High Rate of BCR-ABL Transcript Undetectability Achieved by Treating with Imatinib Mesylate Very Late CML Patients in Stable CCR after IFN.
Authors: Giuliana Alimena , Daniela Diverio , Massimo Breccia , Marco Mancini , Nicoletta Giuliani , Roberto Latagliata , Mauro Nanni , Franco Mandelli 
Published: October 2019

Abstract
Background. Interferon alfa (IFN a) induces complete cytogenetic response (CCR) in small proportion of CML patients, with almost all of these patients still presenting BCR-ABL transcript at the molecular level, even after prolonged period of CCR. Imatinib mesylate induces CCR in a 60–80% of patients but a high percentage of these still show residual disease as detectable by RT-PCR, and can be at risk of disease relapse. Thus combining synergistic drugs might be required to eliminate the disease effectively.
Methods. We treated with imatinib 16 CML patients (8 M and 8 F) who were in very late CP and in stable CCR achieved with IFNa, but still were persistently positive at molecular level by RT-PCR. According to Sokal’s score, 11 patients were low risk (LR) and 5 were intermediate risk (IR). Median time from diagnosis was 125 mos.(r. 52–202), median duration of stable CCR was 79 mo.s (r.9–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. The level of residual disease was then monitored on BM cells at planned intervals ( baseline, 3, 6, 12 mo.s), by assaying BCR-ABL transcript at nested PCR and real-time quantitative RT-PCR; ABL was used as an internal control and results expressed as a ratio of BCR-ABL/ABL transcripts on a log scale.
Results. The median transcript levels, as measured at various time points, appeared to progressively and consistently decrease in all patients with respect to the baseline values. In particular, BCR-ABL transcript undectectability was observed in 6/15 patients with evaluable analyses at 3 mo.s, in 9/16 patients analysed at 6 mo.s, and in 5/8 with available results also at 12 mo.s; of these latter patients, 4 were already negative in previous analyses and one become negative at 12 mo.s. Thus, altogether, 10/16 (62.5%) patients with at least two examinations within 12 mo.s had at least one negative molecular result. Correlations between degree of transcript reduction and clinical/biological factors detected at diagnosis and during follow-up, evidenced not significant results for age, type of transcript (either b2a3 or b3a3), baseline transcript level pre-imatinib, duration of disease and of stable CCR prior imatinib, while a trend was apparent for a higher rate of LR vs IR score among the 10 patients reaching transcript undetectability (8/10 LR vs 2/10 IR) with respect to the 6 persistently positive subjects(3 LR vs 3 IR). In present cases, imatinib was well tolerated and no side effects required drug dose reduction or discontinuation. At a median follow-up of 13 months (8–16) from start imatinib, all 16 patients are alive in CCR with progressively improving molecular response, 10 of whom with persistent transcript undetectability.
Conclusion. Albeit obtained in a series of very selected patients, present results represent a further evidence stressing on the efficacy of combining imatinib and IFN a; through different, possibly complementary, mode of action, these two drugs might mutually potentiate their effect while reducing the emergence of drug resistance. The additive toxicity caused by their concurrent use might be overcome by a sequential combination; this could also be applied to patients reaching stable CCR on imatinib but still maintaining detectable residual disease.