Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evaluation of Peroxiredoxins (PRDX1, PRDX2 and PRDX6) Expression in Patients with Chronic Myeloid Leukemia (CML) Treated with Imatinib in First Line

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5545-5545
Author(s):  
Cintia Mascarenhas ◽  
Lara Woldmar ◽  
Maria Helena Almeida ◽  
Rosangela Vieira Andrade ◽  
Anderson Ferreira Cunha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Blood Donors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Cdna Synthesis ◽  
First Line

Abstract Introduction: Satisfactory response is present for the majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP) treated with tyrosine kinase inhibitors (ITK) . However, some pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The oxidative stress modulation is tightly related with the physiopathology of various hematologic diseases and can cause cell death, apoptosis and necrosis. Peroxiredoxins (Prdx) are a family of multifunctional antioxidant thioredoxin-dependent peroxidases that protect cells against oxidative stress and modulate signaling cell proliferation pathways and may influence the metabolism of ITKs.The aim of this study was to analyze PRDX1, PRDX2 and PRDX6 levels of CML pts and correlate with cytogenetics and molecular responses. Methods: PRDX1, PRDX2 and PRDX6 expression was evaluated in 20 blood donors, 18 newly diagnosed CML pts and 22 previously treated pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis or during treatment and RNA samples were submitted to the synthesis of complementary DNA (cDNA) using the kit RevertAid™ HMinus First Strand cDNA Synthesis Kit (Fermentas, Life Sciences). For cDNA synthesis, 3 ug of RNA was used and peroxiredoxins expression was evaluated by real-time PCR with Syber Green (Applied Biosystems) and endogenous (β-Actina and GAPDH) controls. The results were analyzed using 2-ΔΔCT. Statistical analysis were made by using Mann Withney’s T test. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RQ-PCR. Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Results: 40 CML pts, 55% male, median age of 53 years (23-84) were evaluated, 60% in chronic phase (CP), 30% in accelerated phase (AP) and 10% in blast crisis (BC). The mean of PRDX transcript levels in the total group was (PRDX1: 0.006 and 10.10 / PRDX2: 0.002 and 16.26 / PRDX6: 0.003 and 49.97) respectively (PRDX1: 1.2 / PRDX2: 0.9 / PRDX6: 15.36). The results showed that there are a significantly difference (p<0.05) in the PRDX gene expression between pts and blood donors. All PRDX expression was reduced in responsive patients, and increase expression in pts resistant to TKI. The median duration of imatinib treatment was 29 months (1-104) and 97% achieved complete hematological response, 75% complete cytogenetic response and 65% major or complete molecular response. The analysis showed that higher levels of PRDX were maybe correlated with a no reduction of BCR-ABL transcripts (p<0.05). As well as, there was may influence of the PRDX levels at diagnosis in the response at 24 months of treatment. Conclusion:Is known that that the increase of ROS in CML leads to an increase of DNA damage, triggering genomic instability and resulting in accumulation of mutations and chromosomal aberrations, and contribute to the mechanism of acquisition of resistance to TKI inhibitors. The decrease of Peroxiredoxins expression observed in the responsive group, could contribute to this process, since the detoxification of these species are compromising and the effects caused by oxidative stress are even more drastic, leading to mutations that could be followed by TKi resistance. The relation between Prdx and CML not yet been elucidated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Relevance of Failure to Achieve Early Molecular Response in Chronic Myeloid Leukemia in Chronic Phase

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5160-5160
Author(s):  
Ji Yun Lee ◽  
Sung Hee Lim ◽  
Hae Su Kim ◽  
Kwai Han Yoo ◽  
Haa-Na Song ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Transcript Levels ◽  
Significant Difference ◽  
First Line Treatment

Abstract Purpose The early molecular response (EMR, ≤ 10% BCR-ABL1 at 3 months) of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML) in chronic phase (CP) has been reported to have strong correlation with long-term outcome. We aim to investigate the prognostic interaction of the EMR and major molecular response (MMR). Methods We retrospectively reviewed data for a total of 165 patients with newly diagnosed CML-CP who received TKIs (imatinib, nilotinib, or dasatinib) as first-line treatment between January 2003 and April 2013. Of the total 128 patients who were regularly monitored by peripheral blood molecular analysis, 85 had a BCR-ABL1 assessment at 3 months and were finally included in the analysis. Results The median age of all patients was 49 years and 87.1% received imatinib as first line treatment. High risk group by Sokal and EUTOS were 29.4% and 14.1%, respectively. Patients with EMR (n = 56, 65.9%) had a tendency to have low risk disease and to be treated with 2nd generation of TKIs. With a median follow-up duration of 53.6 months (range, 5.4-131.3), the 5-year OS, 5-year FFS, and 5-year EFS were 92.5%, 74.8%, and 68.0%, respectively. Median time to achieve MMR was 11.1 months (95%CI, 8.4 - 13.8). The outcomes at 5 year comparing patients whose BCR-ABL1 transcript levels ≤ 10% vs >10% at 3 months were as follows: OS, 92.2% (95% CI 84.9-99.1) vs 92.8% (95% CI 83.7-102.3), p = 0.819; FFS, 84.7% (95% CI, 75.6-94.4) vs 57.4% (95% CI, 39.0-75.0), p < 0.001; and EFS, 73.6% (95% CI 62.5-85.5) vs 57.8% (95% CI 40.0-76.0), p = 0.050. Six (10.7%) of 56 patients with BCR-ABL1 transcript levels ≤ 10% at 3 months failed to achieved an MMR and 18 (62.1%) of 29 patients with > 10% at 3 months achieved an MMR. Based on these heterogeneous clinical outcomes, we further explored subgroup analysis according to the achievement of MMR for refined discrimination of survival outcomes. There was no significant difference of clinical outcomes between ≤ 10% vs > 10% at 3 months among the patients who achieved MMR (OS, p = 0.376; FFS, p = 0.793; and EFS, p = 0.266). In patients who did not achieved MMR, only FFS was significantly difference between ≤ 10% vs > 10% at 3 months (OS, p = 0.489; FFS, p = 0.014; and EFS, p = 0.199). Conclusion Patients who failed to achieve EMR but finally reached MMR have excellent prognosis that whether we have to change TKI for EMR failure is to be addressed by ongoing prospective clinical trials. Disclosures Jang: Alexion Pharmaceuticals: Research Funding.

Significant Discrepancy In Peripheral Blood Compared to Bone Marrow BCR-ABL Transcript Levels In Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4471-4471
Author(s):  
Jason N Berman ◽  
Wenda Greer ◽  
Ridas Juskevicius ◽  
Conrad V Fernandez ◽  
Mark Bernstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Health Centre ◽  
Chronic Phase ◽  
Transcript Level ◽  
Transcript Levels ◽  
Significant Difference

Abstract Abstract 4471 Chronic myeloid leukemia (CML) is associated with the reciprocal t(9;22)(q34;q11) translocation, which generates the BCR-ABL fusion oncogene and is the most common myeloproliferative disease affecting adults. The clinical outcome in this disease has been revolutionized with the use of imatinib mesylate (Gleevec), a targeted tyrosine kinase inhibitor, and molecular surveillance, with the development of quantitative PCR (qPCR) approaches to measure BCR-ABL transcript levels. A number of guidelines outlining follow-up strategies for patients with chronic phase CML on imatinib therapy have been established. Once a patient is stable, a typical recommendation includes peripheral blood (PB) monitoring by qPCR of BCR-ABL levels every 3–6 months to determine response or relapse, with consideration of annual bone marrow (BM) examinations to assess for cytogenetic evolution. At the Queen Elizabeth II Health Sciences Centre and IWK Health Centre in Halifax, Nova Scotia, 34 patients with chronic phase CML on imatinib were identified from 2006 to 2008, with 36 paired samples, where transcript levels were assessed in both PB and BM within one week of each other. In 24 of the cases, the BCR-ABL transcript levels in PB and BM were within 0.5 log values of each other. In the remaining 12 cases, BCR-ABL transcript levels differed by greater than 0.5 log. Three cases had higher BM levels, but surprisingly, 9 patients had a higher BCR-ABL transcript level in the PB. In all cases, BCR-ABL levels were assessed by Q-RT-PCR using the ABI7500 instrument and primers and probe designed to detect p210 and p190 breakpoints. Results were recorded as a ratio of %BCR-ABL to GAPDH that was amplified as an internal control. There was no significant difference in clinical, morphological or laboratory parameters between these patients and others who had comparable PB and BM BCR-ABL levels. These findings highlight the need to compare BCR-ABL transcript levels derived from the same tissue during longitudinal monitoring. Moreover, while potentially due to stochastic factors, the striking observation of higher PB BCR-ABL transcript levels raises the question of which tissue represents the most accurate source for monitoring of BCR-ABL transcript levels and whether there is value in confirming a significant change in PB transcript level with BM evaluation. The discrepant levels in PB and BM could not be attributed to technical issues; the timing of sample processing from collection and quality of mRNA were comparable and no variability was observed in GAPDH levels to account for the difference. Without a technical explanation, the mechanism underlying this phenomenon remains uncertain. We speculate that it may reflect CML stem cell geography with one possibility being that the CML niche may be located external to the BM. Further studies are needed to confirm these observations. If corroborated, then revision of surveillance approaches for chronic phase patients may be indicated. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5529-5529
Author(s):  
Irina Martynkevich ◽  
Vasily Shuvaev ◽  
Ekaterina Petrova ◽  
Lyubov Polushkina ◽  
Lyudmila Martynenko ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Long Term Outcome ◽  
Transcript Levels ◽  
Optimal Response

Abstract Objectives and background: The level of early MR is important for the optimization of therapy and making a decision to a switch to 2nd line therapy in patients (pts) who have not achieved an optimal response (OR). According to the recent recommendations at definition of OR on CML therapy, pts must have the level of BCR-ABL transcript gene at 10% or less and Ph-positive cells 35% or less at 3 months. But, in half of all cases of pts with BCR-ABL >10% at 3 months progression events happen between 3 and 6 months. The goal of our research was to investigate the prognostic impact of a large BCR-ABL transcript amount at 3 months on the subsequent response and the long-term outcome of CML pts treated frontline with IM. Methods: We have examined 185 pts, who have got IM from January 2010 up to the present. Molecular monitoring has been done regularly in all patients according to ELN recommendations. Median age was 49 years. All pts were in CP. BCR-ABL transcript levels were assessed by real-time quantitative PCR. Results: In our study 54% (100/185 cases) of pts achieved the optimal response with BCR-ABL transcript levels ≤10% at 3 months, 50,3% (93/185 cases) did it - with BCR-ABL transcript levels ≤1% at 6 months, and only 18% achieved the optimal response at 12 months. The comparative analysis has shown statistical differences in all characteristics in 2 groups of pts, who either achieved or not the optimal response at 3 months. Pts with BCR-ABL transcript levels ≤10% more often achieved CCgR at 6 months (g=0,0000), CCgR during all period (g=0,0004), MMR at 12 months (g=0,0000), MMR during all period (g=0,0012) and MR4 during all period (g=0,0000), pts had londer event-free (g=0,0432) and overall (g=0,0279) 4-year survival. Figure 1 Figure 1. In our center we have switched 6 patients to the 2nd TKI - those who didn't achieve the optimal response at 3 months. The switching showed the positive influence on loss level expression of BCR-ABL gene in 5 out of 6 patients. After that all patients achieved the optimal response in the future. For example, we had one patient with failure of IM at 3 months. We switched him the therapy to NI in 5 months after the diagnosis. As a result the patient achieved CCgR at 1,5 months, and the deep molecular response 4,5 log at 3 months. Conclusions: Early and deep responses to TKIs are predictive of long-term response and favorable survival outcomes. 3-month reduction in BCR-ABL transcript levels to >10% is a factor of bad effectiveness of TKI therapy and requires switching to the 2nd TKI. Timely switching to the 2nd TKIs allows us to achieve an optimal response in CML patients with level BCR-ABL >10% at 3 months. References: Timothy P. Hughes, Giuseppe Saglio, Hagop M. Kantarjian et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 27 February 2014 x Volume 123, Number 9. Disclosures No relevant conflicts of interest to declare.

Landmark Analyses of BCR-ABL Using ES-FISH Early After Start of Imatinib Treatment to Newly Diagnosed CMLcp Patients Predicts Longterm Clinical Outcome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4269-4269
Author(s):  
Lotta Ohm ◽  
Robert Hast ◽  
Ingrid Arvidsson ◽  
Gisela Barbany ◽  
Leif Stenke
Keyword(s):  
Clinical Outcome ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Newly Diagnosed ◽  
Control Gene ◽  
First Line ◽  
Molecular Responses

Abstract Abstract 4269 Background Imatinib (IMA) is recommended as first-line therapy for patients diagnosed with CML in chronic phase (CMLcp). Earlier studies, based particularly on the IRIS trial, have indicated that a favorable long-term clinical outcome to therapy is clearly associated with a reduction of the Ph-pos cell population and of BCR-ABL transcripts, as measured with cytogenetics and qPCR, respectively. We have investigated the response to IMA in a CMLcp cohort treated at our institution and assessed the prognostic value of early and repeated determinations BCR-ABL expression, using both ES-fluorescence in situ hybridization (FISH) and qPCR. Methods 45 pts with newly diagnosed CMLcp (24M/21F; median age 54 yrs, range 19-87; 5 with 9q del, 5 with variant translocations; Sokal scores 16 LR, 20 IR, 9 HR) were started on IMA (400mg qd) and hematologic, cytogenetic and molecular responses were followed at regular 3-mo intervals. Median IMA treatment time at follow-up was 29 mo (range 9-94). Regular cytogenetic karyotyping (CG) and interphase ES-FISH were performed on bone marrow cells (the latter method by scoring BCR-ABL in at least 500 cells on smear preparations, detection limit 20.2%) while qRT-PCR was performed on peripheral blood leukocyte samples with ABL as control gene. Major molecular response (MMR) was defined as the ratio BCR-ABL/control gene 20.1%. Results At diagnosis the pts displayed a median of 100% (range 67-100) Ph-pos metaphases by CG, while ES-FISH revealed BCR-ABL gene expression in a median of 86,2% (range 45,9-97,3) of cells. The response to IMA-treatment during the first 12 mo, displayed in Table I, included CCyR in 80%, MMR in 48% and reduction of FISH-detected BCR-ABL to <1% in 62% of analyzed pts. When first obtaining CCyR (negative CG), patients showed a median ES-FISH value of 0.27% (range 0 to 7.4%). Comparing pts who did vs. did not achieve CCyR at 12 mo (n= 36 vs. 9) FISH and PCR analyses at 3, 6 and 9 mo showed clear differences between the groups (Table II). At 24 months from start of IMA, 39 pts were evaluable for response and ‘events‘ (defined according to ELN as any of: death during study treatment, loss of CHR, loss of MCyR, progression to AP/BC or WBC>20). A total of 6 pts showed ‘event‘ (4 AP, 1 BC, 1 loss of CHR; 2 died). Table III provides landmark data related to FISH and PCR levels at 3 time points. Patients with a high remaining BCR-ABL expression were more likely to develop ‘events‘, as compared to those with low expression. Conclusion Our single centre data from an unselected CMLcp pat cohort on first-line IMA shows good clinical and molecular responses, well in line with results from the IRIS study. We propose that repeated, longitudinal interphase ES-FISH analyses may provide additional and important prognostic information regarding later targeted clinical endpoints. The method gives reliable information also early during the treatment, at higher disease penetration when PCR may be less reproducible, and can also be performed on peripheral blood samples. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Role of Monitoring the Bcr-Abl Transcript Levels in the Management of Patients with Chronic Myeloid Leukemia

2013 ◽  
Vol 59 (2) ◽  
pp. 71-74
Author(s):  
Aliz-Beáta Tunyogi ◽  
I Benedek ◽  
Judit Beáta Köpeczi ◽  
Erzsébet Benedek ◽  
Enikő Kakucs ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Transcript Levels

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

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.

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