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An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors

Mariella D'adda, Mirko Farina, Francesca Schieppati, Elisa Cerqui, Giuseppina Ruggeri, Samantha Ferrari, Chiara Bottelli, Chiara Pagani, Angela Passi and Giuseppe Rossi

Abstract

BACKGROUND A substantial proportion (40-60%) of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), achieving sustained deep molecular response (DMR), can safely stop TKIs therapy. According to Euro-Ski and STIM1 trials, Sokal score and TKIs duration influence the probability of molecular relapse after discontinuation, whereas few information are available about the influence of BCR-ABL transcript type on treatment free remission (TFR).

AIM To investigate the impact of different parameters on achievement of a sustained DMR, a prerequisite to safely stop TKIs therapy, and on maintenance of TFR in 134 CML-CP pts with a follow up of at least 36 months, treated at a single center.

METHODS The 181 CML-CP pts presently managed at our Institution according to ELN guidelines and treated with 1st or 2nd generation TKIs (2GTKIs) were analyzed. BCR-ABL transcripts were determined by RQ-PCR analysis in accordance with EAC protocol (Gabert et al, Leukemia 2003) and to the Italian national network Labnet. Criteria for TKIs discontinuation were sustained DMR (MR4 or better) for at least 2 years and treatment duration with TKIs ≥ 3 years. After TKIs withdrawal, RQ-PCR for BCR-ABL was performed every month during the first year and every 2 months thereafter. TKI treatment was reintroduced if DMR loss occurred.

RESULTS Of 181 pts, 134 with a minimum follow up of 36 months were evaluated. Sustained DMR (sDMR) was obtained in 75/134 pts (56%). The characteristics of the two cohorts are summarized in figure 1A. They didn't significantly differ in sex, age, Sokal score distribution, frontline TKIs treatment (imatinib vs 2GTKIs) and duration of TKIs treatment. The type of BCR-ABL transcript was the only parameter at diagnosis which significantly predicted the achievement of sDMR: the e14a2 transcript was present in 56/75 (75%) sDMR+ pts vs 29/59 (49%) not achieving sDMR (sDMR- pts), - p 0.0023-. In e14a2 CML pts, the type of frontline TKIs didn't impact on sDMR achievement (39/58, 67% for imatinib, 17/27, 63% for 2GTKIs), whereas in e13a2 pts, frontline therapy with 2GTKIs increased the probability of sDMR, although not significantly (10/31, 32% with imatinib, 9/18, 50% with 2GTKIs). The number of different TKIs treatment lines also impacted on sDMR, being lower in sDMR+ pts (p 0.0001). Of 75 sDMR+ pts, 62 discontinued TKIs, given as first-line therapy in 57 (13 had received prior r-interferon) or as second-line therapy in 5 pts, respectively. Thirteen pts refused the option of TKIs discontinuation. Thirty-nine pts stopped imatinib, 20 nilotinib and 3 dasatinib. At discontinuation, median age was 62 (30-85), median time from TKI start 95 months (36-153) and median duration of DMR 48 months (24-153). Sokal distribution was 45%, 34% and 19% for low, intermediate and high risk, respectively. The e14a2 transcript was expressed in 49 (79%) cases, e13a2 transcript in 13 (21%). Median follow up after treatment discontinuation was 19 months (1-81), including 44 patients with follow up > 12 months. DMR was lost in 16/62 (26%): median time off-therapy for relapsed pts was 3,5 months (2-21). Therapy was restarted in all 16 pts, 13 achieved a second DMR after a median interval of 3 months (1-8), 1 is in MR3, 2 have resumed TKIs for 1 month. Univariate analysis showed no difference in the risk of DMR loss according to age, gender, TKI type, duration of TKIs treatment and of stable DMR. Of note, only the type of BCR-ABL transcript significantly impacted DMR loss. After 12 months from TKI discontinuation 79% (SE +/-6%) of e14a2 and 40% (SE +/-17%) of e13a2 patients were still in TFR (log-rank: P=0.012)- figure 1B. There was a trend towards relapse for pts with intermediate + high risk Sokal score vs low risk pts (p 0.05). Eleven out of 13 pts treated with INF before imatinib remained in TFR. At multivariate analysis the type of BCR-ABL transcript and previous INF treatment were independently associated with DMR loss (p 0.011 and p 0.033).

CONCLUSION In this unselected series of CML-CP pts managed at a single institution, having e13a2 type of BCR-ABL transcript was the most important adverse prognostic factor (the only at diagnosis) for achieving sustained DMR as well as for maintaining a TFR after TKIs discontinuation. On the other hand, having the e14a2 transcript was a favorable prognostic factor for obtaining sustained DMR, irrespective of the TKI type received, and was associated with a very high rate of TFR maintenance.

Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

  • * Asterisk with author names denotes non-ASH members.