SIGNIFICANCE OF ADDITIONAL CHROMOSOMAL ABNORMALITIES FOR THE OUTCOMES AFTER THE SECOND LINE NILOTINIB THERAPY IN THE CHRONIC MYELOID LEUKEMIA PATIENTS

Background. There is limited information about impact of additional chromosome aberrations (ACA) on the efficacy of the 2nd line nilotinib therapy. Objective. The aim of the study was to analyze significance of ACAs for the outcome after second line tyrosine kinase inhibitors (TKI) therapy with nilotinib in the chronic myeloid leukemia (CML) patients, who experienced previous imatinib therapy failure. Methods. The CML patients in chronic phase treated with nilotinib after imatinib failure were analyzed for outcomes. Results. Among a total of 114 patients, 18 patients (15.8%) had ACAs at the beginning of the 2nd line therapy with nilotinib. Seven patients (38.9%) of 18 had variant translocations and 11 patients (61.1%) had other chromosomal abnormalities in addition to t(9;22), known as clonal evolution. Complete cytogenetic response (CCR) at 12 months was achieved in 37.5%, 42.8% and 45.5% (p=0.842) of patients with classic t(9;22) translocation, variant translocations and ACAs respectively. In the patients with variant translocations t(9;V;22) or clonal evolution treated with nilotinib after the imatinib failure, the CCR and major molecular response (MMR), event free survival (EFS), progression free survival (PFS) and overall survival (OS) rates did not differ from those in the CML patients with t(9;22) only. At the same time quantitative characteristics of leukemic and ACA clones had prognostic value for CCR. The increased number of Ph-positive cells and the number of cells with the ACA at the start of nilotinib therapy reduced the probability of CCR. Conclusions. Higher nilotinib inhibitory activity compare with imatinib allows us to overcome imatinib resistance in the CML patients regardless of the ACA presence at the beginning of nilotinib therapy.

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

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692117666190925115852 ◽

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.

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

Blood ◽

10.1182/blood-2010-03-277152 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1141-1145 ◽

Cited By ~ 234

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.

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Study of different mutations in chronic myeloid leukemia in India and their co-relation with drug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7083 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7083-7083

Author(s):

Priti Mitra ◽

Swati Dasgupta ◽

Chinmay Kumar Basu ◽

Firoj Hossain Gharami ◽

Subrata Mandal ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Mutation Screening ◽

Resistance Mutation ◽

Tyrosine Kinase Domain ◽

Molecular Response ◽

Imatinib Resistance ◽

Imatinib Resistant ◽

Resistant Mutation

7083 Background: Emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML. Aim of our study is to investigate two potential resistance mechanisms i.e.,mutations of BCR-ABL tyrosine kinase domain (TKD) and Additional Chromosomal Abnormalities during TKI treatment in CML. Methods: Karyotyping and BCR-ABL TKD mutation screening are performed in 100 imatinib resistant CML patients who were on imatinib at the time of loss of hematologic response, cytogenetic or molecular response. Imatinib–Resistance Mutation Analysis (Qualitative) were detected by Nested RTPCR and Sanger’s Sequencing. In 100 cases, 34 received escalated imatinib, 34 nilotinib and another 32 dasatinib. Results: In 100 BCR-ABL positive imatinib, nilotinib and dasatinib resistant cases, 11 different BCR-ABL TKD mutations were detected. Analysis revealed no mutations-43 cases, M351T-12 cases, G250E-10 cases, F317L-8 cases, M244V-5 cases, E255K-4 cases, V379I-4 cases, F359V-3 cases, H396R-3 cases, Y253F-3 cases, E355G-3 cases, T315I-2 cases. 11 novel mutations (F317L, G250E, M244V, Y253F, E255K, M351T, F359V, H396R, V379I, E355G, T315I) conferring imatinib resistance, 10 nilotinib–resistant mutations (M244V, F359V, T315I, E355G, G250E) and 8 dasatinib-resistant mutations (H396R, F317L, H396R, T315I, M351T) were seen in our patient population. T315I was found more frequently in cases on dasatinib than on imatinib therapy. Conclusions: T315I which confers resistance to all TKIs was detected only in 2/100 patients who demonstrated loss of response in our population. As compared with other western studies, incidence of T315I mutation was very low in our study. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. For cases with TKI resistance, mutation and ACA screening may play role in identifying patients with poorer prognosis. In our practice if nilotinib–resistant mutation was detected, dasatinib was preferred and for dasatinib-resistant mutation, nilotinib was preferred. We are planning for using bosutinib, panotinib and omacetaxine (SC route) in third line therapy in imatinib resistant different mutation positive chronic myeloid leukemia.

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Long-Term Results and Characteristics of Pleural Effusion in Late Chronic Phase Chronic Myeloid Leukemia Patients at Dasatinib Therapy after Imatinib Failure

Blood ◽

10.1182/blood.v126.23.5141.5141 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5141-5141

Author(s):

Galina Gusarova ◽

Anastasia Bykova ◽

Alexandra Vorontsova ◽

Sergey Kuznetsov ◽

Oleg Shukhov ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Prolonged Treatment ◽

Molecular Response ◽

Major Molecular Response ◽

Free Survival ◽

Dasatinib Treatment

Abstract Background. The aim of chronic myeloid leukemia (CML) treatment with tyrosine kinase inhibitors (TKI) is not only effectiveness, but also safety. Long treatment duration makes the analysis of most significant complications very important. Pleural effusion (PE) is an important adverse event of dasatinib therapy with largely unclear cause. The optimal management of recurrent PE is unknown and the analysis of its treatment results is actual. Aim. To describe the characteristics of patients with recurrent PE at prolonged dasatinib treatment and to suggest the strategy of their management. Methods. Follow-up data of 23 CML late chronic phase patients at dasatinib therapy after imatinib failure in 2 clinical studies: phase II study comparing dasatinib 140 mg and imatinib 800 mg daily (N = 12) and phase III dasatinib dose-optimizing study in patients with imatinib-resistant or intolerant patients (N = 11). M:F ratio was 7:16. Median age at the beginning of dasatinib - 48 years (26-68), median CML duration - 11 years (4,1-19,2). The reason for TKI change was imatinib resistance: cytogenetic (N = 17) and hematological (N = 6). Results. Median duration of dasatinib treatment - 40 months (10-107); 13 patients (56,3%) are alive, 10 patients (43,5%) have died because of progression of CML. In 19 patients (82,6%) dasatinib treatment was stopped because of: blastic transformation - 6 (26,1%), hematological resistance - 3 (13,1%), cytogenetic resistance - 5 (21,7%), PE - 5 (21,7%). Four patients are still on dasatinib treatment with median duration 8,8 years (8,7-8,9), 3 of them retain complete/major molecular response. The best responses were: complete hematological response in 21 (91,3%), complete cytogenetic response - in 8 (34,8%), major molecular response - in 6 (26,1%) patients. Overall 8-year survival was 55,1%, progression-free survival - 55,4%, event-free survival - 26,1%. PE was observed in 11 (47,8%) patients, in 8 of them (72,7%) - recurrent. In one patient the prolonged PE was associated with fibrosis of adjacent lung and pleura. Median time to PE was 34 (6-83) months. In cases of PE dasatinib was interrupted (mean duration 21 d) and diuretics were started. Six patients (54,5%) also received corticosteroids. Five patients (45,6%) were treated with thoracocentesis. In recurrent PE the dasatinib dosage was decreased. The dasatinib discontinuation in 4 patients with recurrent PE has led to loss of major molecular response in 2 of them; in other 2 it is retained for 6,5 and 1,5 years. Event-free 8-year survival was 36,4% in patients with PE, 16,7% - without it. Discussion. The response rate in patients with PE was not worse, than in those without it. Most often PE begins at 3rd year of treatment; later events were only relapses. Among risk factors of PE 2 patients had arterial hypertension and hypercholesterinemia, 3 patients were > 65 yrs. The significantly high PE on rate (48%) was linked to high initial dasatinib dosage (> 100 mg/d) and bid prescription. We have not observed cases of absolute lymphocytosis due to large granular lymphocytes proliferation. The continuation of treatment generally leads to recurrences of effusion. According to our experience, once arising PE tends to recur. The compensation can be maintained with continuous treatment with diuretics. The prolonged PE may lead to fibrosis of adjacent lung and pleura. Prolonged treatment interruptions and decreased doses can cause treatment failure. The role of corticosteroids is unclear. Conclusion. Our experience in recurrent PE management at dasatinib treatment allow to recommend the usage of alternative TKI in patients with poor treatment response, and discontinuation of treatment in patients with deep molecular response with close monitoring of residual disease by PCR. Disclosures Turkina: Novartis International AG: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy.

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Dasatinib Induces a Higher Molecular Response in Japanese Patients with Chronic Myeloid Leukemia After Imatinib Failure Than in Western Populations: Kanto CML Study

Blood ◽

10.1182/blood.v118.21.4448.4448 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4448-4448

Author(s):

Yoshihiro Hatta ◽

Koiti Inokuchi ◽

Takashi Kumagai ◽

Kazuteru Ohashi ◽

Atsushi Shinagawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tumor Cells ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Japanese Patients ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Resistance ◽

Dasatinib Treatment

Abstract Abstract 4448 Background Dasatinib is a potent tyrosine kinase inhibitor and is highly effective against chronic myeloid leukemia (CML). In Japan, dasatinib was approved in 2009 as a second-line therapy for CML after imatinib failure. Therefore, we conducted a phase II study to investigate the efficacy and safety of dasatinib treatment in Japanese CML-chronic phase (CP) patients with intolerance or resistance to imatinib. Patients and method CML-CP patients who were unable to continue imatinib therapy (400 mg/day) because of adverse events were registered as being intolerant to imatinib. Resistance to imatinib was defined as failure to achieve a partial cytogenetic response (PCyR) after three months of therapy or a complete cytogenetic response (CCyR) after six months of therapy or the expression of over 100 copies/μg RNA of BCR-ABL after 12 months of therapy. For these patients, dasatinib (100 mg) was administered once daily. Patients with T315I and F317I mutations in BCR-ABL were excluded. Major and complete molecular responses (MMR and CMR) were centrally evaluated using RQ-PCR at the BML laboratory. When the study was designed, a conversion factor (CF) had not been introduced to Japan for the adoption of international scale (IS). Subsequently, 0.1% IS (MMR) was defined as being equivalent to 731 copies/μg RNA based on the BML laboratory specific CF obtained in 2011, and 11 patients were identified as having an MMR at the time of study enrollment. Results A total of 61 patients were accrued from 21 centers: 26 with intolerance, and 35 with resistance. The median age was 58 years (range, 16 – 91 years). The median follow-up duration was nine months (range, 0.5 – 18 months). An MMR+CMR was observed in 27 out of 45 patients (60.0%, 13 CMR and 14 MMR) at six months and in 22 out of 31 patients (71.0%, 8 CMR and 14 MMR) at nine months after treatment with dasatinib, respectively. Excluding the patients with an MMR at the time of registration, dasatinib had induced an MMR+CMR in 21 out of 39 patients (53.9%, 11 CMR and 10 MMR) at six months and 19 out of 28 patients (67.9%, 7 CMR and 12 MMR) at nine months, respectively. The response rates in intolerant and resistant patients were comparable. Twelve patients discontinued dasatinib treatment because of drug toxicity (four patients), patient request (one), disease progression or the development of a T315I mutation (three), or unknown causes (four). Although grade 1 – 2 pleural effusion was observed in five patients, no severe cases were observed. Ten mutations in BCR-ABL occurred in eight patients during dasatinib treatment; a low IC50 of dasatinib against tumor cells in five of these mutations (M244V, M351T, F359I, F359V, H396R), an intermediate value against tumor cells in one of these mutations (Q252H), a high value against tumor cells in two of these mutations in three patients (T315I in two patients and E459K), and an unknown sensitivity against tumor cells in one of these mutations (A397P). Patients with M244V+Q252H, H396R, or T315I did not respond to dasatinib treatment. Conclusion Dasatinib is a safe and efficacious alternative for the treatment of CML following imatinib failure. Because MMR rate in the global study was 31% at one year and 44% at 5 years, the molecular response rate among Japanese patients was higher than that in western populations. Mutation in BCR-ABL remains a major issue. Disclosures: Okamoto: Bristol-Myers Squibb: Research Funding.

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BCR-ABL1 Transcript Levels at 3 and 6 Months Are Better for Identifying Chronic Myeloid Leukemia Patients with Poor Outcome in Response to Second-Line Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure: A Report from a Single Institution

Acta Haematologica ◽

10.1159/000430835 ◽

2015 ◽

Vol 134 (4) ◽

pp. 248-254 ◽

Cited By ~ 4

Author(s):

Beatriz Felicio Ribeiro ◽

Bruna Rocha Vergílio ◽

Eliana Cristina Martins Miranda ◽

Maria Helena Almeida ◽

Marcia Torresan Delamain ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Second Line ◽

Second Line Therapy ◽

Free Survival ◽

Transcript Levels ◽

Real Time Quantitative Pcr ◽

Better Than

Early reduction of BCR-ABL1 transcript levels has been associated with improved outcome in chronic myeloid leukemia (CML) treatment. We evaluated 54 chronic-phase CML patients treated with imatinib who switched therapy to dasatinib (n = 33) or nilotinib (n = 21). BCR-ABL1 transcript levels were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) every 3 months from the start of second-line treatment. Patients with BCR-ABL transcript levels >10% at 3 months and >1% at 6 months had significantly inferior progression-free (PFS) and event-free survival (EFS) than patients with RQ-PCR <10% at 3 months and <1% at 6 months (66 vs. 100%, p = 0.01, and 33 vs. 73%, p = 0.02, respectively). Patients with RQ-PCR <10% at 3 months and >1% at 6 months also had inferior PFS and EFS than patients with RQ-PCR <10% at 3 months and <1% at 6 months (48 vs. 100%, p = 0.002, and 25 vs. 73%, p < 0.0001, respectively). Two measurements of BCR-ABL levels were better than a single one to stratify chronic-phase CML patients as failure after second-line therapy.

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Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study

Blood ◽

10.1182/blood-2007-10-116475 ◽

2008 ◽

Vol 111 (8) ◽

pp. 4022-4028 ◽

Cited By ~ 410

Author(s):

Richard A. Larson ◽

Brian J. Druker ◽

Francois Guilhot ◽

Stephen G. O'Brien ◽

Gilles J. Riviere ◽

...

Keyword(s):

Steady State ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Plasma Concentrations ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Free Survival ◽

Clinical Responses ◽

Trough Levels

AbstractImatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (Cmins) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (± SD, CV%) steady-state Cmin for imatinib and CGP74588 were 979 ng/mL (± 530 ng/mL, 54.1%) and 242 ng/mL (± 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). Cmin of imatinib was significantly higher in patients who achieved CCyR (1009 ± 544 ng/mL vs 812 ± 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.

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EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience

Blood ◽

10.1182/blood-2011-10-388967 ◽

2012 ◽

Vol 119 (19) ◽

pp. 4524-4526 ◽

Cited By ~ 41

Author(s):

Elias Jabbour ◽

Jorge Cortes ◽

Aziz Nazha ◽

Susan O'Brien ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Major Molecular Response ◽

Free Survival ◽

Eutos Score

Abstract To validate the recently reported European Treatment and Outcomes Study (EUTOS) score, we applied it to 465 patients with early chronic phase chronic myeloid leukemia treated with standard-dose imatinib (n = 71), high-dose imatinib (n = 208), or second-generation tyrosine kinase inhibitors (n = 186), and assessed its ability to predict event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS). The median follow-up was 69 months. The overall complete cytogenetic response and major molecular response rates were 92% and 85%, respectively. The 3-year EFS, TFS, and OS rates were 86%, 95%, and 97%, respectively. Of the 465 patients, 427 (92%) were in low EUTOS score category. There was no difference in the major molecular response, TFS, EFS, and OS rates between patients with low and high EUTOS score, overall and within specific therapies. In conclusion, 8% of patients with chronic phase chronic myeloid leukemia treated at our institution are in the high EUTOS score; in this population, the EUTOS score was not predictive for outcome.

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Clonal evolution of AML1-ETO coexisting with BCR-ABL and additional chromosome abnormalities in a blastic transformation of chronic myeloid leukemia

Journal of International Medical Research ◽

10.1177/0300060520919237 ◽

2020 ◽

Vol 48 (5) ◽

pp. 030006052091923 ◽

Cited By ~ 1

Author(s):

Cheng-Cheng Ma ◽

Ye Chai ◽

Hui ling Chen ◽

Xin Wang ◽

Ying Gao ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Copy Number ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chromosomal Abnormalities ◽

Blast Crisis ◽

Clonal Evolution ◽

Molecular Genetic ◽

Chronic Phase ◽

Interesting Case

Blast crisis develops in a minority of patients with chronic myeloid leukemia even in the era of tyrosine kinase inhibitor (TKI) therapy. Reports suggest that we know little about the mechanism of BCR-ABL and AML1-ETO co-expression in blast crisis of chronic myeloid leukemia, and that other chromosomal abnormalities also coexist. Here, we document an unusual and interesting case of a 51-year-old female diagnosed in the chronic phase of chronic myeloid leukemia. After undergoing TKI treatment for 3 months, her bone marrow aspirates in the chronic phase had transformed to blast crisis. Molecular genetic testing indicated she was positive for p210 form of BCR-ABL (copy number decreased from 108.91% to 56.96%) and AML1-ETO fusion (copy number, 5.65%) genes and had additional chromosomal abnormalities of t(8; 21)(q22; q22)/t(9; 22)(q34; q11), t(2; 5)(p24; q13) and an additional +8 chromosome.

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Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

Journal of Clinical Oncology ◽

10.1200/jco.2009.21.8230 ◽

2009 ◽

Vol 27 (25) ◽

pp. 4204-4210 ◽

Cited By ~ 197

Author(s):

Timothy Hughes ◽

Giuseppe Saglio ◽

Susan Branford ◽

Simona Soverini ◽

Dong-Wook Kim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Resistance ◽

Mutational Status ◽

Imatinib Resistant

Purpose Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.

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