was molecular response, defined as a BCR1-ABL to ABL ratio of 0 plus a positive non-quantifiable response,3 with induction therapy followed by 2 cycles of consolidation therapy. Secondary study endpoints included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, and safety, among others.
Of the 63 patients enrolled in the study, the median patient age was 54 years. The number of patients completing induction therapy, and 2 cycles of blinatumomab, were 61 and 56, respectively. By the end of induction therapy and the second cycle of blinatumomab, 29% and 60% of patients had achieved a molecular response, respectively, and the molecular response rates were higher in the subgroups receiving additional cycles of blinatumomab.
Of the 15 patients with evidence of minimal residual disease during induction therapy, ABL1 mutational analysis revealed that, “all but one of the mutations occurred between day 57 and 85 (the end of induction therapy), before the initiation of blinatumomab, and all the mutations were cleared by blinatumomab,” the study authors noted.1
Regarding treatment toxicity, grade 3 or higher adverse events included cytomegalovirus reactivation/infection (6 individuals), neutropenia (4 individuals), persistent fever (2 individuals), pleural effusion (1 individual), pulmonary hypertension (n 1), and a neurologic disorder (1 individual). Only 1 patient death occurred during the administration of induction/consolidation therapy.
At a median follow-up of 18 months, OS and DFS for the overall group were 95% and 88%, respectively. In addition, OS was 100% and 85% in those patients achieving a molecular response vs not. Disease relapse occurred in 6 patients, and 4 patient deaths occurred on study.
In the subgroup of 24 patients who underwent allogeneic HSCT, the posttransplantation mortality rate was only 4%.
Regarding the low posttransplantation mortality rate observed in this study compared with results of previous studies of patients with Philadelphia-positive ALL treated with other induction/consolidation regimens, Dieter Hoelzer, MD, PhD, University of Frankfurt, Germany, the author of an editorial accompanying this publication, commented that “it is possible that patients who have not received systemic chemotherapy are less prone to serious transplantation-related complications than those who have received systemic chemotherapy.2
He further noted that “several factors contributed to these outcomes, including the very low incidence of induction therapy–induced death, the high molecular response, the eradication of cells expressing ABL1 mutations, and the low mortality after allogeneic transplantation.”2
In summarizing the results of this study, the study authors stated that “a chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with [Philadelphia chromosome-positive] ALL.”1
Dr Hoelzer also explained that large, prospective studies will be needed to address questions such as whether minimal residual disease, as well as the BCR1-ABL mutation, T315I, will recur with longer follow-up, and whether this approach will also be beneficial in the treatment of children with ALL.
- Foa R, Bassan R, Vitale A, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Eng J Med. 2020;383:1613-1623. doi:10.1056/NEJMoa2016272
- Hoelzer D. Chemotherapy-free Treatment—A New Era in Acute Lymphoblastic Leukemia? N Engl J Med. 2020;383(17):1673-1674. doi:10.1056/NEJMe2027937
- Pfeifer H, Cazzaniga G, van der Velden VHJ, et al. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1. Leukemia. 2019;33:1910-1922. doi:10.1038/s41375-019-0413-0