RESEARCH ARTICLE. Introduction. Methods Wiley Periodicals, Inc.

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1 BCR/ABL level at 6 months identifies good risk CML subgroup after failing early molecular response at 3 months following imatinib therapy for CML in chronic phase AJH Dennis (Dong Hwan) Kim, 1 * Nada Hamad, 1 Hong Gi Lee, 1 Suzanne Kamel-Reid, 2 and Jeffrey H. Lipton 1 It is unclear if patients with CML treated with imatinib who fail to achieve BCR/ABL transcript levels <10% IS at 3 months i.e. an early molecular response (EMR) have a better prognosis if they achieve a response by 6 months. We reviewed 320 patients with chronic myeloid leukemia (CML) in chronic phase receiving Imatinib therapy with 3and6monthBCR/ABL transcript levels available, and divided them into four groups. Group I (achieved an EMR at 3 months), Group II (did not achieve an EMR at 3 months, but achieved a transcript level of <1% at 6 months), Group III (did not achieve an EMR at 3 months, then at 6 months achieved a level between 1% and 10%) and Group IV (failed to achieve a response at 3 and 6 months). Compared to Group I, Group IV showed significantly worse freedom from treatment failure (FTF; 93.1% vs 69.0%, P < 0.001), progression free survival (97.7% vs 77.3%, P < 0.001) and overall survival (98.3% vs 78.9%, P < 0.001). While, group III showed inferior PFS (98.3% vs 90.4%, P ) and OS (97.7% vs 90.4%, P ), but no difference in FTF (93.1% vs 92.0%, P ). There were no significant differences between Groups I and II. A BCR/ABL transcript level at 6 months can identify a goodrisk subgroup among patients who fail to achieve an EMR on Imatinib therapy for CML. Am. J. Hematol. 89: , VC 2014 Wiley Periodicals, Inc. Introduction The prognostic role of an early molecular response (EMR) defined as 10% IS of the BCR/ABL transcript level at 3 months following Imatinib [1,2] or Dasatinib [3] therapy for chronic myeloid leukemia (CML) has been well established. An EMR was demonstrated to have a strong correlation with long-term outcomes including progression free (PFS) and overall survival (OS) not only following Imatinib therapy but also after 2 nd generation tyrosine kinase inhibitor (2GTKI) therapy for Imatinib failure. Marin et al. [1] reported that the BCR/ABL transcript level at 3 months can help predict long-term outcomes in CML patients treated with Imatinib as first line therapy. They reported that BCR/ABL transcript levels of 9.84% IS at 3 months and 1.67% IS at 6 months were the cutoff values with the strongest stratification power for OS. Another study by Hanfstein et al. [4] in CML patients treated with imatinib suggested that BCR/ABL transcript levels at 6 as well as 3 months correlated with prognosis. A BCR/ABL transcript level at 3 months >10% IS showed excellent separation of a high risk group (87%) from those with levels of 1 10% IS (94%) and levels 1% IS (97%) in terms of 5 year OS. Furthermore, the 6 month BCR/ABL transcript level was reported to have a strong association with survival. A BCR/ABL transcript level at 6 months >1% IS (89%) was found to be associated with inferior 5 year OS survival compared to a level 1% IS (97%). The recently published new ELN recommendations for the management of CML have incorporated the concept of EMR into the clinical decision making process [5]. The milestones of a BCR/ABL transcript level 10% IS at 3 months as well as 1% IS at 6 months were included. The ELN recommendations do not consider a single measurement of the BCR/ABL transcript level at 3 months as sufficient to define failure necessitating a change of treatment and therefore recommend a repeat level at 6 months [5]. Levels >10% IS at 3 months were defined as warning and not failure. Levels >10% IS at 6 months were defined as failure whereas those between 15% and 10% IS at 6 months were also defined as warning. Levels <1% IS at 6 months were defined as an optimal response. However, there are no long-term data that differentiate between patients who achieve an EMR at 3 months and those who fail to achieve an EMR at 3 months but go on to achieve BCR/ABL transcript levels 1% IS at 6 months. This study attempted to address this issue. Methods Patient groups. We reviewed 361 patients with CML in chronic phase (CP) who received imatinib therapy and monitored at the Princess Margaret Hospital (Toronto, ON, Canada). Patients who had BCR/ABL transcript levels at 3 and 6 months were included. Of the 361 patients who were diagnosed with CML and treated with imatinib at a dose of 400 mg daily, 320 patients had BCR/ABL transcript levels at 3 and 6 months available for review and were therefore included in this study for final analysis. This retrospective study was approved by the Research Ethics Board of the University Health Network. Patient demographics and disease characteristics at the time of imatinib therapy are presented in Table I. The median age was 51 years (range 17 82), and 43.4% were female. The median follow-up duration of imatinib therapy was 77 months (range 6 139). Additional Supporting Information may be found in the online version of this article. 1 Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario, Canada; 2 Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Ontario, Canada Conflict of interest: Nothing to report. *Correspondence to: Dennis (Dong Hwan) Kim; Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9. dr.dennis.kim@uhn.ca Received for publication: 23 January 2014; Revised: 18 February 2014; Accepted: 7 March 2014 Am. J. Hematol. 89: , Published online: 12 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh VC 2014 Wiley Periodicals, Inc. 626 American Journal of Hematology, Vol. 89, No. 6, June 2014 doi: /ajh.23707

2 BCR/ABL PCR at 3 and 6 months after Imatinib TABLE I. The Demographics, Disease Characteristics and the Frequency of BCR/ABL Transcript Levels >10% IS, 1 10% IS, and 1% IS at 3 and 6 Months in Patients Treated with Imatinib for Chronic Myeloid Leukemia in Chronic Phase Patient s characteristics No of pts (%) 23 (7.2) Age (median, year) 51 (17 82) Gender (female:male) 139/181 (43.4:56.6) Previous treatment 108 (33.8) Previous history of Interferon therapy 92 (28.8) Previous history of BMT 13 (4.1) Additional chromosomal abnormalities other than Philadelphia chromosome a Median follow-up (month) 77 (6 139) BCR/ABL transcript level <10% following imatinib therapy At 3 months >10% IS 136 (42.5) 1 10% IS 84 (26.3) 1% IS 100 (31.3) At 6 months >10% IS 83 (25.9) 1 10% IS 64 (20.0) 1% IS 173 (54.1) Abbreviations: BMT, bone marrow transplantation; IS, international scale. a -Y (n 5 5); double Ph (n 5 3); t(9;22;22) (n 5 2); -X (n 5 1); inv(5) (n 5 1); inv(9q) (n 5 1); inv(11) (n 5 1); t(1;22;8), t(1;22), der(1), del(9), der(22), der(9) (n 5 1); t(15;19)( n 5 1); t(2;9;22) (n 5 1); t(6;9;22) (n 5 1); t(7;9;22) (n 5 1); t(9;17),t(15;22),t(17;22) (n 5 1); t(9;17;22) (n 5 1); t(8;16) (n 5 1); 18 (n 5 1). BCR/ABL transcript evaluation following imatinib therapy. BCR/ABL transcript PCR testing was performed every 3 months as follows [6]: peripheral blood samples were analyzed using quantitative PCR to determine BCR/ABL transcript levels, according to the manufacturer s instructions (ABI 7900HT Fast Real-Time PCR System, Applied Biosystems, Foster City, CA) and the international recommendations established for standardization of this test [7]. BCR/ABL transcript levels were measured and recorded using the international scale. The ABL gene was used as a reference gene. Definition of response criteria and end points. The response criteria used in this study are those previously defined [7 10]. Briefly, Cytogenetic responses were categorized as complete (CCyR; 0% Ph 1 cells in marrow by conventional cytogenetics), partial (1 34% Ph 1 cells in marrow), or minor (35 90% Ph 1 cells in marrow). A major cytogenetic response (MCyR) was defined as the sum of CCyR and partial cytogenetic response (i.e. 0 35% Ph 1 cells in marrow). A major molecular response (MMR) was defined as a BCR/ABL transcript level 0.1% IS, and a molecular response (MR 4.5 ) was defined as a BCR/ABL transcript level of % IS, equivalent to a 4.5 log reduction in the BCR/ABL transcript level. Time to treatment failure was defined as the interval between the initiation of imatinib and the occurrence of events that indicated possible treatment failure, including primary hematologic resistance, cytogenetic resistance, loss of CCyR, development of tyrosine kinase domain mutation, clonal evolution and progression to accelerated phase (AP), or blastic crisis (BC) [6,11]. Time to progression free survival (PFS) was defined as the interval between initiation of imatinib and confirmed progression to accelerated AP or BC or death from any cause, whereas OS was calculated from initiation of imatinib until the date of death from any cause or until last follow-up. Imatinib discontinuation was also recorded [11]. Statistical analysis. Medical records were reviewed until December The cumulative incidences of CCyR, MMR, and MR 4.5 were estimated using the cumulative incidence method considering the competing risks [12] of imatinib discontinuation and death. The probabilities of freedom from treatment failure (FTF), PFS, and OS were estimated by the Kaplan-Meier method. Patients were divided according to their BCR/ABL transcript levels at 3 and 6 months using cutoff levels of <1% IS, 1 10% IS and 10% IS. Correlation was evaluated for patient proportions in the <1% IS, 1 10% IS, and 10% IS BCR/ABL transcript level groups at 3 and 6 months. Four groups were defined as follows: Group Figure 1. (A) Distribution and group assignment of CML-CP patients into four groups according to BCR/ABL transcript levels at 3 and 6 months with 1%IS and 10%IS as cutoff value. Group I indicates those who achieved EMR at 3 months 10%IS regardless of BCR/ABL transcript level at 6 months. Groups II, III, and IV indicate those who failed to achieve 10%IS at 3 months, then achieved 1%IS (Group II), between 1% and 10%IS (Group III) and failed at 6 months (Group IV). (B) Distribution of BCR/ABL transcript levels at 3 and 6 months with 1%IS and 10%IS as cutoff values. I included those who achieved an EMR at 3 months regardless of BCR/ABL transcript levels at 6 months. Groups II, III, and IV included those who failed to achieve an EMR at 3 months. Groups II included those who went on to achieve BCR/ABL transcript levels <1% at 6 months. Group III included patients who went on to achieve BCR/ABL transcript levels between 1% and 10% at 6 months. Group IV included patients who did not achieve a response by 6 months and were considered to have failed therapy. The cumulative incidences of CCyR, MMR. and MR 4.5 were compared and plotted among the four groups using the Gray test, while survival analysis for FTF, PFS and OS were performed among the four groups using the log-rank test. The overall P-value and separate P-values were calculated for Group II IV compared to Group I (i.e. reference). For multivariate analyses, Fine-Gray methods were adopted for CCyR, MMR, and MR 4.5, and Cox proportional hazard models were adopted for FTF, PFS, and OS. A stepwise selection algorithm was applied for model selection using the criteria for variable selection, P for variable entry and P for variable removal. The following variables were considered for modeling: (1) The TABLE II. Correlation of Proportion of Patients by BCR-ABL Transcript Levels at 3 and 6 Months (P < 0.001; ) Following Imatinib Therapy 1% IS 1 10% IS >10% IS 3mo 6mo 100/320 (31.3) 84/320 (26.3) 136/320 (42.5) 1% IS 173/320 (54.1) 97/320 (30.3) 58/320 (18.1) 18/320 (5.6) 1 10% IS 64/320 (20.0) 3/320 (0.9) 19/320 (5.9) 42/320 (13.1) >10% IS 83/320 (25.9) 0 (0) 7/320 (2.2) 76/320 (23.8) doi: /ajh American Journal of Hematology, Vol. 89, No. 6, June

3 Kim et al. TABLE III. Clinical Outcomes of Imatinib Therapy According to the Groups by BCR/ABL Transcript Levels at 3 or 6 Months Group 3 months 6 months No of pts (%) CCyR at 18 mo MMR at 3 years MR 4.5 at 6 yrs FTF at 3 years PFS at 10 yrs OS at 10 yrs I. 10% IS 184 (57.5) 95.1% 90.2% 72.5% % % % II. >10% IS 1% IS 18 (5.6) 100% 77.0% 53.1% 100% % % III. >10% IS 1 10% IS 42 (13.1) 77.0% 68.8% 29.6% % % % IV. >10% IS >10% IS 76 (23.8) 22.2% 17.0% 12.3% % % % P-value a <0.001 <0.001 <0.001 < P-value between II vs I P-value between III vs I. <0.001 <0.001 < P-value between IV vs I. <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; MR 4.5, molecular response with 4.5 log reduction; FTF, freedom from treatment failure; PFS, progression free survival; OS, overall survival. a P-values among the four groups. four groups based on 3 and 6 month BCR/ABL transcript levels (Group I vs. Group II vs. Group III vs. Group IV), (2) Previous history of CML therapy, (3) Previous interferon therapy, (4) Previous history of allogeneic transplantation, (5) Age (continuous variable), and (6) additional cytogenetic abnormality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the significant risk factors, based on a multivariate analysis with a statistical significance level of Serial 3 monthly BCR/ABL transcript levels were plotted up to 60 months, and compared at each time point among the four groups using the ANOVA test. Also, post hoc multiple comparison procedures were performed using the Tukey HSD method. Statistical analyses were performed using EZR software based on R (available at [13]. Results Patients and outcome Patient characteristics are summarized in Table I. Overall, the cumulative incidences of CCyR at 18 months, MMR at 3 years and MR 4.5 at 6 years were %, %, and %, respectively. The probability of FTF at 3 years was %, while those of PFS and OS at 10 years were % and %, respectively. However, there were no differences in the incidences of CCyR, MMR, MR 4.5, treatment failure, PFS, or OS based on a previous history of CML treatment other than TKI therapy. Additional cytogenetic abnormality was associated with a lower incidence of CCyR or MMR, but not with other parameters. No significant differences in basic characteristics between de novo patients and those previously treated except for age and median follow-up duration (Supporting information Table 1). The difference in age can be explained by longer history of CML in the group previously treated than de novo patients which also explains their longer followup duration. According to the previous history of allogeneic transplantation, no differences in characteristics were noted between those who received transplant versus not in terms of age, additional cytogenetic abnormalities or sokal risk groups (Supporting information Table II). BCR/ABL transcript levels at 3 and 6 months Using BCR/ABL transcript cut off levels of 1% IS and 10% IS,at3 months 136 (42.5%) patients had levels 10% IS, 84 (26.3%) patients had levels of 1 10% IS, and 100 (31.3%) patients had levels <1% IS. For BCR/ABL transcript level at 6 months, 83 (25.9%) patients had levels 10% IS, 64 (20.0%) patients had levels of 1 10% IS and 173 (54.1%) patients had levels <1% IS (Fig. 1 and Table I). When we compared the proportion of patients based on BCR/ABL transcript levels at 3 and 6 months (Table II), a strong correlation was observed between levels at 3 and 6 months (P < by chi square test). Most of the patients who achieved a level <1% IS at 3 months went on to maintain a similar level (<1% IS ) at 6 months (n 5 97/100; 97%) and only three patients had levels of 1 10% IS at 6 months (Table II). In the 136 patients who failed to achieve an EMR at 3 months,18 (13.2%) showed a significant reduction in the BCR/ ABL transcript level <1% IS at 6 months while 42 (30.9%) had a slow reduction to 1 10% IS. However, 76 (55.9%) patients still failed to achieve a BCR/ABL transcript level <10% IS at 6 months. Long-term outcomes based on the BCR/ABL transcript level at 3 or 6 months When long-term outcomes were compared among the four groups, statistical differences were noted in FTF, PFS, and OS (Table III). Consistently, subgroup analyses comparing Group I vs IV consistently showed differences in FTF (93.1% vs 69.0% at 3 years, P < 0.001), PFS (97.7% vs 77.3% at 10 years, P < 0.001) and OS (98.3% vs 78.9% at 10 years, P < 0.001) in favor of Group I. However, when subgroup analyses were restricted to Groups I and II, there were no differences in FTF (93.1% vs 100% at 3 years, P ), PFS (97.7% vs 93.3% at 10 years, P ), or OS (98.3% vs 93.3% at 10 years, P ) between the two groups as presented in Fig. 2. Comparing Groups I and III, Group III showed inferior PFS (98.3% vs 90.4% at 10 years, P ) and OS (97.7% vs 90.4% at 10 years, P ), but no difference in FTF (93.1% vs 92.0% at 3 years, P ). Response and treatment failure outcomes based on the BCR/ABL transcript level at 3 or 6 months We compared the responses to imatinib therapy among the four groups including CCyR, MMR, and MR 4.5 (Table III and Fig. 3). As expected, there were significant differences in response between Group I vs IV in favor of Group I; CCyR (95.1% vs 22.2% at 18 months, P < 0.001), MMR (90.2% vs 17.0% at 3 years, P < 0.001) and MR 4.5 (72.5% vs 12.3% at 6 years, P < 0.001). Similar findings were observed between Groups I and III, with statistically significant lower response rates in Group III; CCyR (95.1% vs 77.0% at 18 months, P < 0.001), MMR (90.2% vs 68.8% at 3 years, P < 0.001), and MR 4.5 (72.5% vs 29.6% at 6 years, P < 0.001). However, there were no differences between Group I and II; CCyR (95.1% vs 100.0% at 18 months, P ) and MR 4.5 (72.5% vs 53.1% at 6 years, P ) as shown in Table III and Fig. 3. The comparison between group I III versus group IV is presented in the Supporting information Table III with respect to basic characteristics and prior treatments. Multivariate analysis for response and long-term survival In order to verify the above results, we performed multivariate analyses for CCyR, MMR, and MR 4.5, and a Cox proportional hazard model was adopted for FTF, PFS, and OS. As shown in Table IV, there were no differences in response or survival between Groups I vs II for CCyR (P ), MR 4.5 (P ), FTF (P ), PFS (0.708), and OS (P ), but there was a difference for MMR (P 628 American Journal of Hematology, Vol. 89, No. 6, June 2014 doi: /ajh.23707

4 BCR/ABL PCR at 3 and 6 months after Imatinib Figure 2. Overall and progression free survival among the four groups based on 3 and 6 months BCR/ABL transcript levels following imatinib therapy for CML patients in CP ). There were statistical differences between Groups I and III, in CCyR (P < ), MMR (P < ) and MR 4.5 (P < ), but not in FTF (P ), PFS (P ), and OS (P ). However, between Groups I and IV, it was evident that treatment outcomes were significantly worse in Group IV in terms of CCyR (P < ), MMR (P < ), MR 4.5 (P < ), FTF (P < ), PFS (P ), and OS (P ). In summary, Group II showed almost equivalent long-term outcomes following imatinib therapy compared to Group I. Group III Figure 3. Treatment failure and CCR among the four groups based on 3 and 6 month BCR/ABL transcript levels following imatinib therapy for CML patients in CP. showed similar long-term outcomes but a slower response compared to Group I. Group IV exhibited significantly worse short- and longterm responses and outcomes compared to Group I. Serial changes in BCR/ABL transcript level based on the BCR/ABL transcript level at 3 months We also compared serial changes in the BCR/ABL transcript levels over time up to 60 months among the four groups. As shown in Fig. 4, Group I showed an excellent decrease in BCR/ABL transcript level over time, especially within the first 18 months to almost 0.01% IS, then maintained their molecular response well over time. As doi: /ajh American Journal of Hematology, Vol. 89, No. 6, June

5 Kim et al. TABLE IV. Multivariate Analyses for Response and Long-Term Outcomes of Imatinib Therapy According to the Groups by BCR/ABL Transcript Levels at 3 or 6 Months Multivariate Endpoint Risk factors Univariate P-value P-value HR (95% C.I.) CCyR Grouping by BCR/ABL transcript at 3 and 6 months < < [ ] Failed at 3 months but 1% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months but 1 10% at 6 months (vs 10% at 3 months) <0.001 < [ ] Failed at 3 months and 6 months (vs 10% at 3 months) <0.001 < [ ] Previous history of BMT [ ] Age, continuous 0.1 NS Additional cytogenetic abnormality NS MMR Grouping by BCR/ABL transcript at 3 and 6 months < < [ ] Failed at 3 months but 1% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months but 1 10% at 6 months (vs 10% at 3 months) < < [ ] Failed at 3 months and 6 months (vs 10% at 3 months) < < [ ] Previous history of BMT < < [ ] Age, continuous 0.2 NS Additional cytogenetic abnormality NS MR 4.5 Grouping by BCR/ABL transcript at 3 and 6 months < < [ ] Failed at 3 months but 1% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months but 1 10% at 6 months (vs 10% at 3 mo) < < [ ] Failed at 3 months and 6 months (vs 10% at 3 months) < < [ ] Previous history of BMT < < [ ] Age, continuous 0.1 NS Additional cytogenetic abnormality NS NS FTF Four groups by BCR/ABL transcript at 3 and 6 months <0.001 <0.001 Failed at 3 months but 1% at 6 months (vs 10% at 3 months) Failed at 3 months but 1 10% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months and 6 months (vs 10% at 3 months) <0.001 < [ ] Previous history of BMT NS Age, continuous NS Additional cytogenetic abnormality 0.01 NS PFS 4 groups by BCR/ABL transcript at 3 and 6 months Failed at 3 months but 1% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months but 1 10% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months and 6 months (vs 10% at 3 months) < [ ] Previous history of BMT NS Age, continuous NS Additional cytogenetic abnormality NS NS OS 4 Groups by BCR/ABL transcript at 3 and 6 months Failed at 3 months but 1% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months but 1 10% at 6 months (vs 10% at 3 months) [ ] Failed at 3 months and 6 months (vs 10% at 3 months) < [ ] Previous history of BMT NS Age, continuous NS [ ] Additional cytogenetic abnormality NS NS Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; MR 4.5, molecular response with 4.5 log reduction; FTF, freedom from treatment failure; PFS, progression free survival; OS, overall survival; HR, hazard ratio; 95% C.I., 95% confidence interval expected, Group II had higher BCR/ABL transcript levels compared to Group I at 3 (P < 0.001) and 6 months (P ), but had a rapid decline in levels after 6 months and achieved a level of 0.01% IS at around 27 months without any statistical differences between these two groups. Group III showed a slow but continuous decrease in BCR/ABL transcript levels and eventually there was no difference in levels compared to Group I beyond 57 months (P at 57 months and P at 60 months). Group IV also showed a continuous but very slow decline in BCR/ABL transcript levels with continuous statistical differences when compared to Group I as shown in Fig. 4. Details of serial changes of BCR/ABL transcript level are presented in the Supporting information Table IV according to the BCR/ ABL transcript level at 3 months. Discussion This study demonstrates that (1) 6 13% of patients were able to achieve BCR/ABL transcript levels <1% IS or 1 10% IS after failing to achieve an EMR at 3 months following imatinib therapy, while 24% of patients eventually failed to achieve levels <10% IS at 3 as well as 6 months; (2) those who achieve levels <1% IS at 6 months after failing to achieve an EMR at 3 months do well without significant differences in short- or long-term outcomes compared to those who achieve an EMR at 3 months; and (3) those who failed to attain levels <10% IS at 3 as well as 6 months showed the worst short- and longterm outcomes. In the treatment of CML the measurement of the BCR/ABL transcript level at 3 months to assess EMR, has become the standard of care as it is highly predictive of long-term outcomes including PFS and OS [1,2]. Very few controversies still remain surrounding the cutoff value of 10% IS at 3 months. However, the question that remains is how to manage patients who fail to achieve an EMR. It is unclear if changing treatment based on a single BCR/ABL transcript level at 3 months is warranted [5]. The panel of the new ELN recommendations concluded that a single measurement of the BCR/ABL transcript level at 3 months is not sufficient to define failure thus recommending at least two follow-up consecutive tests at 6 and 9 months. However, there are no available data to establish if long-term outcomes are equivalent between those who achieve an EMR at American Journal of Hematology, Vol. 89, No. 6, June 2014 doi: /ajh.23707

6 BCR/ABL PCR at 3 and 6 months after Imatinib Figure 4. Serial BCR/ABL transcript levels up to 60 months according to the groups by BCR/ABL transcript levels at 3 or 6 months. months and those who fail to achieve an EMR at 3 months but go on to achieve levels <1% IS at 6 months [5]. This study divided patients into four groups according to the BCR/ ABL transcript levels achieved at 3 and 6 months. There were no differences in short- and long-term outcomes between Group I (i.e. achieved an EMR at 3 months, n 5 184; 57.5%) and II (i.e. failed to achieve an EMR at 3 months but achieved levels <1% IS at 6 months, n 5 18; 5.6%; Table III). In addition, serial changes in the BCR/ABL transcript level suggest that Group II showed a higher transcript levels over Group I at 3 months (P < 0.001) and at 6 months (P ), but a rapid decline in levels after 6 months down to 0.01% IS at around 27 months without any statistical differences in outcomes (Fig. 4). These results support the new ELN recommendations in that failure to achieve an EMR is not a failure but a warning and that the BCR/ABL transcript level needs to be rechecked at 6 months [5]. Further more the patients who achieved a BCR/ABL transcript level <1% IS at 6 months fit the optimal response category as their shortand long-term outcomes were excellent and did not require treatment modification. The patients who failed to achieve an EMR at 3 months but attained levels of 1 10% IS at 6 months (Group III, n 5 42, 13.1%), had a lower PFS (90.4% vs 97.7% at 10 year) and OS (90.4% vs 98.3% at 10 year) compared to those achieving an EMR at 3 months (i.e. Group I) as shown in Table III. However, these differences in long-term outcomes were not confirmed in multivariate analyses as shown in Table IV (P for PFS, P for OS). The new ELN recommendations categorize these patients in the warning group and recommend close monitoring of these patients with repeat BCR/ABL transcript level testing at 6 months [5]. The group who failed to achieve BCR/ABL transcript levels 10% IS at 3 and 6 months (n 5 76, 23.8%) had the worst short- and longterm outcomes (77.3% vs 97.7% PFS at 10 year and 78.9% vs 98.3% OS at 10 year). This was also confirmed by the multivariate analyses (Table IV). The new ELN recommendations consider these cases as failure of treatment. A single measure of the BCR/ABL transcript level at 3 months after initiating a new treatment may overestimate the need for treatment intervention even though its prognostic power is well established. Some patients fail to achieve an EMR at 3 months because of intolerability and subsequent drug interruption. However, after dose adjustment some of these patients can restore their response by 6 months achieving levels 10% IS or even <1% IS. A switch in TKI in these circumstances is not always necessary. Adherence and compliance to TKIs can also significantly affect EMR. This is difficult to manage without improvement in patient compliance but a switch in TKI is not usually helpful. It is important to consider and remedy drug intolerance or compliance prior to switching TKIs. Nevertheless, the repeat measurement of the BCR/ABL transcript level at 6 months in this study could potentially rescue approximately 19% of patients from changes in treatment. The remaining 23.8% of patients in this study were potential candidates for a switch to an alternative TKI. The question of the best TKI after treatment failure with Imatinib still remains. The results of the TIDEL-1 and -2 trials suggest that early intervention with dose escalation or a switch to a second generation TKI may not improve outcomes [14.] Allogeneic stem cell transplantation can be an alternative but this is a very aggressive treatment option associated with a high transplant-related mortality. The 5 year OS following transplant is approximately 70% and it is associated with significant complications compared to the outcomes of patients treated with a TKI as seen in this study with 10 year OS of 79% even if patients who fail to achieve BCR/ABL transcript levels 10% IS at 3 and 6 months. The remaining treatment options are clinical trials of novel drugs such as ponatinib or an alternative drug class [5.] There are still no treatment options with proven efficacy that improve outcomes if initiated after failure to achieve an EMR at 3 months. In conclusion, the BCR/ABL transcript level at 6 months is helpful in identifying a good-risk subgroup among patients who fail to achieve an EMR at 3 months following Imatinib therapy for chronic phase CML. The results of this study support the categories of failure and warning in the new ELN recommendations. Author Contributions DK contributed to the design of study, the supervision of data collection, data interpretation, data analysis, and writing the manuscript. doi: /ajh American Journal of Hematology, Vol. 89, No. 6, June

7 Kim et al. NH contributed to the analysis and interpretation of the data as well as writing of the manuscript HL contributed to the data collection, analysis and interpretation of the data as well as critical revision of the manuscript. SKL and JL were involved in the design of the study, supervision of the data collection, interpretation of the data and critical revision of the manuscript. References 1. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 Transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 2012;30: Hanfstein B, Muller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012; doi: /leu Hochhaus A, Saglio G, Chuah C, et al. Dasatinib and imatinib-induced reductions in BCR-ABL transcript levels below 10% at 3 months are associated with improved responses in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Analysis of molecular response kinetics in the DASISION trial. Blood (ASH Annual Meeting Abstracts) 2011;118: Hanfstein B, Muller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012;26: Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Blood 2013;122: Kim DD, Lee H, Kamel-Reid S, Lipton JH. BCR- ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib. Br J Haematol 2013;160: Druker BJ, Guilhot F, O Brien SG, et al. Fiveyear follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349: Kantarjian HM, O Brien S, Cortes JE, et al. Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 2002;8: O Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: Kim DH, Sriharsha L, Jung CW, et al. Comprehensive evaluation of time-to-response parameter as a predictor of treatment failure following imatinib therapy in chronic phase chronic myeloid leukemia: which parameter at which time-point does matter? Am J Hematol 2010;85: Zhang MJ, Zhang X, Scheike TH. Modeling cumulative incidence function for competing risks data. Expert Rev Clin Pharmacol 2008;1: Kanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow Transplant 2013;48: Yeung DT, Osborn M, White DL, et al. Upfront imatinib therapy in CML patients with rapid switching to nilotinib for failure to achieve molecular targets or intolerance achieves high overall rates of molecular response and a low risk of progression An update of the TIDEL-II trial. Blood (ASH Annual Meeting Abstracts) 2011;118: American Journal of Hematology, Vol. 89, No. 6, June 2014 doi: /ajh.23707

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