PS1179 TREATMENT FREE REMISSION IN CHRONIC MYELOID LEUKEMIA PATIENTS HARBORING ATYPICAL BCR‐ABL1 TRANSCRIPTS
Authors: M. Dragani, G. Rege‐Cambrin, E. Gottardi, F. Daraio, G. Caocci, C. Aguzzi, E. Crisà, G. Andreani, G. Saglio, C. Fava
Journal: HemaSphere (2019)

Background: The majority of chronic myeloid leukemia (CML) patients carry a t(9;22) translocation characterized by chromosomal breakpoints located on exon 13 or 14 of the BCR gene and on exon 2 of the ABL1 gene. This translocation generates a fusion gene e13a2 or e14a2. In rare cases of CML, breakpoints on chromosome 9 and 22 are located in unusual regions, giving rise to atypical rare transcript which are carried by 1.9% of the patients (Baccarani, Leukemia 2019). These transcripts, including e13a3, e14a3, e1a2, e19a2, e8a2, are not amplified by RT‐qPCR which is the standardized method of molecular response evaluation. In patients with atypical fusion genes, two‐step qualitative (nested) RT‐PCR can represent an alternative method of MRD with a sensitivity of 10 –4 , 10 –5 at the second step (Van Dongen, Leukemia 1997). It is nowadays judged safe to discontinue treatment TKI for CML both in experimental trials on treatment free remission (TFR) and in clinical practice. Nonetheless, clinical trials and current guidelines exclude patients with atypical transcripts (Hochhaus, Ann Oncol 2017) Aims: To evaluate safety issue and duration of TFR in patients with atypical transcripts who discontinue TKI treatment. Methods: We retrospectively identified patients with chronic phase CML and rare atypical transcripts who stopped treatment with TKIs. Identification of transcript was done by RT‐PCR followed by sequencing. Molecular follow‐up was performed by qualitative two‐step nested RT‐PCR. For the purpose of this study, we defined Deep Molecular Response (DMR) as undetectable transcript at nested RT‐PCR. Results: Seven patients carrying atypical transcripts with a stable DMR discontinued TKIs for various reasons such as severe comorbidities, toxicity or patient request. Median duration of treatment with the tyrosine kinase inhibitors was 71 months (range: 34–195), median duration of DMR at nested PCR before discontinuation was 43 months (30–93). Only one patient resumed TKI therapy two months after stop due to RT‐PCR positivity in two consecutive controls. The other six patients remained off‐treatment at last observation after a median follow‐up of 25 months (5 ‐ 77). Five patients remained negative (undetectable transcript) in all samples after discontinuation. In patient 3, who stopped 2 nd line Nilotinib for intolerance, fluctuation after stopping TKI was observed between negative RT‐PCR and low‐level positivity at the second step of nested PCR (2 out of 13 samples). No progressions occurred. All patients, including the one that resumed therapy, are in DMR at the last follow‐up. Summary/Conclusion: To our knowledge there are no reports in the literature about patients with atypical transcript who discontinued therapy. Although current guidelines do not recommend discontinuation for patients lacking a standardized method for response monitoring, we observed that in clinical practice patients with atypical transcript stopped the treatment successfully. Further clinical observations as well as the application of new technologies such as digital PCR in these rare cases are both required. image