N Engl J Med
Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.
Abstract
Background
Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.
Methods
We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.
Results
Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).
Conclusions
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 Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).
Related Questions
Is there any benefit to transplant patients with Ph+ ALL who have achieved MRD-negativity?
First, some semantics: Asking if there is a "benefit to transplant" may imply there are randomized controlled trials addressing this question, but none to my knowledge have been performed. The last "donor-no donor" trials done in adults with ALL in first remission largely occurred in the pre-TKI era...
How do you decide between blinatumomab or traditional chemotherapy in combination with TKI for upfront treatment of adult patients with Ph + ALL?
This question is likely inspired by the recent publication of a "chemotherapy-free induction and consolidation first-line treatment" for adults with Ph+ ALL (Foà et al., PMID 33085860; GIMEMA LAL2116). The authors reported relatively high rates of MRD- remissions by bone marrow BCR-ABL1 RT-PCR and i...
How would you approach a patient with relapsed Ph+ ALL and MRD positive after blinatumomab?
There is currently no defined standard-of-care treatment for pediatric relapsed Ph+ ALL. Nevertheless, many patients with relapsed Ph+ ALL can be successfully salvaged in the TKI era (especially those who had not undergone HSCT in CR1) since the 5-year EFS of pediatric Ph+ ALL on the recently publis...