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Letters to the Editor
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Figure 1. Molecular monitoring of BCR-ABL1 transcripts and ABL1 point mutations in a patient with Philadelphia chromosome-positive acute lym- phoblastic leukemia. (A) Patient #1 was treated according to the GMALL eld- erly protocol including imatinib. BCR-ABL1 expression (BCR-ABL/ABL1 in %) was measured by quantitative polymerase chain reaction. (B) The variant allele frequency (VAF in %) is given for two follow-up time-points.
tion in ABL1. They identified the mutation in three of 23 patients prior to treatment.12 We speculate that muta- tions which confer resistance but reduce kinase activity or transformative capacity would not outgrow before TKI treatment and therefore only a subset of resistance mutations can exist in therapy-naïve patients. The high turnover rate of ALL cells should allow a much faster selection of mutated clones with a relative growth advantage if compared to the situation in chronic myeloid leukemia. In an initial dataset of treatment- naïve patients with chronic phase chronic myeloid leukemia, only minor subclones (<1%) were identified, and showed no correlation with endpoints.13
In summary, known resistance mutations in the ABL1 kinase domain were detected in five of 91 (5.5%) thera- py-naïve patients with BCR-ABL1-positive ALL. For patient #1 (Figure 1) we can show that the mutated clone expands rapidly if treatment with an insensitive TKI is chosen. At present, we see no significant difference in outcome for the five patients with mutations, but the heterogeneity of the cohort and the small number of cases with mutations need to be considered. Further studies will be necessary, especially involving the full spectrum of TKI, which are now increasingly a backbone and guarantor of success of improving outcomes in Ph+ disease. Next-generation sequencing is a direct and sen- sitive (1%) strategy to identify patients at risk of resist- ance before any TKI therapy is started. However, 93% (14/15 patients) of mutations found in relapse samples were most likely acquired under the selective pressure of (TKI) treatment. Therefore, testing at initial diagnosis should only be considered in addition to established mutation testing in refractory/relapsed disease.
Constance Baer, Manja Meggendorfer, Claudia Haferlach, Wolfgang Kern and Torsten Haferlach
MLL Munich Leukemia Laboratory, Munich, Germany Corresponding author:
CONSTANCE BAER - constance.baer@mll.com doi:10.3324/haematol.2021.279807
Received: August 17, 2021. Accepted: November 3, 2021. Pre-published: November 11, 2021.
Disclosures: CB and MM are employees in MLL Munich Leukemia Laboratory; WK, CH and TH own equity in MLL Munich Leukemia Laboratory.
Contributions: CB and MM analyzed the data; CB, CH, WK and TH designed the study; CB and TH wrote the manuscript.
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