AbstractResponse to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.
Despite the excellent response to frontline therapy with imatinib and 2nd generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib,1–4 some patients with chronic myeloid leukemia (CML) fail to responsd to therapy and have poor long-term outcome.5 It has been suggested that the achievement of early response to TKIs is a major determinant for long-term outcome.6–9 The assessment of cytogenetic or molecular response at three months has been defined as a strong predictor for outcome of patients treated with front-line TKIs.6,8–12 Patients who do not achieve a major cytogenetic response (MCyR) or BCR-ABL transcript level less than 10% at three months have inferior event free survival (EFS) and perhaps overall survival (OS).10–12 It is still a question of debate as to whether this finding is enough to justify a change in therapy for such patients.
The purpose of this analysis is to define whether additional assessment at six months may improve the ability to identify those patients destined to have a poor long-term outcome among those with a poor response at three months.
Between July 2000 and June 2011, a total of 456 newly diagnosed CML patients in chronic phase (CP) were treated at the MD Anderson Cancer Center with: imatinib 400 mg daily (n=67), imatinib 800 mg daily (n=196), or 2 generation TKIs (2nd GTKIs, dasatinib and nilotinib; n=193) in consecutive or parallel trials. All trials were approved by the institutional review board (IRB) and all patients signed informed consent in accordance with the Declaration of Helsinki. Cytogentic and molecular responses were generally evaluated at baseline and every three months for the first year and then every six months. Cytogenetic responses were defined as described previously.13
Differences among variables were evaluated by Fisher’s exact test for categorical and Mann-Whitney U test for continuous variables. Time-to-event analyses were performed by the Kaplan-Meier method, and survival curves were compared with the log rank test. All P values were two-sided. P>0.05 was considered significant.
Results and Discussion
Among 456 patients treated, 44 (10%) did not achieve MCyR at 3 months: 18 of 67 (27%) treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd GTKI. Compared to patients who achieved MCyR at three months, these patients were younger, had a higher Sokal score, lower hemoglobin, higher white blood cell count, higher peripheral blood blast percentage, larger spleen, and were mainly treated with imatinib 400 mg daily (Table 1). Since some patients (mostly treated with imatinib 400) started treatment with imatinib in 2000 when early molecular monitoring was not done routinely, 24 (54%) patients had no BCR-ABL transcript level at three months, thus we focused on cytogenetic response.
Among these 44 patients, at six months, 19 (43%) achieved MCyR: 8 (18%) complete cytogenetic response (CCyR) and 11 (25%) partial cytogenetic response (PCyR. In addition, 17 (38%) continued to have no MCyR, 2 (5%) had inevaluable cytogenetic analysis, and 6 (14%) were off study: one transformed to blast phase at three months; one changed therapy (to dasatinib) at three months because of lack of complete hematologic response (CHR) on imatinib 400, achieved a CCyR, and subsequently received a matched unrelated donor allogeneic stem cell transplant with ongoing complete molecular response (CMR) for over six years; one initially achieved CHR on nilotinib and then lost it, had irregular follow up because of non-compliance, and subsequently received hydroxyurea for white blood cell count control and more recently started dasatinib; and 3 were lost to follow up. Among patients with low and intermediate Sokal score at baseline who did not achieve MCyR at three months, 9 of 17 (53%, 4 CCyR and 5 PCyR) and 8 of 16 (50%, 3 CCyR and 5 PCyR) achieved a MCyR at six months, respectively; however, only 2 of 11 (18%, 1 CCyR and 1 PCyR) patients with high-risk Sokal were able to achieve this response at six months.
During the first six months of therapy, 23 (52%) of the 44 patients required dose interruption of their initial therapy due to side effects (4 on imatinib 400, 14 imatinib 800, and 5 2nd GTKI). Among them, 11 (48%) patients required dose interruption in the first three months, 6 (26%) between 3–6 months, and 6 (26%) in both periods. Median duration of interruption was 19 days (range 1–59). Thirteen (30%) patients required dose reduction of their original dose during the first six months, 8 (62%) during the first three months, 4 (31%) between 3–6 months, and one (7%) in both periods.
With a median follow up of 95 months, the OS, failure free survival (FFS) and transformation free survival (TFS) for patients who did not achieve MCyR at three months and subsequently achieved a MCyR at six months were very similar to those of patients who achieved a MCyR at three months, and superior to that of patients still with no MCyR at six months (Figure 1).
The identification of the prognostic significance of response to TKI three months after the start of therapy has triggered a controversy as to the optimal management of these patients. There are no currently available data from prospective studies suggesting change of therapy among these patients alters the outcome. The NCCN has recommended that these patients should be offered a change of therapy, with no option for continuation of therapy. However, only approximately 20% of those who have a poor response at three months have a poor outcome (i.e. an ‘event’) and up to 10% of those with a good outcome at three months still have a poor long-term outcome. Thus, a change for all would be aimed at helping only 10–15% of patients. In this analysis, we attempted to determine whether an additional observation at six months might better discriminate those patients destined to have a poor outcome. Indeed, those who still have not achieved a MCyR (currently considered suboptimal response by ELN)13 have a poor outcome, whereas those who by then have achieved MCyR have an excellent outcome. In our series, only one patient progressed to blast phase and this occurred at three months, with no transformations occurring between 3–6 months. Our patient population had a higher percentage of patients with a low risk Sokal score at baseline than that reported in other series. This score seems to be a good surrogate to predict the response at three and six months. Patients with high-risk Sokal score at baseline had a higher chance of failing to achieve MCyR at three months. Moreover, among patients with a high-risk score who achieve MCyR at three months, only 18% of them may subsequently achieve this response at six months suggesting that Sokal score may be helpful to identify those patients with the worse outcome that may need a different approach. In contrast to our data, a recent series suggested that waiting for six months does not offer additional discrimination,14 although the cutoff sought at six months was different (BCR-ABL 1%, grossly equivalent to CCyR).15 The differences between these two analyses can only be sorted by prospective studies that investigate these options and the long-term value of change of therapy versus continuation for patients with poor response at three months. Until such studies are available, it appears sensible to monitor patients closely and continue therapy for at least three more months.
- The study was presented in part at the 54th Annual Meeting of the American Society of Hematology in Atlanta, GA, USA, December 12-9-2012.
- Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
- Received April 19, 2013.
- Accepted June 27, 2013.
- Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012; 120(7):1390-7. PubMedhttps://doi.org/10.1182/blood-2012-03-378919Google Scholar
- O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348(11):994-1004. PubMedhttps://doi.org/10.1056/NEJMoa022457Google Scholar
- Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012; 119(5):1123-9. PubMedhttps://doi.org/10.1182/blood-2011-08-376087Google Scholar
- Kantarjian HM, Baccarani M, Jabbour E, Saglio G, Cortes JE. Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy. Clin Cancer Res. 2011; 17(7):1674-83. PubMedhttps://doi.org/10.1158/1078-0432.CCR-10-2922Google Scholar
- Cortes J, Goldman JM, Hughes T. Current issues in chronic myeloid leukemia: monitoring, resistance, and functional cure. J Natl Compr Canc Netw. 2012; 10(Suppl 3):S1-S13. Google Scholar
- Quintas-Cardama A, Kantarjian H, Jones D, Shan J, Borthakur G, Thomas D. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. 2009; 113(25):6315-21. PubMedhttps://doi.org/10.1182/blood-2008-07-166694Google Scholar
- Jabbour E, Kantarjian H, O’Brien S, Shan J, Quintas-Cardama A, Faderl S. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011; 118(17):4541-6. PubMedhttps://doi.org/10.1182/blood-2011-04-348110Google Scholar
- Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006; 108(1):28-37. PubMedhttps://doi.org/10.1182/blood-2006-01-0092Google Scholar
- Wang L, Pearson K, Ferguson JE, Clark RE. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. 2003; 120(6):990-9. PubMedhttps://doi.org/10.1046/j.1365-2141.2003.04200.xGoogle Scholar
- Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM. 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(3):232-8. PubMedhttps://doi.org/10.1200/JCO.2011.38.6565Google Scholar
- Marin D, Hedgley C, Clark RE, Apperley J, Foroni L, Milojkovic D. Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood. 2012; 120(2):291-4. PubMedhttps://doi.org/10.1182/blood-2012-01-407486Google Scholar
- Hughes TP, Hochhaus A, Branford S, Muller MC, Kaeda JS, Foroni L. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010; 116(19):3758-65. PubMedhttps://doi.org/10.1182/blood-2010-03-273979Google Scholar
- Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27(35):6041-51. PubMedhttps://doi.org/10.1200/JCO.2009.25.0779Google Scholar
- Neelakantan P, Gerrard G, Lucas C, Milojkovic D, May P, Wang L. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood. 2013; 121(14):2739-42. PubMedhttps://doi.org/10.1182/blood-2012-11-466037Google Scholar
- Ross DM, Branford S, Moore S, Hughes TP. Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL. Leukemia. 2006; 20(4):664-70. PubMedhttps://doi.org/10.1038/sj.leu.2404139Google Scholar