Combination of EUTOS score and 3‐month BCR‐ABL transcript level identifies a group of good‐risk chronic myeloid leukemia patients with favorable response to frontline imatinib therapy
Authors: Mario Tiribelli, Gianni Binotto, Elisabetta Calistri, Elena Maino, Luigi Scaffidi, Marta Medeot, Mitja Nabergoj, Achille Ambrosetti, Gianpietro Semenzato, Renato Fanin, Massimiliano Bonifacio
Journal: American Journal of Hematology (2015)

The availability of three tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, and nilotinib, all considered suitable for the frontline treatment of chronic myeloid leukemia (CML) according to the 2013 European Leukemia Net (ELN) recommendations 1, raises questions about the optimal strategy in individual patients. Since decades, efforts has been made to stratify CML patients at diagnosis, to guide the choice of treatment. In 2011 ELN evaluated more than 2000 CML patients treated with front-line imatinib and developed the EUTOS score 2, that divides patients in 2 groups of low- and high-risk, with different rates of 18-month complete cytogenetic response (CCyR) and progression-free survival (PFS). In addition to parameters at diagnosis, response to TKI is considered the strongest predictor of long-term outcome; in particular, a BCR-ABL/ABL transcript ≤10% on the International Scale (IS) at 3 months of TKI treatment, defined as early molecular response (EMR), is associated with improved overall survival (OS) and PFS 3, 4. Since the predictive power of EUTOS score on long-term outcome is still a matter of debate, we tested if it could be improved by association with EMR in patients receiving front-line imatinib. All patients treated from 2004 to 2013 with imatinib 400 mg/day for newly diagnosed chronic phase CML, and for whom both EUTOS score and molecular evaluation at 3 months were available, were included in this retrospective analysis. Patients were stratified into 3 subgroups: “good” = low EUTOS score and 3-months BCR-ABL ≤10%; “intermediate” = high EUTOS or BCR-ABL >10%; “poor” = high EUTOS and BCR-ABL >10%. Informed consent was obtained in accordance with the Declaration of Helsinki before the start of therapy. CCyR was defined as 0% Ph+ by standard bone marrow assessment on ≥20 metaphases. Molecular response was assessed by Q-PCR and expressed as BCR/ABL transcript logarithmic reduction until 2006, and according to IS thereafter; major molecular response (MMR) was defined as a 3-log reduction or as BCR-ABL/ABL ratio ≤ 0.1%IS. Event-free survival (EFS) was defined as the time from the start of imatinib until progression to accelerated/blastic phase (ABP), death from any cause, imatinib dose increase (≥600 mg/day), or switch to 2G-TKIs for primary or secondary resistance. Patients intolerant to imatinib were censored at the time of discontinuation. PFS was defined as the time from imatinib start until ABP or death for any cause. Survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test. A total of 196 patients (107 males and 89 females), with a median age at diagnosis of 55.4 (range: 19.9–84.7) years were included. Median time from diagnosis to imatinib therapy was 0.6 (range: 0–12.2) months; all but three females, diagnosed with CML during pregnancy, started imatinib within three months. EUTOS score was low in 175 patients (89.3%) and high in 21 (10.7%). The two groups were similar for all the analysed variables, except for a higher percentage of low Sokal patients in low EUTOS group and high Sokal patients in the high EUTOS cohort (Table 1). At the 3 month time-point, 145 patients (74%) achieved EMR while 51 patients (26%) did not. There was a strong association between EUTOS score and attainment of EMR: 136/175 (77.7%) in low EUTOS patients compared with 9/21 in the high EUTOS (42.9%; P = 0.0013). Male/female, no. 92/83 15/6 0.11 Age at diagnosis (years); median (range) 55.6 (19.9–84.7) 53.0 (25.1–81.3) 0.27 Time from diagnosis to imatinib start (months); median (range) 0.6 (0–12.2) 0.5 (0–2.2) 0.33 Bcr-Abl transcript type, no. (%) b2a2 66 (37.7) 9 (42.9) 0.64 b3a2 84 (48.0) 9 (42.9) 0.82 Unknown 25 (14.3) 3 (14.2) 1.00 Sokal risk group, no. (%) Low 79 (45.1) 1 (4.8) <0.001 Intermediate 71 (40.6) 10 (47.6) 0.64 High 24 (13.7) 10 (47.6) <0.001 Unknown 1 (0.6) 0 (0) 1.00 Dividing patients according to EUTOS score and 3-month BCR-ABL we identified 136 (69.4%) “good risk”, 48 (24.5%) “intermediate risk,” and 12 (6.1%) “poor risk” cases. Patients in the three groups have a significantly different probability of achieving CCyR at 6 months (84% in the “good risk,” 37% in the “intermediate risk,” and 20% in the “poor risk”; P < 0.0001) and MMR at 12 months (67, 15, and 14%, respectively; P < 0.0001). Deep molecular response, defined as BCR-ABL transcript ≤ 0.01% (MR4.0), was evaluable in a minority of patients; however, cumulative incidence of MR4.0 on imatinib therapy were different between “good risk” (44/136, 32%), “intermediate risk” (3/48, 6%) and “poor risk” (0/12, 0%) (P < 0.0001). With a median follow-up time of 50 months, 11/12 (92%) “poor risk” patients experienced imatinib failure, compared with 36/48 (75%) “intermediate risk” and 37/136 (27%) “good risk” patients (P < 0.0001). EFS for “good”, “intermediate” and “poor” risk patients at 2 and 5 years were 80% (95% confidence interval [CI]: 72–86), 47% (95%CI: 31–61) and 25% (95%CI: 11–38; P < 0.0001) and 70% (95%CI: 59–78), 23% (95%CI: 11–38), and N/A (P < 0.0001), respectively (Fig. 1). We recorded 6/136 progressions or deaths (4%) in “good”, compared to 7/48 (15%) in the “intermediate” and 4/12 (33%) in the “poor risk” patients; consequently, 5-year PFS were 94% (95%CI: 84–98), 86% (95%CI: 71–94), and 65% (95%CI: 32–86), respectively (P = 0.0001; Fig. 2). Finally, there was a trend for a superior OS in the “good risk patients”: 5-year OS were 94% (95%CI: 83–97) in “good”, 90% (95%CI: 74–96) in “intermediate” and 90% (95%CI: 47–98) in “poor risk” groups (P = 0.12). Failure-free survival according to combined EUTOS score and 3-month molecular response. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Progression-free survival according to combined EUTOS score and 3-month molecular response. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] EUTOS score at diagnosis and EMR, defined as BCR-ABL transcript ≤10% after 3 months of therapy, separately proved able to predict long-term outcomes 2−8. In our study, 74% of all patients attained EMR, a percentage similar to those reported by other groups 3, 4, 9. We found a strong association between low EUTOS and achievement of EMR, confirming the predictive value of the EUTOS score. Combining the baseline (low EUTOS) and the dynamic response-related parameter (EMR), we identified a “good risk” group of about 70% of CML patients with excellent outcomes on front-line imatinib, both as high probability of a subsequent optimal response (6-month CCyR 84%, 12-month MMR 67%) and favourable survival (5-year EFS 70%, PFS 94% and OS 94%). The few patients (6%) in the “poor risk” group displayed a dismal prognosis, with low chances of CCyR and MMR, almost unavoidable imatinib failure and high rates of progression. Around one quarter of our patients fell in the “intermediate risk” group, comprising a majority of low EUTOS patients failing EMR and few cases with high EUTOS and BCR-ABL ≤10% at 3 months. Clinical outcomes of this group were closer to the “poor” than to the “good” risk cohort. Patients with high EUTOS could maximally benefit from front-line use of second-generation TKIs, and low EUTOS patients failing optimal 3-month molecular response are candidate for early switch to alternative treatment strategies. Due to the relatively small sizes of the “poor” and “intermediate” risk groups and the retrospective nature of our research, these results need to be confirmed in larger and prospective studies. Mario Tiribelli,1* Gianni Binotto,2 Elisabetta Calistri,3 Elena Maino,4 Luigi Scaffidi,5 Marta Medeot,1 Mitja Nabergoj,2 Achille Ambrosetti,5 Gianpietro Semenzato,2 Renato Fanin,1 Massimiliano Bonifacio5; for the Gruppo Triveneto LMC 1Division of Hematology and BMT, Department of Experimental and Clinical Sciences, Azienda Ospedaliero-Universitaria, Udine, Italy; 2Padua School of Medicine, Department of Medicine, Hematology and Clinical Immunology, Padua, Italy; 3Division of Hematology, Ca' Foncello Hospital, Treviso, Italy; 4Division of Hematology, Dell'angelo Hospital, Venezia-Mestre, Italy; 5Department of Medicine, Section of Hematology, University of Verona, Italy