Discontinuation of first-line dasatinib safe for certain adults with chronic myeloid leukemia
Discontinuation of first-line dasatinib after 3 years of treatment appeared safe among a cohort of patients with chronic myeloid leukemia who had achieved a sustained deep molecular response, according to results of the single-arm, multicenter, phase 2 DADI trial published in The Lancet Haematology.
Results of a prior study showed second-line or maintenance therapy with dasatinib (Sprycel, Bristol Myers Squibb), a BCR-ABL1 tyrosine kinase inhibitor, can be safely discontinued by patients with CML who maintain a deep molecular response for at least 1 year.
“We initiated this study because we wanted patients with CML to be free from expensive treatment and the adverse effects of long-term administration of dasatinib,” Shinya Kimura, MD, professor in the division of hematology, respiratory medicine and oncology at Saga University in Japan, told Healio. “We had previously reported that 49% of patients with CML who had been treated with second-line dasatinib could safely stop treatment. Thus, we expected that more [patients with] CML who had been treated with first-line dasatinib could also safely stop dasatinib therapy.”
The trial included 68 patients with a deep molecular response after at least 2 years of first-line dasatinib therapy. Researchers assigned them to a 12-month consolidation treatment phase.
After excluding nine patients during the consolidation phase and one patient after study completion, researchers assessed 58 patients (median age, 62.5 years; 52% women) in the final analysis.
Molecular RFS 6 months after dasatinib discontinuation served as the primary endpoint. Secondary endpoints included molecular RFS 1 year after dasatinib discontinuation, molecular remission after dasatinib rechallenge in cases of molecular relapse, and potential prognostic variables for molecular relapse.
Median follow-up was 23.3 months (interquartile range [IQR], 11.7-31).
More than half (55.2%; 95% CI, 43.7-69.6) of patients achieved 6-month molecular RFS after dasatinib discontinuation. This rate was unchanged at 12 months.
Median time to molecular relapse was 2 months (IQR, 1.3-2.7). Forty-five percent of patients (n = 26) experienced loss of deep molecular response, and 16 of those 26 patients had loss of major molecular response.
Kimura and colleagues observed a significant association between low CD4 T-cell counts and sustained molecular RFS (HR = 0.39; 95% CI, 0.16-0.97). Thus, adaptive T-cell mediated immune response may contribute to the elimination of CML cells, according to the researchers.
Twenty-five patients who relapsed received the previously effective dasatinib dose. All of them achieved major molecular response, and 23 (92%) achieved deep molecular response within 1 year (median time, 3.2 months; 95% CI, 2.9-5.7).
The most common hematologic adverse effect was anemia (21%). Three patients (4%) experienced grade 3 neutropenia and one patient had grade 4 lymphopenia.
“We previously reported that specific genotypes are favorable factors for achieving deep molecular response in this population of patients,” Kimura told Healio. “However, it is unclear whether these factors also affect treatment-free remission. We are investigating this now.”
The results reinforce the concept that immunological control of residual disease after therapy discontinuation likely contributes to treatment-free remission outcomes, Massimo Breccia, MD, professor in the department of cellular biotechnologies and hematology at Sapienza University in Italy, and Robin Foà, MD, professor of hematology and head of the division of hematology at the same institution, wrote in an accompanying editorial,
However, certain clinical or biological biomarkers that may predict outcomes after TKI discontinuation remain poorly understood, they added.
“Further studies with larger cohorts of patients and homogeneous baseline clinical features are needed; new combinations of drugs aimed at targeting residual leukemic stem cells or at enhancing the potential immunosurveillance need to be tested to improve treatment-free remission,” they wrote. – by Jennifer Southall
For more information:
Shinya Kimura, MD, can be reached at Saga University, 1 Honjo-machi, Saga 849-8502, Japan; email: firstname.lastname@example.org.