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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 106-111 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2373 Long-Term Outcome of Complete Cytogenetic Responders After Imatinib 400 mg in Late Chronic Phase, Philadelphia-Positive Chronic Myeloid Leukemia: The GIMEMA Working Party on CML
From the Department of Hematology/Oncology "L. and A. Seràgnoli" S. Orsola Malpighi Hospital, University of Bologna, Bologna; Department of Cellular Biotechnology and Hematology, University "La Sapienza"; University Tor Vergata, Rome; Hematology Section, University of Bari; Division of Hematology, Ospedali Riuniti, Reggio Calabria; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples; and Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce Perugia, Italy Corresponding author: Francesca Palandri, MD, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli," St. Orsola-Malpighi University Hospital, Via Massarenti, 9-40138 Bologna, Italy; e-mail: francesca.palandri{at}libero.it
Purpose Imatinib mesylate (IM) has rapidly become the front-line treatment of Philadelphia-positive (Ph-pos) chronic myeloid leukemia, but the number of patients who were treated and are being treated with IM second-line is still substantial.
Patients and Methods We have monitored and analyzed the cytogenetic and molecular response to IM 400 mg/d in a cohort of 277 late chronic phase (LCP) patients who were resistant or intolerant to interferon- Results One hundred fifty-three patients (55%) achieved a complete cytogenetic response (CCgR). Seventy-seven percent of them were still in CCgR after 5 years. The rate of response loss did not increase over time. The 6-year progression-free survival and overall survival of these 153 complete cytogenetic responders were 90% and 91%, respectively. Molecular response was less than major in 21%, major in 78%, and complete in one patient only. Conclusion These data confirm that, in LCP the CCgR rate to IM is 50% to 60%, and show that CCgR is stable and is associated with a prolonged survival, even if leukemia continues to be molecularly detectable.
Imatinib mesylate (IM) has become the front-line treatment of Philadelphia-positive (Ph-pos) chronic myeloid leukemia (CML), on the basis of the results of an International Randomized Study of IM versus interferon-alfa (IFN-  ) and low-dose cytarabine (LDAC; the IRIS trial),1,2 which was conducted in early chronic phase (ECP) patients. However, before this study, IM had been tested and registered for the treatment of patients with advanced disease, in blast crisis (BC),3,4 in accelerated phase (AP)5,6 and in late chronic phase (LCP).7-13 The definition of LCP patients covered the cases where IM was administered after prior treatment, mainly IFN-, had failed to achieve or maintain a hematologic and/or a cytogenetic response, or when it was no longer tolerated. The interest on these patients is still substantial, because their number is still large in the countries where IM became available only later on. Moreover, IM may be not fully available as front-line treatment worldwide for economic reasons. In LCP patients, the reported major cytogenetic response (MCgR) rate ranged between 60% and 73%, and the complete cytogenetic response (CCgR) rate ranged between 41% and 63%. These response rates are high, but are substantially lower than in ECP patients.1,14 The long-term outcome of the patients treated with second-line IM has not yet been fully described. In particular, it would be important to establish whether, for LCP patients who achieve a CCgR, the cytogenetic response is as durable as for ECP patients, with a similar benefit in terms of progression-free survival (PFS) and overall survival (OS). For this purpose, we have reviewed the updated database of a prospective study of LCP patients that was promoted and sponsored by the Italian Cooperative Study Group (now Gruppo Italiano Malattie Ematologiche Adulto [GIMEMA]) Working Party on CML in 2000.
Patients The patients were enrolled into a prospective study (CML/002/STI571) which was designed, sponsored, and implemented by the Italian Cooperative Study Group on CML according to good clinical practice and the principles of the Declaration of Helsinki. The general outline of the study, inclusion criteria, and response definitions have been previously published.8,15 All of the patients were naïve to IM treatment and had never participated in prior similar studies. Briefly, LCP Ph-pos CML patients were eligible if they were resistant (either hematologically or cytogenetically) or intolerant to IFN- . The definition of chronic phase required the presence of less than 15% blast cells and less than 30% of blast cells plus promyelocytes in blood or bone marrow, less than 20% basophils, and more than 100 x 109/L platelets in blood. Primary or secondary hematologic resistance to IFN- was defined as failure to achieve a complete hematologic response (CHR) after 6 months of IFN- treatment, or as a doubling of the leukocyte count (to a minimum level of 20 x 109/L, confirmed by two samples collected at least 2 weeks apart) during IFN- therapy. Primary or secondary cytogenetic resistance was defined as failure to achieve a minor cytogenetic response after 12 months of IFN-–based therapy, or as an increase of Ph-pos marrow metaphases by 30% or more documented on two occasions, or as an increase of Ph-pos marrow metaphases to 65% or more documented once. Intolerance to IFN- was defined as a grade 3 or 4 hematologic and nonhematologic toxicity. Patient age ranged from 18 to 82 years (median, 52 years). The duration of chronic phase before IM treatment ranged from 1 to 202 months (median, 38 months). Treatment was IM 400 mg/d through the study period, with few exceptions of dose increase to 600 or 800 mg. Criteria for dose modifications were described previously.8 Two hundred ninety-five patients were enrolled between July 2000 and June 2001. Eighteen patients (6%) were not included in the analysis because treatment and response were not reported and the patients were lost to follow-up after 3 to 36 months. The main characteristics of the remaining 277 patients are listed in Table 1. As of December 2006, 72 (26%) of 277 patients have died. The median observation period of the remaining 187 patients who are still alive is 72 months (range, 48 to 79 months). An interim report of the first 197 patients who were enrolled onto this study was previously published.8
Cytogenetic and Molecular Studies Cytogenetic studies were performed on marrow cells by standard banding techniques before treatment (baseline), after 3, 6, and 12 months, and every 6-12 months thereafter. In patients who achieved a CCgR, residual disease was assessed every 3 to 6 months on blood cells by a standardized reverse-transcriptase quantitative polymerase chain reaction (RQ-PCR) method that was established in the framework of the European Union concerted action.8,15,16 RQ-PCR was performed on an ABI PRISM 7700 Sequence Detector (Perkin Elmer, Faster City, CA), and results were expressed as a ratio of BCR-ABL to the housekeeping gene percentage. Samples with ABL Ct values higher than 30 were discarded as to ensure that RNA was not degraded. From 2000 to December 2003, the housekeeping gene was β2microglobulin (β2M). In January 2004, it was decided to substitute β2M with ABL as housekeeping gene, to make the data more consistent with recommendations and with other reports.16 To transform BCR-ABL:β2M data into BCR-ABL:ABL data, from January 2004 to April 2004, 50 samples were assessed in duplicate, using both β2M and ABL. The BCR-ABL:β2M ratio was plotted against the BCR-ABL:ABL ratio, and the slope of the linear regression equation was used to derivate the estimated BCR-ABL:ABL ratios, applying the following formula: BCR-ABL:ABL ratio = 57.74 x BCR-ABL:β2M ratio.17
Response Definition
Statistics We used the Kaplan-Meier18 method to calculate the duration of the CCgR from the date of the first CCgR to the date of CCgR loss or of last cytogenetic evaluation, whichever came first. The significance level for all statistical tests was .05. Differences were measured using the log-rank test.19 All statistical calculations were performed using GraphPad Prism 4 (http://www.graphpad.com/prism/Prism.htm).
Cytogenetic Response Rate and Duration Forty-four (16%) of 277 patients achieved a partial CgR, and 153 (55%) obtained a CCgR. The first CCgR was documented within 1 year of treatment in 106 of 153 patients (early responders), and after more than 1 year (13 to 62 months) in the remaining 47 patients (late responders). After 6 years of treatment, 77% (95% CI, 74% to 80%) of complete cytogenetic responders (CCgRs) were still in CCgR (Fig 1A). The proportion of patients remaining in stable CCgR was similar for early and late responders (80% [95% CI, 75% to 85%] v 75% [95% CI, 70% to 80%]; log-rank P = .25; Fig 1B). Among the 33 patients with unstable CCgR, 22 (67%) lost the CCgR within 24 months from the date of its first achievement, and only 11 of 33 patients lost CCgR at a later time point (five patients during the third year and six patients thereafter; Table 2). Therefore, the probability of losing the CCgR tended to decrease over time, as shown in Figure 1. The duration of the CCgR was not related to the duration of the disease before IM treatment.
Molecular Response To evaluate the degree and the pattern of the molecular response (MolR), we focused on the molecular results of the patients who achieved and maintained a stable CCgR during IM therapy and had repeated molecular data during follow-up. One hundred fifteen (96%) of 120 patients in continuous CCgR were tested at different time points, and 75 had molecular evaluations after 48 to 60 months of CCgR. In 24 patients (21%), MolR was never major. Ninety-one patients (78%) achieved an MMolR, which was stable in 44 patients (38%), whereas MolR fluctuated from major to less than major in 19 patients (17%) and from major to undetectable in 27 patients (23%). Only one patient became and remained molecularly negative. The distribution of the MolR during the whole study period is shown in Table 3. The proportion of patients in MMolR increased steadily from 3 months (29%) to 36 months (70%) and reached a plateau thereafter (68%). The proportion of patients with occasionally undetectable BCR-ABL transcripts remained low throughout, ranging from 2% to 16%.
PFS and OS A progression to AP or BC was reported in eight (5%) of 153 CCgRs. After 6 years of treatment, the PFS of the 153 CCgRs was 90% (95% CI, 86% to 94%; Fig 2A), without any difference between early and late responders (93% [95% CI, 88% to 98%] v 88% [95% CI, 84% to 92%]). Fourteen (9%) of 153 CCgRs have died, for a 6-year OS of 91% (95% CI, 87% to 95%; Fig 2B).
Among the 124 patients who never achieved a CCgR, 54 (44%) have progressed to AP/BC and 58 (46%) have died. Twenty-nine (44%) of 66 living patients discontinued IM therapy after a median time of 53 months (range, 1 to 75 months), because of adverse events (4%) or unsatisfactory therapeutic effect (96%). Thirty-seven patients are still receiving IM treatment, 11 (29%) in MCgR, 10 in minor, and 16 in minimal or null cytogenetic response. After 6 years from start of IM therapy, PFS and OS of all patients, including partial cytogenetic responders and nonresponders, were 72% (95% CI, 67% to 77%) and 77% (95% CI, 72% to 82%), respectively.
Dose Adaptation
In this report, we describe the outcome of a cohort of 277 CML patients treated with IM 400 mg/d in LCP, with particular focus on complete cytogenetic responders because the degree and the stability of the CgR are the most important predictors of the long-term outcome. The demonstration of the striking effectiveness of front-line IM was so rapid and consistent1,2 that the interest on the fate of the patients treated in LCP tended to vanish over time, with the most recently updated reports in 2004.12,13 However, because the number of these patients is still substantial worldwide, their surveillance continues to be important to understand whether the pattern of response to IM is similar to that observed in ECP patients, and particularly whether the relapse rate tends to become stable or to increase over time. The data of the major reports of the treatment of LCP CML with IM 400 mg/d are summarized in Table 4. The MCgR rate ranged between 60% and 73% (71% in this study), and the CCgR rate ranged between 41% and 63% (55% in this study). The MMolR rate, reported in three studies, ranged between 60% and 74% (68% in this study). The OS and the PFS of cytogenetic responders was always more than 90% but the follow-up was relatively short, ranging from 18 months9,11 to 48 months.12 In this study, we show that both PFS and OS of CCgRs remained superior to 90% after a median observation time of 6 years. Moreover, we show that the CCgR was remarkably stable, with 77% of CCgRs still in CCgR after 6 years, and that the rate of response loss did not tend to increase over time, but rather to decrease, as has been reported for ECP CML.2 This updated analysis of a multicentric cohort of Italian patients supports the concept that, in LCP CML patients, achieving a CCgR is prognostically as important as in ECP patients, and reinforces the expectation that LCP patients may have a very long-term, as yet undefined, benefit from continuing the treatment after a CCgR has been achieved, despite the fact that, in almost all cases, leukemia remains detectable at a molecular level.
We found that almost all of the patients who never achieved an MMolR also lost their CCgR, reinforcing prior reports and the concept that the better the MolR, the better the outcome.1 However, we also noticed that a substantial proportion (21%) of patients in stable CCgR never achieved an MMolR, and that in other 17% of cases, the level of the MolR fluctuated from major to less than major. On the other hand, in 24% of stable CCgRs, the MolR became occasionally undetectable by RQ-PCR. These findings do not challenge the indication of monitoring the molecular response and the prognostic value of molecular response,20,21 but warn that the molecular response may fluctuate over time and that standardized laboratory procedures are needed.21 Longer follow-up with meticulous monitoring is required to update the role of IM in the management of Ph-pos CML, including efficacy data and reporting on late and unexpected adverse effects. In this cohort of 277 patients, no cases of grade 3 to 4 late toxicities have been observed and, in particular, no severe cardiac heart failure was reported.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Giovanni Martinelli, Novartis; Giuseppe Saglio, Novartis, Bristol-Myers Squibb Co; Fabrizio Pane, Novartis, Bristol-Myers Squibb Co, Roche; Gianantonio Rosti, Novartis Bristol-Myers Squibb Co; Michele Baccarini, Novartis Pharma Research Funding: Giovanni Martinelli, Novartis, Bristol-Myers Squibb Co; Giuseppe Saglio, Novartis; Fabrizio Pane, Novartis; Gianantonio Rosti, Novartis; Michele Baccarani, Novartis Pharma Expert Testimony: None Other Remuneration: None
Conception and design: Gianantonio Rosti, Giovanni Martinelli, Michele Baccarani Provision of study materials or patients: Ilaria Iacobucci, Marilina Amabile, Angela Poerio, Nicoletta Testoni, Simona Soverini, Fausto Castagnetti, Antonello De Vivo, Massimo Breccia, Giorgina Specchia, Elisabetta Abruzzese, Bruno Martino, Daniela Cilloni, Giuseppe Saglio, Fabrizio Pane, Anna Marina Liberati Collection and assembly of data: Francesca Palandri, Ilaria Iacobucci Data analysis and interpretation: Francesca Palandri, Ilaria Iacobucci, Gianantonio Rosti, Michele Baccarani Manuscript writing: Francesca Palandri, Ilaria Iacobucci, Michele Baccarani Final approval of manuscript: Michele Baccarani
We thank Katia Vecchi and Katia Vitali for their skillful assistance.
Supported by the Italian Association for Cancer Research (AIRC), by Fondazione del Monte di Bologna e Ravenna, by European LeukemiaNet funds, and by grants from the Associazione Italiana Contro le Leucemie. F.P. and I.I contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. 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 349:1423-1432, 2003 2. Druker BJ, Guilhot F, O'Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006 3. Sawyers CL, Hochhaus A, Feldman E, et al: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. Blood 99:3530-3539, 2002 4. Kantarjian HM, Cortes J, O'Brien S, et al: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99:3547-3553, 2002 5. Talpaz M, Silver RT, Druker BJ, et al: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 99:1928-1937, 2002 6. Kantarjian H, Talpaz M, O'Brien S, et al: Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia: Comparison with historic experience. Cancer 103:2099-2108, 2005[CrossRef][Medline] 7. Kantarjian H, O'Brien S, Cortes J, et al: Survival advantage with imatinib mesylate therapy in chronic-phase chronic myelogenous leukemia (CML-CP) after IFN-alpha failure and in late CML-CP, comparison with historical controls. Clin Cancer Res 10:68-75, 2004 8. Rosti G, Martinelli G, Bassi S, et al: Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103:2284-2290, 2004 9. Cervantes F, Hernandez-Boluda JC, Steegmann JL, et al: Imatinib mesylate therapy of chronic phase chronic myeloid leukemia resistant or intolerant to interferon: Results and prognostic factors for response and progression-free survival in 150 patients. Haematologica 88:1117-1122, 2003 10. Lahaye T, Riehm B, Berger U, et al: Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: A 4.5-year follow-up. Cancer 103:1659-1669, 2005[CrossRef][Medline] 11. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645-652, 2002 12. Kantarjian HM, Cortes JE, O'Brien S, et al: Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 104:1979-1988, 2004 13. Silver RT, Talpaz M, Sawyers CL, et al: Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase II trials. Blood 104:11a, 2004 (abstr 23)[CrossRef] 14. Müller MC, Gattermann N, Lahaye T, et al: Dynamics of BCR-ABL mRNA expression in first-linetherapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. Leukemia 17:2392-2400, 2003[CrossRef][Medline] 15. Iacobucci I, Rosti G, Amabile M, et al: Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment. J Clin Oncol 24:454-459, 2006 16. Gabert J, Beillard E, van der Velden VH, et al: Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia: A Europe Against Cancer program. Leukemia 17:2318-2357, 2003[CrossRef][Medline] 17. Iacobucci I, Galletti L, Amabile M, et al: Monitoring BCR-ABL transcript levels by real-time quantitative polymerase chain reaction: A linear regression equation to convert from BCR-ABL/B2M ratio to estimated BCR-ABL/ABL ratio. Haematologica 92:429-430, 2007 18. Kaplan EL, P M: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 19. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II, Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 20. Baccarani M, Saglio G, Goldman J, et al: Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108:1809-1820, 2006 21. Hughes T, Branford S: Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev 20:29-41, 2006[CrossRef][Medline] Submitted June 28, 2007; accepted September 26, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
