Sensitive Detection of BCR-ABL1 Mutations in Patients With Chronic Myeloid Leukemia After Imatinib Resistance Is Predictive of Outcome During Subsequent Therapy

2011 ◽  
Vol 29 (32) ◽  
pp. 4250-4259 ◽  
Author(s):  
Wendy T. Parker ◽  
Rebecca M. Lawrence ◽  
Musei Ho ◽  
Darryl L. Irwin ◽  
Hamish S. Scott ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Detection Limit ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Imatinib Resistance ◽  
Low Level ◽  
Clinical Resistance ◽  
The Impact

Purpose BCR-ABL1 mutation analysis is recommended to facilitate selection of appropriate therapy for patients with chronic myeloid leukemia after treatment with imatinib has failed, since some frequently occurring mutations confer clinical resistance to nilotinib and/or dasatinib. However, mutations could be present below the detection limit of conventional direct sequencing. We developed a sensitive, multiplexed mass spectrometry assay (detection limit, 0.05% to 0.5%) to determine the impact of low-level mutations after imatinib treatment has failed. Patients and Methods Mutation status was assessed in 220 patients treated with nilotinib or dasatinib after they experienced resistance to imatinib. Results Mutations were detected by sequencing in 128 patients before commencing nilotinib or dasatinib therapy (switchover). In 64 patients, 132 additional low-level mutations were detected by mass spectrometry alone (50 of 132 mutations were resistant to nilotinib and/or dasatinib). When patients received the inhibitor for which the mutation confers resistance, 84% of the low-level resistant mutations rapidly became dominant clones detectable by sequencing, including 11 of 12 T315I mutations. Subsequent complete cytogenetic response rates were lower for patients with resistant mutations at switchover detected by sequencing (0%) or mass spectrometry alone (16%) compared with patients with other mutations or no mutations (41% and 49%, respectively; P < .001). Failure-free survival among the 100 patients with chronic phase chronic myeloid leukemia when resistant mutations were detected at switchover by sequencing or mass spectrometry alone was 0% and 0% compared with 51% and 45% for patients with other mutations or no mutations (P = .003). Conclusion Detection of low-level mutations after imatinib resistance offers critical information to guide subsequent therapy selection. If an inappropriate kinase inhibitor is selected, there is a high risk of treatment failure with clonal expansion of the resistant mutant.

Outcome of Patients with Philadelphia Positive Chronic Myeloid Leukemia Post Imatinib Failure: Prognostic Significance of ABL Mutation and Additional Clonal Abnormality.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4673-4673 ◽  
Author(s):  
Monika Conchon ◽  
Patricia B Ferreira ◽  
Mafalda MY Novaes ◽  
Luciana Nardinelli ◽  
Mariana Serpa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Point Mutation ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Fish Analysis ◽  
Imatinib Treatment ◽  
Abl Kinase ◽  
Clinical Resistance

Abstract Abstract 4673 Point mutation within the ABL kinase domain of the BCR-ABL gene has been associated with clinical resistance to imatinib in chronic myeloid leukemia (CML). However, several other mechanisms have been proposed to underlie the development of imatinib resistance such overexpression and amplification of the BCR-ABL gene locus; development of additional chromosomal abnormalities (ACA), activation of BCR-ABL independent mechanisms; increased drug efflux through multidrug resistance gene and binding of imatinib to serum alfa-1 acid glycoprotein. In this regard, we report the outcome of 54 patients Ph+ CML who were resistant to imatinibe and the association with point mutation, ACA and overexpression of BCR-ABL through in situ hybridization (FISH). Patients and Methods Of 54 CML patients, 16 were in early chronic phase (ECP), 24 in late chronic phase (LCP) and 14 in accelerated phase (AP) before imatinib treatment. They were considered imatinib resistant for the following reasons: hematologic resistant or recurrence (7 patients), cytogenetic resistance or recurrence (30 patients) or progression to more advanced phase (17 patients). Mutational analysis was carrying out by direct sequencing and FISH analysis using commercial BCR/ABL t(9;22), dual color, dual fusion probe (Kreatech, Poseidon, The Netherlands). Subsequent therapy was also analyzed, as to whether they underwent to allogeneic SCT, chemotherapy, or received, dasatinib or nilotinib. Results A total of 24 BCR-ABL kinase domain mutations were detected in 54 patients. Two patients had more than 1 mutation. The most frequent mutations were F359V (6/24), T315I (5/24) and F317L (3/24). P-loop mutations accounted for 60% of the remaining amino acid substitutions. Twelve patients were treated with nilotinib 400 mg bid, 50% presented mutation at resistance (3 F359V, 1 Q252H, 1 E355G, and 1 T315I), and all alive but one with T315I mutation died after 1 month. Dasatinib, 100-140 mg daily, was dispensed for 37 patients, mutations were identified in 40%, where 10 patients are still alive (2 T315I, 2 F317L, and 6 others). Allogeneic SCT was performed in 2 patients (1 G250E), and both died. Two patients died (1 F359V) after systemic chemotherapy and 1 patient who received 800 mg of IM is in CCyR after 40 months. There was no difference in overall survival when mutation was present or not at the moment of resistance (log rank, p=0.9). We also compared the karyotype tacked before imatinib treatment with the karyotype performed at the time of resistance; 17 patients developed ACA and were associated with worse overall survival (log rank, p=0,046) when compared with those patients without ACA. FISH analysis did not identify overexpression of BCR-ABL, but 4 cases presented 3 signals for BCR-ABL indeed had an extra Ph chromosome. Conclusions Second-generation TK inhibitors improve overall survival of those patients who presented mutations at resistance. The presence of ACA during imatinib treatment was related with a higher mortality despite the treatment applied and the presence or not of mutations. We also conclude that overexpression of BCR-ABL was not responsible for resistance to imatinib in our study population. Disclosures: No relevant conflicts of interest to declare.

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1039-1043 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian Druker ◽  
Charles Sawyers ◽  
Francois Guilhot ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Imatinib Treatment ◽  
Serious Adverse Events ◽  
Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

scholarly journals Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Molecular Response ◽  
Open Label ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4844-4844
Author(s):  
Hana Klamova ◽  
Jana Brezinova ◽  
Kyra Michalova ◽  
Zuzana Zemanova ◽  
Marek Trneny
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Cytogenetic Abnormalities ◽  
Ph Chromosome ◽  
Cytogenetic Evolution

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

Inhibiting Alternative Non Homologus Endjoining (NHEJ) Pathways: Therapeutic Targets in Chronic Myeloid Leukemia (CML).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1088-1088
Author(s):  
Annahita Sallmyr ◽  
Lisa Tobin ◽  
Alan E. Tomkinson ◽  
Feyruz V. Rassool
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Therapeutic Targets ◽  
Chronic Phase ◽  
Dna Ligase ◽  
Imatinib Treatment ◽  
Dna Ligases ◽  
Dna Deletions

Abstract BCR-ABL fusion tyrosine kinase in chronic myeloid leukemia (CML), induces high levels of ROS that generate DNA double strand breaks (DSBs). We previously showed that CML cells repair DSBs by aberrant non homologous end-joining (NHEJ) that is characterized by large DNA deletions. The generation of DNA deletions represents a mechanism by which genomic alterations may be acquired in the progression of chronic phase CML to blast crisis. Recently, we demonstrated that a “back-up” or alternative NHEJ pathway is involved in aberrant repair of DSBs in CML. Proteins in this pathway include, DNA ligase IIIα, XRCC1 and poly(-ADP) ribose polymerase (PARP). We have identified that NHEJ proteins, DNA ligase IIIα and WRN are overexpressed in CML. This increased expression appears to be dependent on the presence of BCR-ABL. “Knockdown” of these proteins leads to an accumulation of unrepaired DSBs, demonstrating their essential involvement in DSB repair in CML cells. The goal of the current study is to evaluate the effect of inhibiting “back-up” DNA repair proteins in proliferation and apoptosis of BCR-ABL-positive CML compared with standard Imatinib therapy. To evaluate whether “back-up” repair proteins may be therapeutic targets, we used siRNA down-regulation and small molecule inhibition of DNA ligase IIIα and PARP in BCR-ABL positive cell lines. Importantly, we have recently identified small molecule inhibitors of DNA Ligases by computer aided drug design (CADD). Inhibition of DNA ligases and PARP result in a significant increase in apoptosis of CML cells (K562, Kasumi 4, MEG01 and KU812 and P210 MO7e), comparable with the cell death observed with imatinib treatment. Importantly, CML cell lines resistant to imatinib treatment demonstrate similar apoptotic levels in response to “back-up” repair protein inhibition. These inhibitors are in the process of being tested in CML xenografts and mouse models for therapeutic efficacy in vivo. Our data suggest that the survival of CML cells is at least in part maintained by repair of DSBs using “Back-up” NHEJ. The main proteins involved in this pathway, which include DNA ligase IIIα, XRCCI, DNA Ligase I, PARP and WRN have the potential to be novel therapeutic targets in CML patients that have acquired resistance to imatinib.

Significance of Minimal Residual Disease in Patients with Chronic Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3269-3269
Author(s):  
Iwona Solarska ◽  
Barbara Nasilowska-Adamska ◽  
Maria Bieniaszewska ◽  
Jan Maciej Zaucha ◽  
Piotr Rzepecki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Chronic Phase ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Low Level ◽  
High Level ◽  
Minimal Residual

Abstract Abstract 3269 Poster Board III-1 Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for patients (pts) with chronic myeloid leukemia (CML). AlloHSCT is associated with long-term disease-free survival in 40% to 80% pts transplanted in early chronic phase of disease. The probability of relapse for pts transplanted in first chronic phase is 10% to 20% at 5 years, and is even higher (30% – 60%) for pts who received transplant in advanced phases of CML. The significance of minimal residual disease (MRD) in this clinical setting is uncertain. We enrolled 63 consecutive pts with CML who had received an alloHSCT between 1995 and 2007 and had BCR-ABL transcript quantity measured by RQ-PCR method on at least 2 occasions during follow-up in the period starting 6 months after alloHSCT. The reverse transcription was preformed using SuperScriptIII and random hexamers. Quantification of BCR-ABL was performed by RQ-PCR assay according to ‘Europe Against Cancer' protocol. BCR-ABL expression was normalized with endogenous control ABL gene and expressed as a ratio BCR-ABL/ABL. According to the amount of BCR-ABL transcript detected in blood or bone marrow after alloHSCT pts were allocated into 3 categories, including pts with no-detectable or stable very low-level of BCR-ABL transcripts (ratio BCR-ABL/ABL below 0.005%), pts with fluctuating-low level of BCR-ABL transcripts (0.005 – 0.01%) and pts with high-level of BCR-ABL transcripts (0.01 – 0.1%). We didn't find any relationships between different BCR-ABL levels after alloHSCT and clinical parameters at the time of CML diagnosis or transplantation, including Sokal, Hasford and Gratwohl scores. Median time from alloHSCT to molecular relapse (MR) was 38 months (range, 8.5 – 88.5 months). The 3-year progression rate into cytogenetic or hematological relapse of CML since MR was 70%. This progression occurred at a median time of 1.4 months (range, 0 – 3.2 months). We found strong correlation between the levels of BCR-ABL transcripts after alloHSCT and a risk of relapse. The incidence of MR was 0%, 26%, 71% for the low-level, fluctuating-low level and high-level of BCR-ABL transcript (p<.0001), respectively. Similarly the risk of cytogenetic and hematological relapse was 0%, 21%, 43% for these pts (p=.001), respectively. Five-year leukemia-free survival was 100%, 83.9% and 66.7% for the pts with low-level, fluctuating-low level and high-level BCR-ABL transcript (p=.003), respectively. There was no apparent relationship between the level of BCR-ABL transcript and overall survival. We conclude that pts with fluctuating-low and/or high levels of BCR-ABL transcripts are at higher risk of disease progression. Sequential RQ-PCR monitoring coupled with pre-emptive therapy can provide a valid strategy to reduce rates of relapse and development of a more individualized approach to management of pts with CML in major molecular response after alloHSCT. Disclosures: Warzocha: BMS: Consultancy, Honoraria; Celgene: Consultancy; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria.

Delayed Cytogenetic Response and Reduced Rate of Major Molecular Response Associated to Increased Body Mass Index At Baseline in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2784-2784
Author(s):  
Massimo Breccia ◽  
Giuseppina Loglisci ◽  
Adriano Salaroli ◽  
Alessandra Serrao ◽  
Paola Volpicelli ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Body Mass ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Normal Weight ◽  
First Line ◽  
Reduced Rate ◽  
The Impact

Abstract Abstract 2784 Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for the onset of several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in CML. Three hundred and thirty-nine chronic phase (CP) CML patients treated with imatinib entered the study: 142 patients first received interferon alpha outside clinical trials and were then switched to imatinib for failure. For this group of patients, BMI was collected at the time of start of imatinib. The remaining patients were consecutively treated with imatinib first-line from January 2000 onward. BMI was defined as the individual's body weight divided by the square of his of her height and patients were categorised according to WHO into four categories: underweight (BMI < 18.5), normal weight (BMI 18.5-< 25), overweight (BMI 25-<30) and obese (BMI ≥ 30). All patients were followed according to ELN guidelines. We also analysed 25 CP-CML patients treated frontline with nilotinib. One hundred and fifty-six patients (46%) were categorized as underweight/normalweight, while 183 patients (54%) were classified as overweight/obese. BMI increased with age, with a median age of 29 years in underweight category, 43.4 years in normal weight, 54.9 years in overweight and 62.4 years in obese patients (p=0.001). We did not reveal statistically significant association between BMI and prognostic risk stratification at baseline, even when we used new EUTOS score, or type of BCR/ABL transcript. No statistically significant difference was revealed in terms of overall CCyR rate which was 87% for underweight/normal weight categories compared to 84% for overweight/obese group (p=0.34). If compared to patients with low BMI (< 18.5–25), patients with increased BMI (> 25–40) at diagnosis who received imatinib, showed a significantly longer median time to reach CCyR (6.8 months vs 3.3 months, p=0.01), a reduced rate of MMR (77% vs 58%, p=0.01) which was also achieved in a longer median time (29 months compared to 14 months, p=0.03). At 18 months, molecular kinetics revealed that median BCR-ABL/ABL ratio was 0.6% IS (range 0.001%-2%) in underweight/normal weight group compared to 1.6% IS (range 0.01%-3%) in overweight/obese category (p=0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR, with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch to a second generation TKI or, as an alternative, should preferably be candidate to receive these drugs as a first line therapy. Disclosures: No relevant conflicts of interest to declare.

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