Discontinuation of first-line dasatinib safe for certain adults with chronic myeloid leukemia
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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: shkimu@cc.saga-u.ac.jp.
Perspective
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Michael J. Mauro, MD
In the second of a series of DADI trials from Japan, Kimura and colleagues bring to light more evidence regarding the success of treatment-free remission after therapy with the ABL1 TKI dasatinib. Having previously reported treatment-free remission rates of 49% for patients who received dasatinib in the second line or beyond, the first-line DADI study examined treatment-free remission among patients with chronic phase CML treated for at least 2 years with dasatinib and with deep molecular response for 12 months or more. These patients entered into a consolidation year, ensuring deep remission for an additional 12 months and treatment duration of 3 years or more, making the population compatible with current treatment-free remission recommendations from both the National Comprehensive Cancer Network and European LeukemiaNet.
With 55% success in this cohort, the authors provide more proof that treatment-free remission after front-line use of second-generation TKIs can be successful while harnessing the ability of these agents to move patients into deep remission more rapidly, potentially shortening the total time on treatment before treatment-free remission may be feasible.
As they had in the prior DADI study, researchers queried the potential predictors for treatment-free remission success, focusing on immune cell subsets. In this study, proportionally lower CD4 cell count appeared predictive of treatment-free remission success, whereas other T cell subsets (natural killer, large granular and regulatory T lymphocytes) — in theory, the immune “flip side” of CD4 cells — were not predictive. Ironically, the CD4 count threshold above and below which treatment-free remission success was improved correlates with the lower range for normal healthy CD4 cell levels.
More study is needed in this area to understand the exact predictors, immune and otherwise, for treatment-free remission success after TKI treatment for CML. However, this second DADI study adds to our confidence that front-line dasatinib therapy is an efficient and successful path to treatment-free remission for newly diagnosed CML.
HemOnc Today Editorial Board Member
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Breccia M and Foà R. Lancet Haematol. 2020;doi:10.1016/S2352-3026(19)30251-0.
Kimura S, et al. Lancet Haematol. 2020;doi:10.1016/S2352-3026(19)30235-2.
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