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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

From the Institute of Hematology and Medical Oncology "Seràgnoli", University of Bologna, Bologna; Division of Hematology and Internal Medicine, Department of Clinical and Biological Science, University of Turin, Turin; Division of Hematology, University "Tor Vergata", and Division of Hematology, University "La Sapienza", Rome; Division of Hematology, Hospital "Pugliese Ciaccio", Catanzaro; Division of Hematology, University of Brescia; Division of Hematology and Internal Medicine, University of Genova; Division of Hematology, Hospital "Bianchi Malacrino Morelli", Reggio Calabria; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy

Address reprint requests to Giovanni Martinelli, MD, Molecular Biology Unit, Institute of Hematology and Medical Oncology "Seràgnoli", University of Bologna, Via Massarenti, 9-40138 Bologna, Italy; e-mail: gmartino{at}kaiser.alma.unibo.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia.

Patients and Methods We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) –positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon- failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders).

Results After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively.

Conclusion The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progession-free and overall survival.

	INTRODUCTION

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Chronic myeloid leukemia (CML) is a clonal disorder arising from neoplastic transformation of hematopoietic stem cells, most of which are characterized by the presence of a Philadelphia chromosome (Ph) and by constitutive activation of Bcr-Abl tyrosine kinase.¹ Recent therapies in CML have attempted to suppress the Ph-positive (Ph+) cells or the Ph-related Bcr-Abl kinase activity in order to alter the natural course of the disease. Allogenic stem-cell transplantation (SCT) produced long-term event-free survival rates of 30% to 80% and 1-year mortality rates of 5% to 50%.² Interferon-alfa (IFN-) yielded cytogenetic response rates of 30% to 70%, which were complete in 5% to 30%.^3,4 Median survival duration with IFN- was 5 to 7 years. Achievement of a complete cytogenetic response was associated with 10-year survival rates of 70% to 85%.⁵

The introduction of imatinib mesylate (formerly STI571; Glivec in Europe, Gleevec in the United States; Novartis Pharmaceuticals, Basel, Switzerland) has proven highly effective in the treatment of CML and is now approved for the first-line pharmacotherapy of newly diagnosed CML. Imatinib was rationally and specifically designed to bind to the adenosine triphosphate (ATP)–docking site of tyrosine kinase proteins, including ABL itself (p160), and the hybrid BCR/ABL proteins (p190, p210, p230, and so on), which cause Ph+ leukemias.⁶ With this drug, complete hematologic remission can be achieved in almost all Ph+ patients with CML in the chronic phase, in approximately 50% of those in the accelerated phase and in a smaller proportion of those in the blastic phase or in those with Ph+ acute leukemia.^7-13 More importantly, a major cytogenetic response can be achieved in more than 50% of the patients who begin the treatment in the late chronic phase^9-12 and in more than 80% of those who are treated in the early phase.¹⁴ The proper follow-up of imatinib-treated patients is based on cytogenetic (conventional and fluorescent in situ hybridization, as appropriate) and molecular techniques: particularly, complete cytogenetic responders (CCgR) require assessment of the molecular response (MR) through molecular quantification. The long-term molecular follow-up of these patients would make it possible to evaluate the overall and major molecular response rates and the prognostic impact of different levels of BCR-ABL transcript reduction, given the same, complete cytogenetic result. As the presence of the BCR-ABL gene and its products are considered a surrogate for disease activity, its disappearance is regarded as the prerequisite for cure and the ultimate therapeutic goal.

This article aims to compare two groups of late, chronic phase CML patients who achieved complete cytogenetic response with imatinib therapy. The difference between two groups is based on time to achieve complete cytogenetic response and we choose 1 year as cutoff point. We examined whether the behavior of two groups during the 4 years of follow-up was in any way different, whether the complete cytogenetic response is sustained or even improved at long-term follow-up and whether the low annual mortality rates persist in later years.

	PATIENTS AND METHODS

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Patients
The patients treated belonged to a study protocol (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 Helsinki Declaration. Novartis Pharma supplied the drug free of charge and partly provided the support for data and sample collection and for the monitoring of adverse events. Patients were required to have Ph-positive chronic phase CML after IFN- failure because of hematologic or cytogenetic resistance or relapse, or because of IFN- toxicity. Chronic phase CML was defined as the presence, in the peripheral blood and bone marrow, of blasts less than 15%, basophils less than 20%, blasts together with promyelocytes less than 30%, and platelets more than 100 x 10⁹/L. Failure of the hematologic response to IFN- was defined as hematologic resistance (failure to achieve a complete hematologic response [CHR] after at least 6 months of IFN-) or relapse (> 30% increase in Ph-positive metaphases on two occasions, or a 65% increase in Ph+ metaphases on 1 occasion). Intolerance of IFN- therapy was defined as grade 3 or 4 nonhematologic toxicity. The median age at the time of imatinib start was 55 years (range, 29 to 74 years).

Patients received 400 mg of imatinib alone, once daily at the same dosage until disease progression. Criteria for dose reductions and treatment discontinuation have been described in a previous study.¹⁵

Cytogenetic and Molecular Studies
Cytogenetic studies were performed by standard banding techniques and at least 20 metaphases were analyzed. The cytogenetic response (CgR) was rated according to the proportion of Ph negative (Ph–) metaphases, as complete (Ph– 100%), partial (Ph– 66% to 99%), minor (Ph– 34% to 65%), and minimal or none (Ph– 33%). BCR-ABL transcripts were detected by real-time quantitative reverse transcriptase-polymerase chain reaction (Q-PCR) analysis on bone marrow aspirate. Bone marrow samples were collected before treatment (baseline), after 3 and 6 months and at the end of the study treatment period (12 months). Subsequent samples were obtained every 6 months only from the patients who were in CCgR. Total leukocytes were extracted from 3 to 5 mL of bone marrow aspirate after separation on a Ficoll Hypaque gradient. Mononuclear cells were resuspended in 500 µL of GITC and stored at –20°C. Total RNA was isolated using the RNA easy kit (Qiagen, Spoorstraat, the Netherlands) according to the manufacture's instructions. RNA quality was assessed on an ethidium bromide–stained 2% agarose gel.

Minimal residual disease was detected during the follow-up by a standardized RTQ-PCR method that was established within the framework of the EU Concerted Action.^16,17 The method independently measures, in each sample by real time PCR, the copy number of mRNA encoding for the p210 BCR/ABL protein and for a control gene to verify sample-to-sample RNA quality variations. In this study β2 microglobulin (β2M) was selected and used as a control gene. The reverse transcription (RT) reaction conditions were the same for BCR-ABL and β2M mRNA amplifications. Real time quantitative RT-PCR was performed on an ABI PRISM 7700 Sequence Detector (Perkin Elmer, Foster City, CA). The quantification principles and procedure using the TaqMan probe have been previously described.¹⁵ All real time RT-PCR experiments were performed in duplicate. The quantitative RQ-PCR assays for the quantification of BCR-ABL were designed to detect b2a2 and b3a2 transcripts in a single reaction. The copy number of BCR-ABL and β2M transcripts was derived by the interpolation of threshold cycle (ct) values to the appropriate standard curve, and the result, for each sample, was expressed as a ratio of BCR-ABL mRNA copies to β2M mRNA. The threshold was systematically set at 0.1 in order to avoid any particular problems of baseline creeping. To ensure that RNA was not degraded, samples that gave β2M ct values higher than 25.7 were discarded. The lowest level of detectability of the method is 0.00001. This ratio would correspond to about 0.001 using ABL or GUS as a control gene.

Statistics
Comparison of means was made with the t-test, and comparison of frequencies with the ² test or the Fisher's exact test, as appropriate. Median ranges between pairs of continuous variables were analyzed by the Wilcoxon rank test. The correlation coefficients between pairs of continuous variables were calculated by Pearson correlation. The significance level for all statistical tests was .05. Overall survival and time to progression to the accelerated or blastic phase were calculated by the product-limits method of Kaplan and Meier.¹⁸ All statistical calculations were performed using GraphPad Prism 4.

	RESULTS

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Cytogenetic Response
A total of 284 patients with late chronic phase CML treated with imatinib mesylate after IFN- failure were analyzed. The cytogenetic response rates throughout the entire study period are reported in Table 1. These results have been previously reported in part. One hundred and fifty-one of 284 (53%) obtained a CCgR and 88 patients (31%) achieved a cytogenetic response ranging from partial to minimal (PCgR). Only 45 patients (16%) had no cytogenetic response to imatinib therapy. Patients who achieved a CCgR were divided into two groups according to the rapidity of the complete cytogenetic response. To the first group belonged 114 of 151 patients (73%) who obtained the CCgR within 12 months on imatinib (early responders) at a median time of 5 months (range, 2 to 12 months). In this group 47 patients (41%) obtained a CCgR within three months, 36 patients (32%) obtained the same response in six months and 31 (27%) patients in the period between 6 and 12 months. The second group consisted of 37 of 151 patients (27%) who achieved the CCgR after 12 months of therapy (late responders). The median time from start of imatinib therapy to achievement of CCgR was 25.5 months (range, 15 to 40 months). In particular, 17 patients (46%) achieved a CCgR within 24 months on imatinib, 18 patients (49%) between 24 and 36 months and the remaining (two patients, 5%) after 36 months of treatment. Overall in the three groups of late responders Ph+ metaphases progressively and slowly decreased over time (ranging from 100% Ph+ to 65% and 35% Ph+ metaphases before 12 months) and finally become negative after 12 months at the checkpoints before described. In this way the most of late responders had already a good cytogenetic response within 1 year, even if not complete. Only two patients had a different pattern of cytogenetic response. In fact, they had 100% Ph+ metaphases for more than 12 months, and then they become negative at 30 and 28 months after the start of therapy. In this case, they lost CCgR after 3 and 5 months, respectively.

Molecular Response
One hundred fifty-one patients with chronic phase CML and failure on IFN- therapy, treated with imatinib mesylate, had RTQ-PCR. The median molecular follow-up was 36 months (range, 9 to 54 months). The amount of BCR-ABL transcript in bone marrow cells was measured with quantitative PCR analysis before treatment (baseline), at 3 months and every 6 months up to 48 months. Table 2 and Figure 1 show the MR patterns in the early and late cytogenetic responders. The amounts of BCR-ABL transcript level, expressed as the ratios of BCR-ABL to β2M x 100 before treatment were 0.2811 and 0.3123, respectively, in early and late responders (median values). At baseline and at 3 months there was no significant difference between two groups of patients (P > .05), but after 12 months of imatinib the amount of BCR-ABL transcript in early responders was decreased by three logs, whereas in late responders the BCR-ABL transcript level gradually decreased by two logs. At 12, 18 and 24 months the differences in BCR-ABL transcript level were significant (P = .0005, P = .0004, P = .0229, respectively). At 36 months and 48 months the amount of BCR-ABL transcript level of late responders was similar to that of early responders (the median values were 0.00047 v 0.00022 and 0.00019 v 0.00026, respectively, P = nonsignificant). Table 3 presents the distribution of complete, stable CCgRs according to the maximum reduction in BCR-ABL level at 12 and 24 months on imatinib therapy and its relationship with CCgR loss. The log reduction patient evaluation method was not based on measurements relative to the baseline value of each individual, but each result was referenced to an absolute value that was referred to as the standardized baseline, similar to that reported by Hughes et al. The original standardized baseline value that was used to determine a log reduction in this study was established by measuring the BCR-ABL levels of 151 patients before commencing imatinib. The median BCR-ABL/β2M x 100 ratio in our laboratory was 0.29766. At 12 months, the maximum reduction in BCR-ABL level was less than 2 logs in 21% of early patients and in 39% of late patients, it was between 2 and 3.9 logs in 63% of early patients and in 42% of late patients, and it was equal to or more than 4 logs in 16% and in 19%, respectively. Although these relationships cannot be significant, due to the small number of cases and events, at 24 months we observed that the molecular response rates become even more similar between two groups of patients. It is interesting to note that the reduction in BCR-ABL level was 4 logs in 33% of early patients and in 29% of late patients. Among these, only one patient lost CCgR during subsequent follow-up.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Molecular response. At 12 months of imatinib, the amount of BCR-ABL transcript in early responders was decreased by 3 logs, whereas in late responders there was a reduction of 2 logs but after 3 or 4 years the amount of BCR-ABL transcript level of late responders has become similar to that of early responders.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Analysis of the association of early and late cytogenetic response with progression-free (A) and overall (B) survival. Late responders showed a progression-free survival rate and an estimated 4-year overall survival rate similar to those of early responders (100% v 88% and 100% v 92%, respectively). DFS, disease-free survival.

	DISCUSSION

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In this analysis, we evaluated the pattern and rapidity of the response to imatinib, making a comparison between patients who obtained the CCgR very quickly, after 3 or 6 months of treatment, and patients where a CCgR could be detected only later, after 12 months of treatment. We have called these two categories of patients "early" and "late" complete cytogenetic responders, respectively, and we examined whether their behavior was any different at subsequent follow-up. Data demonstrate that the response in late cytogenetic responders was only delayed but we were unable to find any evidence that after 3 or 4 years of treatment the molecular response of late cytogenetic responders was worse than that of early cytogenetic responders. We observed that with therapy there was a continued increase in cumulative complete cytogenetic response rates. Given the controversy about dose increase, the consideration for transplant in appropriate patients and the availability of new TK inhibitors, it was important to describe the pattern of response in the late patients. For this group the median time from start of imatinib therapy to achievement of CCgR was 25.5 months (range, 15 to 40 months). Overall in the late responders Ph+ metaphases progressively and slowly decreased over time (ranging from 100% Ph+ to 65% and 35% Ph+ metaphases before 12 months) and finally become negative after 12 months at the checkpoints before described. In this way the most of late responders had already a good cytogenetic response within 1 year, even if not complete. Only two of 37 patients had a different pattern of cytogenetic response. In fact, they had 100% Ph+ metaphases for more than 12 months and then they become negative at 30 and 28 months after the start of therapy.

For CML patients, methods for predicting and monitoring response to treatment have changed considerably in recent years from the repeated examination of bone marrow metaphases for the presence of the Ph+ positive chromosome in patients treated with IFN or SCT, to quantitative assays based on reverse transcriptase polymerase chain reaction. QRT-PCR using specific fluorescent hybridization probes and standard procedures with internal controls has proved extremely valuable for assessing and monitoring minimal residual disease in patients who achieve Ph negativity after treatment with IFN- or with imatinib mesylate or after allogenic SCT. In our study after 36 and 48 months of treatment the amount of residual disease measured by QRT-PCR was similar between early and late responders. O'Dwyer et al reported major differences in treatment outcomes on imatinib therapy at 3 or 6 months¹⁹ in patients with chronic phase chronic myelogenous leukemia treated after failure of IFN- therapy. Similarly, the IRIS trial demonstrated significant differences in progression-free survival as revealed by the 12-month response to imatinib mesylate: patients not achieving a complete cytogenetic response by then had an 80% progression-free survival rate.¹⁴ Our data suggest that in late chronic phase patients a benefit from an early cytogenetic CR versus late CR is not apparent. However the findings in this group of late chronic phase patients may not applicable to newly diagnosed patients in whom the response rate is much higher.

Because complete or major (Q-PCR reduction to less than 0.05% BCR-ABL/ABL or by 3 logs or more) molecular responses have been associated with an excellent prognosis with both IFN- and imatinib mesylate therapy, we compared early and late responders in terms of reduction in BCR-ABL transcript level. According to published reports we chose to compare the log reduction to a standardized PCR value. Cortes et al.²⁰ calculated a log-reduction in two different ways. First they used the median of the total population as the baseline value. Then they used each individual patient's pretreatment BCR-ABL/ABL value as their own baseline to determine log reduction. They demonstrated that the difference between two ways was not statistically significant.

The advantage of defining molecular response in terms of a reduction from a median pretreatment level is that once a laboratory has established its median baseline level, results can be expressed on a common scale internationally. Another advantage is that the molecular response can be calculated without needing to know the actual baseline level for that particular patient. A possible disadvantage is that it may be difficult to realize which minimal residual disease threshold could be "safe" for predicting a cure and possibly for increasing or modulating the individual drug-uptake.

We found no significant difference between early and late responders in the achievement of a 3-log reduction or more in the BCR-ABL/β2M ratio. At 12 months the maximum reduction in BCR-ABL level was equal to or more than 4 logs in 16% of early versus 19% of late responders. At 24 months, good molecular responders were 33% in the first group as against 29% in the second group. We also analyzed whether there was any difference between early and late responders in terms of progression-free survival and overall survival and found no difference. Though late responders achieved complete cytogenetic remission after 1 year of imatinib therapy, they showed a progression-free survival rate and an estimated 4-year overall survival similar to those of early responders (88% v 100% and 92% v 100%, respectively).

These results suggest that the sensitivity and the response to imatinib may require 1 year or more and that it could be possible to continue the same dose of imatinib even if a CCgR had not been reached by 12 months. This is particularly true in patients, as the late responders, who had already a good cytogenetic response within one year, even if not yet complete. For the patients who had not this pattern of response and who had no cytogenetic response within one year of imatinib other approaches, as the dose increase, transplant or therapy with the new TK inhibitors available could be appropriate.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The following members of the ICSG on CML have participated to this study: M. Miglino (Genova); E. Pogliani and M. Miccolis (Monza); B. Giannini (Ravenna); M. Lazzarino, P. Bernasconi and S. Merante (Pavia); R. Fanin and M. Tiribelli (Udine); G. Rossi and A. Capucci (Brescia); F. Nobile (Reggio Calabria); E. Gottardi (Orbassano); A. Bacigalupo and F. Frassoni (Genova); B. Rotoli and L. Luciano (Napoli); F. Ferrara and E. Schiavone (Napoli); M. Martelli and A. Tabilio (Perugia); T. Barbui, U. Giussani and R. Bassan (Bergamo); V. Rizzoli and L. Mangoni (Parma); F. Lauria and M. Bocchia (Siena); E. Volpe and F. Palmieri (Avellino); S. Amadori and A. Cantonetti (Roma); M. Pini (Alessandria); G. Specchia (Bari); E. Angelucci and E. Usala (Cagliari); G.L. Scapoli (Ferrara); F. Radaelli (Milano); E. Pungolino (Milano); S. Rupoli (Ancona); P. Guglielmo (Catania); F. Porretto (Palermo); A. Liberati and E. Donti (Perugia); C. Mecucci (Perguia); E. Zuffa and A. Zaccaria (Ravenna); M. Cervellera (Taranto); D. Ferrero (Torino); M. Candela (Ancona); C. Bergonzi (Cremona); D. Noli (Nuoro); G. Marini Caracciolo (Palermo); A De Miglio (Vicenza); A. Bonati (Parma); F. Parineschi (Pisa); P. Pregno (Torino); A. Ambrosetti (Verona); R. Di Lorenzo (Pescara); S. Bassi (Milano); S. Luatti, C. Nicci, E. Montanari, G. Marzocchi, F. Buontempo, T. Grafone, S. Colarossi and M. Renzulli (Bologna).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Giovanni Martinelli Provision of study materials or patients: Gianantonio Rosti, Giovanni Martinelli Collection and assembly of data: Angela Poerio, Simona Soverini, Daniela Cilloni, Elisabetta Abruzzese, Enrico Montefusco, Francesco Iuliano, Domenico Russo, Marco Gobbi, Giuliana Alimena, Bruno Martino Data analysis and interpretation: Nicoletta Testoni, Emanuela Ottaviani, Carolina Terragna, Fabrizio Pane, Giuseppe Saglio, Ilaria Iacobucci, Gianantonio Rosti, Marilina Amabile Manuscript writing: Ilaria Iacobucci Final approval of manuscript: Michele Baccarani

 

	ACKNOWLEDGMENTS

 
The assistance of Katia Vecchi is kindly acknowledged.

	NOTES

 
Supported by COFIN 2003 (Molecular therapy of Ph-positive leukemias), by FIRB 2001, by the University of Bologna (grants 60%), by the Italian Association for Cancer Research (A.I.R.C.), by Fondazione del Monte di Bologna e Ravenna, by European LeukemiaNet founds, and by Associazione Italiana contro le Leucemie grants.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted June 21, 2005; accepted October 24, 2005.

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				F. Palandri, I. Iacobucci, S. Soverini, F. Castagnetti, A. Poerio, N. Testoni, G. Alimena, M. Breccia, G. Rege-Cambrin, M. Tiribelli, et al. Treatment of Philadelphia-Positive Chronic Myeloid Leukemia with Imatinib: Importance of a Stable Molecular Response Clin. Cancer Res., February 1, 2009; 15(3): 1059 - 1063. [Abstract] [Full Text] [PDF]

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				I. Iacobucci, L. Galletti, M. Amabile, S. Soverini, M. Baccarani, and G. Martinelli 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, March 1, 2007; 92(3): 429 - 430. [Abstract] [Full Text] [PDF]

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				A. Quintas-Cardama, H. M. Kantarjian, D. Jones, G. Garcia-Manero, S. O'Brien, J. Shan, F. Ravandi, W. G. Wierda, and J. Cortes Delayed Achievement of Molecular Responses Is Associated with Increased Risk of Progression among Patients (pts) with Chronic Myelogenous Leukemia (CML) In Chronic Phase (CP) Treated with Imatinib (IM). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 432 - 432. [Abstract] [PDF]

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