Management of Patients with Treatment-Free Remission in Chronic Myeloid Leukemia

Background: Chronic myeloid leukemia (CML) is a relatively common BCR-ABL-positive chronic myeloproliferative neoplasm within the structure of morbidity by hematological malignancies with primary bone marrow (BM) involvement, being characterized in the advanced phases by a relapsing evolution, sizable disease burden, unfavorable socio-economic impact and poor prognosis. Tyrosine kinase inhibitors (TKIs) have improved fundamentally the treatment outcomes in CML, bringing the patients' life expectancy closer to that of the general population. Nevertheless, TKI discontinuation studies indicate discordance in the incidence of hematological and molecular relapses.

Objectives: The aim of the study was to evaluate the short- and long-term outcomes of treatment discontinuation in CML patients with complete molecular response (CMR).

Material and methods: This prospective study included 22 patients with chronic phase of CML, treated and followed up at the Oncologic Institute from Moldova between 2017-2022. The age range was 29-73 years (average age - 45.8 years). The male/female ratio was 1:1.2. The quantitative reverse transcription polymerase chain reaction (PCR) was performed in order to determine the expression of the BCR-ABL p210 and p190 transcripts. Five transcription products (b2a2, b3a2, b2a3, b3a3 si e1a2) were analyzed by the usage of the PCR test. The real-time quantitative PCR revealed the wide range of BCR-ABL p210 transcript: 21.84-100% IS. In 7 (31.8%) cases the initial rate of BCR-ABL p210-positive cells was less than 50%. Only 2 (9.0%) patients also proved to be positive for BCR-ABL p190 transcript.

Results: CMR was obtained in 15 (68.2%) patients after imatinib therapy and in 7 (31.8%) patients after therapy with 2nd TKIs generation. The therapy with TKIs was stopped due to the different reasons in all patients after the achievement of CMR. Two (9.1%) patients discontinued the TKIs treatment due to the pregnancy. The molecular relapse occurred in 6 (27.3%) pts, including one pregnant female. There were no subsequent hematological relapses. All patients with molecular relapse had the initial BCR-ABL p210 transcript expression > 50%. One (4.5%) of them was positive for BCR-ABL p190 transcript at diagnosis. The CMR span ranged between 2.5-26 months in relapsed patients. The range of BCR-ABL p210 transcript in the relapsed cases was 0.002-0.56%. These patients attained the 2nd CMR after resuming the treatment with the same or higher TKIs generation. In 2 (9.0%) pregnant females the pregnancy resulted in the healthy newborns. One (4.5%) female with a history of lymphoblastic type of acute phase experienced the minor molecular relapse (BCR-ABL p210 transcript - 0.56%), and reobtained the CMR after restarting imatinib mesylate. The relapsed patients did not develop the 2nd molecular relapse. All patients are alive, with the ECOG-WHO score of 0-1.

Conclusions: TKIs stopping proved to be a reliable management option in CML patients with chronic phase, CMR and low BCR-ABL p210 transcript expression at diagnosis. The stable 2nd CMR may be achieved after resuming the TKIs treatment at a higher dosage or generation in patients with minor molecular relapse. Pregnancy may not influence the molecular relapse rate after TKIs discontinuation and its curability.

No relevant conflicts of interest to declare.