Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4497-4504 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Ibrahim Haznedaroglu ◽  
Kimmo Porkka ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Treatment ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Molecular Response ◽  
Front Line ◽  
To Receive

AbstractImatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph+ CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1098-1098
Author(s):  
Gianantonio Rosti ◽  
Giovanni Martinelli ◽  
Fausto Castagnetti ◽  
Nicoletta Testoni ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Risk Patients

Abstract The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).

scholarly journals Safety and efficacy of nilotinib after 10 years of interferon

2015 ◽  
Vol 6 (2S) ◽  
pp. 19-22
Author(s):  
Filippo Russo
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Interferon Alfa ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Safety And Efficacy ◽  
Optimal Response ◽  
Complete Molecular Response

Here we describe a case of a woman with chronic myeloid leukemia at high risk, according to the Sokal Index. The patient started interferon alfa-2b (IFN) at standard dose obtaining a major molecular response after about four years of treatment. After about 10 years the patient presented a toxicity from IFN and different comorbidities, so she was switched to nilotinib and achieved a complete molecular response (MR4). This case shows how nilotinib is effective and tolerable also in patients with multiple comorbidities. Keywords: Chronic myeloid leukemia; Optimal response; Nilotinib; Interferon alfa-2b

Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2581-2588 ◽  
Author(s):  
Wendy Deenik ◽  
Bronno van der Holt ◽  
Gregor E. G. Verhoef ◽  
Willem M. Smit ◽  
Marie J. Kersten ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Combination Therapy ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
High Dose ◽  
Molecular Response ◽  
Platelet Recovery ◽  
Molecular Responses ◽  
Dose Levels ◽  
Intermediate Dose

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.

scholarly journals Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3428-3434 ◽  
Author(s):  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
Marilina Amabile ◽  
Nicoletta Testoni ◽  
Simona Luatti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Prospective Trial ◽  
Chronic Phase ◽  
Working Party ◽  
Response Rates ◽  
High Dose ◽  
Molecular Response

AbstractImatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.

scholarly journals Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

2015 ◽  
Vol 4 (6S) ◽  
pp. 13-16
Author(s):  
Fausto Palmieri
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Young Patient ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Chronic Phase ◽  
Molecular Response ◽  
Optimal Response ◽  
Increased Risk

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Distinct Characteristics of e13a2 versus e14a2 BCR-ABL Chronic Myeloid Leukemia under Upfront Treatment with Imatinib – an Analysis of the German CML Study IV,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3773-3773
Author(s):  
Benjamin Hanfstein ◽  
Philipp Erben ◽  
Susanne Saussele ◽  
Michael Lauseker ◽  
Ulrike Proetel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Fusion Gene ◽  
Standard Dose ◽  
White Blood Cells ◽  
Molecular Response ◽  
Significant Difference ◽  
Equity Ownership

Abstract Abstract 3773 Introduction: The vast majority of chronic myeloid leukemia (CML) patients express a BCR-ABL fusion gene mRNA encoding a 210 kDa tyrosine kinase which is constitutively activated and hence the mainspring of leukemic transformation. Two typical mRNA variants exist that differ in the presence or absence of the 75 basepair BCR exon 14: the e13a2 (lacking exon 14, also known as “b2a2”) and the e14a2 BCR-ABL transcript (“b3a2”). The significance of the additional 25 amino acid residues of the e14a2 BCR-ABL oncoprotein was extensively studied in the pre-imatinib era. However, the influence of the BCR-ABL transcript variant on the individual disease phenotype and outcome remained controversial and is still undefined in the imatinib era. Patients and methods: A total of 1,104 patients (median age 52 years, range 16–85, 40% female) expressing typical BCR-ABL transcript types (e13a2, n=447; e14a2, n=491; e13a2 and e14a2, n=166) were included in the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg, imatinib 800 mg and combinations of standard dose imatinib with interferon alpha and low-dose cytarabine. The type of BCR-ABL transcript was defined by multiplex PCR. BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (IS). Cytogenetic response was determined by conventional metaphase analyses. Response landmarks were defined according to European LeukemiaNet criteria, MR4 was defined as BCR-ABL IS ≤ 0.01% Results: No differences regarding age, sex and Euro risk were observed. A significant difference was observed comparing white blood cells (90,400/μl vs. 69,100/μl, p<0.001) and platelets (293,000/μl vs. 424,000/μl, p<0.001) at diagnosis (median, e13a2 vs. e14a2, respectively) indicating a distinct phenotype. No significant difference was observed regarding spleen size, basophils, eosinophils, blasts or adverse events under imatinib. Molecular response as determined by a transcript independent quantitative PCR assay was superior in e14a2 patients as compared to e13a2 patients (median time to major molecular response, MMR 1.5 years vs. 1.2 years, p<0.001; median time to MR4 4.2 years vs. 2.5 years, p<0.001). No difference was observed with regard to the achievement of a complete cytogenetic remission (CCyR). The superior molecular response rate of e14a2 patients did not translate into differences in progression free survival (PFS) or overall survival (OS). Conclusion: Distinct initial blood counts suggest a different phenotype of e13a2 and e14a2 driven CML. MMR and MR4 are achieved earlier by e14a2 patients whereas no difference was observed with regard to PFS and OS. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4939-4939
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded (Table 1). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion: BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%. Disclosures: No relevant conflicts of interest to declare.

ABCB1 Haplotypes Are Associated With Lower P-Gp Activity and Major Molecular Response But Do Not Affect Imatinib Plasma Levels In Chronic Myeloid Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3860-3860
Author(s):  
Douglas Vivona ◽  
Luciene Terezina Lima ◽  
Alice C Rodrigues ◽  
Carolina Tosin Bueno ◽  
Cristiane M Gaitani ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Chronic Myeloid Leukemia ◽  
Functional Activity ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Molecular Response ◽  
Wild Type ◽  
Major Molecular Response

Abstract Background Despite the high efficacy of IM treatment in chronic myeloid leukemia (CML), some patients fail to achieve optimal response. Several studies demonstrated that IM is a substrate of membrane transporters, such as ABCB1 (P-gp, MDR1) and variations in protein expression or activity could affect the pharmacokinetics of IM by reducing or increasing its bioavailability. These alterations could be related with single nucleotide polymorphisms in ABCB1 gene. Previous data confirms that haplotypes containing the mutated alleles for ABCB1 c.1236C>T, c.3435C>T and c.2677G>T showed major structural modifications that result in changes in the conformation of the binding sites of P-gp. These modifications could affect the pharmacokinetics of IM. Aim The aim of this study was to evaluate the influence of the different haplotypes for ABCB1 c.1236C>T, c.3435C>T and c.2677TG>T polymorphisms in IM plasma concentration, P-gp activity and IM response from CML patients treated with standard dose of IM (400 mg/day). Methods Twenty eight patients in chronic phase of CML were selected according to the haplotypes for ABCB1 c.1236C>T, c.3435C>T and c.2677G>T polymorphisms at two health centers in São Paulo, Brazil. Ten patients with ABCB1 1236CC/3435CC/2677GG haplotype comprised the wild-type group and 18 carriers of haplotypes with at least one mutated allele in each genotype for three ABCB1 polymorphisms (10 patients with 1236CT/3435CT/2677GT and 8 with 1236TT/3435TT/2677TT) comprised the mutated group. Patients were matched for IM time of use. All patients were in chronic phase of CML, treated with a standard dose of IM (400 mg/day) for a median time of 63.5±12.6 months and with complete cytogenetic response (CCyR). Major molecular response (MMR) was defined as a reduction of BCR-ABL1 transcripts levels to ≤ 0.1% in the peripheral blood standardized on the International scale. Complete molecular response (CMR) was defined as a reduction ≤0.0032% of BCR-ABL1 transcripts levels. Real-Time PCR was performed to evaluate ABCB1 mRNA expression to control gene GAPDH. P-gp functional activity was determinated by rhodamine123 efflux assay. Analysis of P-gp expression and functional activity were performed by flow cytometry. The determination of plasma concentration of IM was performed by capillary electrophoresis. Results Patients without MMR had lower plasma concentration of IM when compared to those that achieved this response (0.51 µg/mL vs. 1.42 µg/mL, P=0.001) but no association was found between the different haplotypes and IM plasma levels or ABCB1 mRNA/P-gp expression. The median of Rh123 efflux in wild-type and mutated groups was 59.1 (54.8 - 69.5) and 38.3 (27.4 - 47.9) (P<0.05), respectively. Patients who did not achieve MMR showed a higher rate of efflux mediated by P-gp compared to individuals who did not achieve this response (64.7% vs. 45.7%, P =0.001). All patients who did not achieve MMR showed efflux above 60%.There was a strong and positive correlation between ABCB1 mRNA expression and P-gp expression (r=0.747, P=0.001). P-gp activity was positive and moderate correlated with BCR-ABL1 transcripts (r=0.570; P=0.001). Conclusion ABCB1 1236CT/3435CT/2677GT and 1236TT/3435TT/2677TT haplotypes are associated with lower P-gp activity and higher frequency of MMR but not with IM plasma concentration in chronic phase CML patients treated with standard-dose of IM (400 mg/day) Disclosures: No relevant conflicts of interest to declare.

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