Relapsed acute T-cell lymphoblastic leukemia: analysis of data from the ALL-2016 registry of the Russian Adult Acute Lymphoblastic Leukemia Study Group

Background. Current approaches to treating acute T-cell lymphoblastic leukemia (T-ALL) in adults have achieved significant results, with approximately 60 % of patients recovering after first-line therapy. However, treatment of relapsed and refractory forms of T-ALL remains an unresolved issue, especially given the lack of targeted agents for this disease. Relapsed T-ALL deserve special attention, as they demonstrate conversion of the initial immunophenotypic variant, i. e., a change in the phenotype of tumor cells. Cases of the complete tumor clone replacement – a phenomenon known as “lineage switch” – have been described. This phenomenon is diagnosed in 6–9 % of all relapses and is more commonly observed in children. In cases of an acute leukemia variant conversion, it is extremely difficult to determine the etiology of the second event: are the blast cells the same leukemic clone or should this aspect be considered within the context of the development of a secondary malignancy associated with previous therapy. An equally important issue in this group of patients is the selection of effective treatment programs. Aim. To analyze long-term treatment outcomes in relapsed and refractory T-ALL forms, to assess the likelihood of immunophenotypic variant change (second event) during relapse in T-ALL patients, and to identify risk factors for the development of this phenomenon. Materials and methods. The study included 34 patients with T-ALL who were enrolled in the ALL-2016 study from 2017 to 2024 and who had relapsed or had a primary refractoriness. Of these, 27 (79 %) were male and 7 (21 %) were female. The median age at the time of relapse / second event was 32 (18–54) years. Eighteen patients underwent next-generation sequencing to identify mutations in genes associated with clonal hematopoiesis. Targeted sequencing of the ASXL1, DNMT3A, and TET2 genes was performed. Results. The 2-year overall survival rate for T-ALL patients after relapse or refractoriness diagnosis was 13 %. Immunophenotypic variant change during relapse in T-ALL patients treated according to the ALL-2016 protocol was diagnosed in 18 % (n = 6): 5 patients developed acute myeloid leukemia, 1 patient developed myelodysplastic syndrome with monosomy 7, with subsequent transformation to acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. All patients diagnosed with immunophenotypic variant change during relapse initially had karyotype abnormalities, and 80 % of them were diagnosed with complex karyotype changes. The 2-year overall survival in patients with immunophenotypic variant change was 0 %, and in patients without variant change – 16 % (p = 0.82). In 2 of 5 patients, the “lineage switch” phenomenon was confirmed at relapse: identical mutations in the DNMT3A and ASXL1 genes were detected, the same as those present at the onset of T-ALL. In the group of patients in whom no changes in the immunological characteristics of the tumor clone were observed at relapse, mutations in genes associated with clonal hematopoiesis were detected in 3 (23 %) patients (p = 0.87). In the group of patients with immunophenotypic variant conversion, at disease onset early immunophenotypic variants (ETP and near-ETP) were detected in 5 of 6 patients, and the thymic variant of T-ALL was verified in only 1 (17 %) patient. Conclusion. Long-term treatment outcomes for relapsed / refractory T-ALL remain unfavorable. Rare cases of immunophenotypic variant conversion in T-ALL during relapse are described. A high risk of disease relapse with immunophenotype shift has been confirmed in a group of patients with early T-ALL (ETP and near-ETP), characterized by complex karyotypic changes at onset.