scholarly journals Factors associated with achievement and durability of cytogenetic response in patients with chronic myeloid leukemia treated with imatinib

2011 ◽  
Vol 68 (11) ◽  
pp. 911-916 ◽  
Author(s):  
Irena Cojbasic ◽  
Lana Macukanovic-Golubovic
Keyword(s):  
Relative Risk ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Complete Cytogenetic Response

Background/Aim. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia and become the standard of care for this disease. The aim of this study was evaluation and analysis of cytogenetic response in different intervals and risk groups as well as finding association between pre-treatment characteristics and later probability of achievement of major cytogenetic response. Methods. We analyzed a total of 22 adult patients with newly diagnosed Philadelphia positive early chronic phase chronic myeloid leukemia treated at our institution from June 2006 to December 2009. Results. The median follow-up time for patients during treatment with imatinib was 25.7 months (range, 12-42 months). A complete hematologic response was achieved in all of the analyzed patients within 6 months from the start of the treatment. The major cytogenetic response rate was 81.8%, and the complete cytogenetic response rate was 72.7%. The patients with low or moderate relative risk had the rate of complementary achieving major and complete cytogenetic response of 75-90%. A multivariate analysis identified the following independent prognostic factors for achieving major cytogenetic response: the absence of splenomegaly, white blood cell count less than 10 ? 109/L, the platelet count less than 450 ? 109/L, the presence of less than 5% of bone marrow blasts and basophils, the absence of blasts in peripheral blood, the presence of less than 7% of basophils in peripheral blood. Conclusion. Patients who early achieve complete and major cytogenetic response as well as those with low and moderate relative risk have a higher rate of achieving and maintaining complete cytogenetic response. There are also characteristics of patients before treatment that may indicate the treatment outcome.

scholarly journals Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4567-4576 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant

Abstract Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

scholarly journals Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3403-3412 ◽  
Author(s):  
H. Jean Khoury ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Carlo Gambacorti-Passerini ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Abl Tyrosine Kinase ◽  
Kaplan Meier

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

Consistency Of RQ-PCR Analysis Results In Peripheral Blood and Bone Marrow Samples In Chronic Myeloid Leukemia Patients: Relevance From The Practical and Logistic Point Of View

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2592-2592
Author(s):  
Giovanna Rege-Cambrin ◽  
Carmen Fava ◽  
Enrico Gottardi ◽  
Filomena Daraio ◽  
Emilia Giugliano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Wilcoxon Test ◽  
Molecular Response ◽  
Two Samples ◽  
The Mean

Abstract Background Consensus has been achieved that standardized molecular quantitative analysis (RQ-PCR) on peripheral blood (PB) is a suitable method for monitoring residual disease in chronic myeloid leukemia (CML). However, BM is still obtained at specific timepoints, and in a number of cases, only bone marrow (BM) sample collected for cytogenetic analysis is available. Being one of the laboratory involved in the standardization process of molecular monitoring for CML patients, we decided to perform a comparative analysis of BM and PB samples in order to evaluate the consistency of the results. Methods Between March 2009 and January 2013, 230 consecutive RQ-PCR tests to assess BCR-ABL transcript levels from simultaneously collected PB and BM samples were performed (for a total of 460 analysis) on 77 patients affected by Ph+ CML in chronic phase treated in our center. All samples were analyzed in the same laboratory following international guidelines (Cross N, Leukemia 2012) and results were expressed according to the International Scale; ABL1 was used as control gene. Time from blood-drawn to processing was within 3-4 hours. Results Among the 230 pairs, 3 were considered as not evaluable because of inadequate material; for the purpose of this study, the remaining 227 pairs were considered as “evaluable”. 204 pairs were classified as “fit” when both BM and PB ABL amplification resulted in more than 10.000 copies; 23 pairs were considered unfit for ABL1 <10.000 in either one of the two samples (21) or both (2). The mean number of ABL1 copies in all evaluable samples was 35.639 for BM (SD 21.465) and 30.958 for PB samples (SD 18.696). Correlation analysis was performed on the whole population and in 4 subgroups: No Complete Cytogenetic Response (CCyR, 22%), CCyR without Major Molecular Response (MMR), (21.6%), CCyR with MMR (excluding patients with MR4 or better,19.8%), and CCyR with MR4 – MR4.5 (32,6%). Cytogenetic response was not available in 9 BM samples (4%), not included in the subgroup analysis. Spearman correlation of BCR/ABL ratio values between PB versus BM paired samples resulted in a statistically significant correlation in all groups, both for evaluable and fit pairs. Correlation was stronger in samples that were not in MMR or better (table 1 and figure 1). The Wilcoxon test showed that the mean difference of BCR/ABL values between paired PB and BM samples was not significantly different from zero (in evaluable and fit pairs by considering the whole population). Concordance was further analyzed by the K test which resulted in a coefficient equal to 0.627, corresponding to a notable degree of concordance. For patients in CCyR, agreement on classification of response (MMR, MR4, MR4.5) between paired PB and BM samples was observed in 125/168 evaluable pairs; 22 out of the 43 evaluable cases of disagreement were due to technical failures (in 10 BM and 12 PB samples). In 14 of the remaining 21 cases, PB was more sensitive. Conclusions In a single center experience of molecular analysis, BCR/ABL ratio was highly consistent in BM and PB samples. In less than 10% of the cases a single test did not reach the required sensitivity of 10.000 ABL copies and the double testing allowed to obtain a valid result. This may be especially valuable in evaluating an early response (i.e. at 3 months), when the amount of disease has prognostic relevance. The analysis will be expanded to include samples coming from different centers to evaluate a possible role of timing and transport on data consistency. Disclosures: Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

scholarly journals The Use of Statin Enhances Chance of Achieving MR4.5 in Chronic Myeloid Leukemia Patients in Chronic Phase Following Imatinib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1804-1804 ◽  
Author(s):  
Dennis Dong Hwan Kim ◽  
Feras Alfraih ◽  
Honggi Lee ◽  
Jeffrey H. Lipton
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Statin Group ◽  
Tki Discontinuation

Abstract BACKGROUND: HMG-CoA reducatase inhibitors, or statins, are commonly prescribed medications which improve life expectancy in general population. They are known to improve hypercholesterolemia and decrease the incidence of cardiovascular events including myocardial infarction or stroke, but also suggested for cancer prevention even though the mechanism is not fully elucidated. Recent studies emphasized the potential role of statins in the cancer treatment to increase response rate to chemotherapy and to improve survival of cancer patients. Statin family of drugs is known to trigger tumor specific apoptosis and to result in growth arrest in leukemias (Penn, Leukemia 2002). The promising result of STIM (STop Imatinb) trial suggested that successful discontinuation of tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML) is possible when patients attain deeper molecular response (defined as 4.5 log reduction or deeper) for 2 years or longer. However, with our current knowledge, there is no known additive intervention facilitates the achievement of MR4.5. We hypothesized that the use of statin improves response rate to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), thus increasing MR4.5 achievement and increasing the chance of being attempted TKI discontinuation. METHODS: A total of 503 patients treated with TKI for CML treatment were initially evaluated for the response to TKI therapy with respect to complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response at 4.5 (MR4.5) and statin use. The inclusion criteria confined the patients with chronic phase (CP) treated with imatinib at the dose of 400mg daily, thus excluding 95 patients. Finally, 408 patients were entered into the final analysis. The statin group was defined as those on statin for cholesterol control at the time of imatinib commencement and remaining on statin while on at least 3 years or longer. Cumulative incidence method considering competing risk was adopted to calculate the incidences of MCyR, CCyR, MMR and MR4.5. Discontinuation of imatinib was accounted as competing risk in the analysis. Treatment failure, progression free- and overall survival was also evaluated. RESULTS: With a median follow-up duration of 6 years (range 3 months to 14 years), 88 patients (21.3%) were defined as “statin” group. Types of statin includes atorvastatin (n=44, 50%), rosuvastatin (n=26, 30%), simvastatin (n=10, 11%), pravastatin (n=6, 7%) and fluvastatin (n=2, 2%). The MCyR and CCyR achievement was not significantly different between the 2 groups (p=0.769 for MCyR and p=0.091 for CCyR). No difference of CCyR at 12 months was noted: 70.1% in statin vs 62.8% in non-statin group. The statin group showed a higher response rate than non-statin group for MMR (p=0.005) and MR4.5 (p=0.001): 67.3% vs 49.2% for MMR at 18 months; 55.8% vs 41.0% for MR4.5 at 5 years (Figure). Multivariate analysis was successful to confirm the use of statin as an independent clinical factor for improving MR4.5 (HR 1.785, 95% CI [1.260-2.530], p=0.001), but other clinical factors were not identified such as Sokal risk, age, gender or additional cytogenetic abnormalities (ACAs) at presentation. For MMR, the use of statin was also confirmed as independent factor for MMR (HR 1.541 95% [1.015-2.341], p=0.043) in addition to ACAs (HR 0.381, p=0.0038) and high sokal risk (HR 0.687, p=0.042). The use of statin was not found to be associated with improvement in treatment failure (p=0.580), progression free survival (p=0.731) or overall survival (p=0.542) in the present study. CONCLUSION: The use of statin suggested to improve deeper molecular response following imatinib therapy in CML-CP patients, therefore is promising to increase chance of attempt to TKI discontinuation. Statin appears to improve the chance of MR4.5 achievement by 78.5%. Careful interpretation is required and replication study in an independent cohort is strongly warranted to reach a clear conclusion on this promising effect of statin. The use of statin to deepen the molecular response of TKI therapy should be evaluated in the context of clinical trial. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
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.

Development of a predictive population survival model according to the cytogenetic response rate for patients with chronic myeloid leukemia in the chronic phase

2006 ◽  
Vol 47 (6) ◽  
pp. 1069-1081 ◽  
Author(s):  
Rudolf J. Schrover ◽  
Michael A. Adena ◽  
Richard De Abreu Lourenco ◽  
H. Miles Prince ◽  
John F. Seymour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Survival Model ◽  
Population Survival

scholarly journals Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

2012 ◽  
Vol 30 (28) ◽  
pp. 3486-3492 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
End Point

Purpose Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and Methods A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. Conclusion This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

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