scholarly journals Clinical characteristics, disease evolution and survival in patients with chronic myeloid leukemia, BCR-ABL1 (+) and T315I mutation.

Folia Medica ◽  
2021 ◽  
Vol 63 (5) ◽  
pp. 670-675
Author(s):  
Veselina Goranova-Marinova ◽  
Alexander Linev ◽  
Hristo J. Ivanov ◽  
Ivan Zheljazkov ◽  
Vily Stoyanova ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Survival ◽  
Group Treatment ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Risk Group ◽  
Molecular Response ◽  
Disease Evolution ◽  
Significant Difference ◽  
T315i Mutation

Introduction: The T315I mutation in patients with chronic myeloid leukemia (CML) has been associated with therapeutic resistance and an unfavourable prognosis. Aim: To study the frequency of T315I mutation in patients with CML, BCR-ABL&nbsp;(+), their clinical characteristics, disease evolution, and median survival. Patients and methods: We studied 75 patients with CML and BCR-ABL1&nbsp;(+). T315I mutation was detected by digital droplet PCR and BCR-ABL1 was analyzed by RT-PCR. A comparative analysis was performed by sex, age, disease phase, risk group, treatment, molecular response (MR), and median survival in T315I&nbsp;(+) and T315I&nbsp;(&minus;) patients. Results: T315I mutation was detected in 11 patients (14.7%). No significant difference was found in the phase, risk group, and first-line therapy. A significantly higher proportion of T315I&nbsp;(+) did not achieve MR&nbsp;>3.5 log: 8 (72.7%) vs. 22 (34.4%) (p=0.023). The lowest mean BCR-ABL1 levels were significantly higher in the CML T315I&nbsp;(+) group compared to the CML T315I&nbsp;(&minus;) group: 12.1&plusmn;6.0 vs. 3.77&plusmn;1.28 (p=0.009). The median survival of T315I&nbsp;(+) patients was significantly shorter: 73 months vs. 175 months (p<0.0001, CI 95%). Conclusions: Our data confirm the world experience on the frequency of T315I mutation, including the unfavourable evolution, resistance to TKI treatment and short survival. ddPCR is a highly sensitive method for early detection of genetic mutations which gives the chance for effective treatment.

Combination Therapy with Tyrosine Kinase Inhibitors and Agents with Different Mechnisms of Actions Is Effective in a Patient with Chronic Myeloid Leukemia Harboring the T315l BCR - ABL1 Mutation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4282-4282
Author(s):  
Fabio P S Santos ◽  
Jorge Cortes ◽  
Charles Koller ◽  
Elias Jabbour
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Combination Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Specific Inhibitor ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
T315i Mutation

Abstract Abstract 4282 Mutations of BCR-ABL1 have been observed in 50% of patients with chronic myeloid leukemia (CML) who develop resistance to imatinib. The gate-keeper mutation T315I is one of the mutations with universal resistance to imatinib and to the second-generation tyrosine kinase inhibitors (TKI) that are approved for the treatment of patients with imatinib failure. The use of new kinase inhibitors with in vitro activity against T315I mutation as well as other agents with different mechanisms of actions is being evaluated in clinical trials. We report the case of a 57-year old man that was diagnosed with CML in 2003. Patient received initial therapy with standard-dose imatinib that was subsequently increased to 800 mg daily. He did achieve a complete cytogenetic response (CCyR) 9 months post dose escalation. He was followed by RT-PCR for BCR-ABL1.. In May, 2007, the patient BCR-ABL1/ABL1 ratio increased to 16.38 but the patient remained in CCyR. BCR-ABL1 sequencing revealed the T315I mutation in 100% of cells (Figure 1). One month later the patient lost CCyR (5% Philadelphia-positive [Ph+] cells) and the BCR-ABL1/ABL1 ratio was 5.08. The patient was started on the T315I specific inhibitor KW-2449 (100 mg orally twice daily for 14 days, every 3 weeks). Patient had a progressive decline in percentage of cells with the T315I mutation (Figure 1). However, at the same time he had an increase in percentage of Ph+ cells. In September, 2007, three months after starting therapy with KW-2449, patient had no cytogenetic response (80% Ph+ cells, PCR for BCR-ABL1 ratio > 100) and the T315I mutation was undetectable. At that time, a new ABL1 sequencing revealed the F359I mutation (no quantification was done). Patient was maintained on KW-2449 for the next 6 months, without significant improvement in cytogenetic response nor BCR-ABL1 ratio, but the clone with the T315I mutation did not reappear. In February, 2008, the patient lost hematologic response and presented with an elevated white blood cell count of 22×109/L. The F359I mutation was still present. Therapy with KW-2449 was stopped and the patient started dasatinib 100 mg/day and Interferon-a 3,000,000 units. Three months later, the patient acheived CCyR with a BCR-ABL1/ABL1 ratio of 0.05. At the last evaluation, 16 months after the start of dasatinib and interferon combination, the patient was maintaining CCyR and major molecular response. In conclusion, this case illustrates the benefit of the use of combination therapy, mainly TKI and agent with different mechanism of action either sequentially (TKI followed by KW-2449) or concomitantly (TKI + interferon) in eradicating resistant disease with T315I clone. Figure 1 Serial Monitoring of Ph+ Cells, T315I Cells and BCR-ABL1/ABL1 Ratio Figure 1. Serial Monitoring of Ph+ Cells, T315I Cells and BCR-ABL1/ABL1 Ratio Disclosures: Cortes: Novartis: Research Funding. Jabbour:Novartis: Speakers Bureau; Bristol Myers Squibb : Speakers Bureau.

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

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

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

Predictive Value Of Early Molecular Responses In Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Imatinib In First-Line Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4941-4941
Author(s):  
Katia B. Pagnano ◽  
Bruna Vergilio ◽  
Eliana C M Miranda ◽  
Marcia Torresan Delamain ◽  
Maria Helena De Almeida ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
First Line ◽  
Molecular Responses ◽  
Advanced Phase ◽  
Significant Difference ◽  
The Impact

Abstract Several studies demonstrated the prognostic significance of an early molecular response in chronic myeloid leukemia (CML) patients (pts) treated with imatinib in first line or other tyrosine kinase inhibitors. Aims: The aim of this study was to evaluate the impact of early molecular responses, at 3 and 6 months after treatment with imatinib in CML pts and correlate these responses with CCR, MMR, overall survival (OS) and event free survival (EFS). Patients and Methods Between February 2006 and June 2012, 95  adult pts with newly diagnosed CML in chronic phase (CP) received imatinib 400mg/daily. CP was defined using WHO 2008 criteria. All pts received a short course of hydroxiurea until imatinib was available. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter. 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% (IS). Statistical analysis: OS was measured from imatinib start until date of death or last visit. An event was defined as death from any cause. EFS was measured from imatinib start until the first event (loss of complete hematological response (CHR); complete cytogenetic response (CCR), progression to advanced phase, death or imatinib discontinuation) or last visit. OS and EFS rates were calculated using Kaplan-Meier method and log-rank test to compare its curves. The MMR probabilities according to molecular responses at 3 and 6 months were calculated by c2 method and cumulative incidence, considering as competitive event death or progression, before the event. Results 95 pts were analyzed, 57 (60%) male, with a median age of 47 years (17-79); Sokal score: high, intermediate and low was 30, 38.6 and 31.4% respectively; EUTOS scores was 81.5% low and 18.5% high. The median time from diagnosis until imatinib therapy was 1 month (0-5) and the follow-up was 39 month (3-89). Responses: 88% achieved CHR; 50% CCR and 53% MMR. One patient progressed to advanced phase during follow-up, while on imatinib treatment. 21 (22%) pts discontinued imatinib due to intolerance (47.6%); resistance (42.9%), death (4.8%) and Allo-HSCT (4.8%). At 3 months from the start of therapy, 30/64 (46.8%) achieved CCR, 15/64 (23.4%) partial cytogenetic response and 20/64 (31.2%) less than partial; by RQ-PCR, 72.3% (68/94) achieved at 3 months BCR-ABL transcripts ≤10% and 27.7% (26/94) > 10%. At 6 months 55.2% (48/87) had BCR-ABL transcripts ≤ 1% and 44.8% (39/87) >1%. The OS was 97% (95%CI: 95-99%) and EFS 63% (95%CI: 52-75%).There was no significant difference in OS and EFS in pts with RQ-PCR > 10% vs ≤ 10% at 3 months (figure 1), but pts with BCR-ABL transcripts > 10 and >1-10% at 6 months had an inferior EFS in comparison with pts with  BCR-ABL transcripts ≤ 1%  (41%,50%,89% respectively - p= 0.005), (figure 2). The CI showed that CCR pts at 3 months reached MMR earlier at 24 month (54% vs 18%, p=0.03), as well as CCR pts at 6 months, albeit no significance statistically (52% vs 37%, p= 0.16). For RQ-PCR at 3 months, pts with BCR-ABL transcripts 0-1% had a probability of 88% to achieve MMR, 1-10% had 52% and >10% 42%, p< 0.0001 (figure 3). In conclusion, our results show that early molecular responses are predictive of achieving MMR and BCR-ABL transcripts <1% at 6 months is predictive of EFS in CP-CML treated with imatinib. Disclosures: No relevant conflicts of interest to declare.

Long Term Outcomes Of Imatinib In Chronic Myeloid Leukemia In Saudi Population, Single Center Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5180-5180
Author(s):  
Enaam Mohammed Alsobhi ◽  
Mohammed m Abrar ◽  
Mohammed A Abdelaal ◽  
Ahmad S. Alsaeed ◽  
Ahmed Al-Absi ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Randomized Study ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Significant Difference

Abstract Background The introduction of Imatinib therapy has significantly changed the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) and improved survival. Since the International Randomized Study of Interferon (IRIS), a number of studies were conducted involving diverse populations and showed significant variations in the treatment outcome. To date, there has been no published study on the effectiveness of imatinib in adult CML patients in Saudi Arabia. The aim of the present study was to present a single-institution experience in the treatment with imatinib of newly diagnosed patients with CML and compare it with results from international studies. Methods A total of 101 medical records of consecutive adult CML patients treated with imatinib as first line therapy at King Abdulaziz Medical City, Jeddah, Saudi Arabia between 2001 and 2012 were retrospectively reviewed. Survival and response rates were evaluated. Results The estimated overall survival (OS) rates at 5 and 10 years were 95%±2.3% when patients were stratified by cytogenetic type (stander vs.variant Ph positive chromosome) at presentations, significant difference in OS, EFS, and PFS were noted (P=0.001). Complete haematological response was achieved in 94 (93.1%) of our patients, cytogenetic response (CR) in 84 (83.2%) while complete and major cytogenetic response (MCR) were observed in 70 (69.3%) and 6 (5.9%) of the patients respectively. (MR), 62 patients (61.4%) achieved major molecular response (MMR) and 34 (33.7%) complete molecular response. Conclusion compared to other studies among different population, our results confirm the previously noted variation in the response to imatinib. Our study has shown that Ph variant has an impact on the outcome. Further study may be indicated. However second TKI generations as first line in treatment CML with Ph variants should be consider! Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Comparison of Dasatinib 70 Mg/Day to 100 Mg/Day in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): A Multicenter, Prospective, Randomized Controlled Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3615-3615
Author(s):  
Dan Yu ◽  
Zhuangzhi Yang ◽  
Hui Cheng ◽  
Rui Jiang ◽  
Jingming Guo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Controlled Study ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Best Response ◽  
Significant Difference

Abstract Background: The purpose of this study is to compare efficacy and safety of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline dasatinib 70 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: From July 2019 to July 2021, 81 patients with newly diagnosed CML-CP were enrolled across 11 centers. All of the patients were randomly treated with dasatinib 70 mg/day (N=43) or standard-dose dasatinib 100 mg/day (N=38). Results: Among 81 enrolled patients, 16 patients were off study at different times for different reasons.All patients achieved hematological remission after 3 months of treatment, and the best response rates were 84.00% (21/25) and 88.89% (24/27) for 70mg/d and 100mg/d groups (P&gt;0.05).At 6 months, the best response, complete cytogenetic response (CCyR) and major molecular response (MMR) rate were 94.44% vs 92.86% (P &gt; 0.05), 94.44% vs 92.86% (P &gt; 0.05) and 55.56% vs 71.43% (P &gt; 0.05), respectively.At 9 months, the rates of CCyR and MMR were 90.91% vs 88.89% (P &gt; 0.05) and 66.67% vs 72.73% (P &gt; 0.05);CCyR and MMR by 12 months, respectively, were 90.91% vs 100.00% (P &gt; 0.05), 81.82% vs 80.00% (P &gt; 0.05).The adverse events (AEs) of the two groups were mild, and there was no significant difference (P &gt; 0.05).The most common grade ≥3 hematological AEs in 70 mg/d group were leukopenia (1/43), neutropenia (1/43) and anemia (2/43), and In 100mg/d group were leukopenia (4/38), neutropenia (6/38), anemia (3/38) and thrombocytopenia (3/38). Conclusions: Our study suggests that patients with newly diagnosed CML-CP treated with dasatinib 70 mg/day or 100 mg/day, there is no significant difference in efficacy and safety. Decreasing the dose of dasatinib can ensure the efficacy of patients, while reducing the economic burden of patients and increasing patient compliance. Disclosures No relevant conflicts of interest to declare.

scholarly journals BCL2L11 (BIM) Deletion Polymorphism Is Associated with Molecular Relapse after ABL Tyrosine Kinase Inhibitor Discontinuation in Patients with Chronic Myeloid Leukemia with Complete Molecular Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1797-1797 ◽  
Author(s):  
Seiichiro Katagiri ◽  
Tetsuzo Tauchi ◽  
Yuu Saito ◽  
Tamiko Sugro ◽  
Michiyo Asano ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Molecular Response ◽  
Deletion Polymorphism ◽  
Significant Difference ◽  
Treatment Free Remission ◽  
Tki Discontinuation ◽  
Complete Molecular Response

Abstract Background: The inhibition of BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of chronic myeloid leukemia (CML). Recently, it has been recognized that some CML patients with a complete molecular response (CMR) are able to maintain treatment-free remission (TFR) after discontinuation of TKIs. However, no predictive prognostic factors for successful discontinuation of the treatment have yet been identified. We set out to further clarify the role of predictive biomarkers in molecular relapse and non-relapse after ABL TKI discontinuation. Materials and methods: Patients in sustained CMR (MR 4.5) undergoing TKI therapy were eligible for inclusion in the study. Molecular relapse was defined as loss of major molecular response (MMR) of at least one point. Genomic DNA was obtained from whole blood using a DNA Extractor WB Kit (Wako, Osaka, Japan), and was subjected to polymerase chain reaction (PCR) amplification using primers designed to detect a deletion site (2903 bp) in intron two of the BCL2L11 gene (forward: 5′-AATACCACAGAGGCCCACAG-3′; reverse: 5′-GCCTGAAGGTGCTGAGAAAG-3′) and JumpStart RedAccuTaq LA DNA polymerase (Sigma Aldrich, St. Louis, MO, USA). Results: 32 CML patients (17 men, 15 women, median age 58.4 years) were included in this study (Sokal category; low 24, intermediate 7, high 1). Six patients were treated with IFNα before TKI treatment, and 3 were treated with IFNα after stopping TKI. Median duration from TKI initiation to discontinuation was 79.3 months (range; 22 to 138 months); median duration of CMR before TKI discontinuation was 47.3 months (range; 5 to 97 months). Seven patients showed loss of MMR; 6 relapsed within 6 months and one showed late relapse at 25 months after discontinuation. The cumulative incidence of MMR loss was estimated as 18.8% at 12 months and at 24 months. Fluctuation of BCR-ABL transcript levels below the MMR threshold (> two consecutive positive values) was observed in 6.25% of patients at 24 months after ABL TKI discontinuation. Treatment-free remission was estimated as 81.2% at 12 months and at 24 months. The median period of restoration of second CMR was 6.0 months in re-treated patients. No patient died during the follow-up period. TKI-free remission was estimated as 78.1% at 30 months. There was only a significant difference in BCL2L11 (BIM) deletion polymorphism between the patients who maintained and those who lost MMR (p = 0.0253). No significant difference was observed in prior IFNα therapy, time to complete cytogenetic response (CCyR), time to MMR, and time to CMR between relapsing and non-relapsing patients. Conclusion: Our study shows a specific association between BCL2L11 (BIM) deletion polymorphism and clinical outcome after ABL TKI discontinuation in patients with long-lasting molecular undetectable residual disease. BCL2L11 (BIM) deletion polymorphism may predict relapse after ABL TKI discontinuation, which may have an impact on future ABL TKI discontinuation trials. These results further illustrate the importance of single nucleotide polymorphisms in successful long-term treatment of CML. Disclosures Ohyashiki: Bristol-Myers Squibb KK : Research Funding, Speakers Bureau; Novartis KK: Research Funding, Speakers Bureau.

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.

Multidrug Resistance Gene (MDR1) C3435T Polymorphism and Imatinib Response in Patients with Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1692-1692 ◽  
Author(s):  
Ahmet Emre Eskazan ◽  
Suzin Catal Tatonyan ◽  
Ayse Salihoglu ◽  
Emine Gulturk ◽  
M. Cem Ar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Resistance Gene ◽  
Gene Polymorphisms ◽  
Myeloid Leukemia ◽  
Mdr1 Gene ◽  
Molecular Response ◽  
C3435t Polymorphism ◽  
Patient Cohort ◽  
Significant Difference

Abstract Abstract 1692 Background: There has been a remarkable improvement in the management of chronic myeloid leukemia (CML) after imatinib mesylate (IM) became available in the market, but there is still a group of patients who are resistant to imatinib. Although point mutations in the BCR-ABL kinase domain is the most common mechanism for resistance in patients with CML receiving tyrosine kinase inhibitor (TKI) therapy, there are several mechanisms that can play a role in the resistance to TKIs. Multi drug resistance gene (MDR1) [ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1) ] product is an ATP-driven efflux pump contributing to the pharmacokinetics of drugs that are P-glycoprotein (P-gp) substrates and to the multidrug resistance of cancer cells. More than 50 single nucleotide polymorphisms (SNPs) have been identified concerning the MDR1 gene, and SNP polymorphisms may affect the expression and function of the P-gp. The SNPs T1236C, G2677T/A, and C3435T are the most common variants in the coding region of ABCB1. Imatinib is a substrate of P-gp-mediated efflux, and P-gp mediated drug efflux can play a role in IM resistance. So identifying these SNPs may allow to predict the drug disposition and responses to IM in CML patients. The aim of the study was to identify the C3435T SNP variants, and the associations between MDR1 C3435T polymorphism and IM efficacy in our CML patients. Methods: Between December 2010 and March 2011, 110 chronic phase (CP) CML patients who consecutively visited our outpatient clinic were enrolled in this study. Hematologic, cytogenetic and molecular response patterns to IM as well as the association between MDR1 C3435T polymorphism and responses to imatinib were evaluated in our patient cohort. MDR1 C3435T polymorphisms were detected by real-time polymerase chain reaction (RT-PCR). We could assess complete cytogenetic response (CCyR) and major molecular response (MMR) in one hundred and six patients (96%) among these 110 patients. The differences in genotype frequencies in all patients taking imatinib treatment was determined by using the chi-square test. All tests were two-sided, and p <0.05 was considered as statistical significant. This study was approved by the local research ethics committee, and written informed consent was obtained from the patients. Results: 59 patients were male (54%), and fifty-one were female (46%). Median age was 50.5 years (range, 19–84 years). 37.6% of the patients were low, 45% were intermediate, and 17.4% were high risk according to Sokal risk score. The CCyR rate was 71%, and MMR rate was 60%. The frequencies of MDR1 3435 CC, CT, and TT genotypes were 22.5%, 55%, and 22.5%, respectively. No statistically significant difference was observed between the frequencies of the genotypes according to gender. The CCyR rates in patients with CC, CT, and TT genotypes were 88%, 62%, and 75%, respectively (Figure 1). The patients with CC genotype had significantly higher CCyR rates when compared to patients having CT/TT and CT genotypes (p =0.04 and p =0.023, respectively) (Table 1). The patients with CC, CT, and TT genotypes did not differ significantly between each other regarding the MMR rates. There were no significant difference between the C3435T genotypes and second generation TKI usage regarding both CCyR and MMR. Conclusion: Before starting IM therapy, the individual patientÕs MDR1 gene polymorphism pattern can be important in determining the treatment strategy in patients with CML. Among our patient cohort, the patients with CC genotype had significantly higher CCyR rates than patients with CT/TT and CT genotypes. Up to now, there are a few studies in CML patients with different results regarding MDR1 gene polymorphisms, and since racial differences can be seen in the frequencies of MDR1 gene polymorphisms, further studies in larger series are needed to define the genetic polymorphisms with therapeutic relevance in patients on imatinib. Disclosure: This study was supported by Istanbul University Research Fund. Disclosures: No relevant conflicts of interest to declare.

Discontinuation of Imatinib in Japanese Patients with Chronic Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3759-3759
Author(s):  
Naoto Takahashi ◽  
Taiichi Kyo ◽  
Yasuhiro Maeda ◽  
Takashi Sugihara ◽  
Kensuke Usuki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Prospective Study ◽  
Myeloid Leukemia ◽  
Dose Intensity ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Immunological Mechanism ◽  
Significant Difference ◽  
Complete Molecular Response

Abstract Abstract 3759 Imatinib treatment dramatically improves survival in chronic myeloid leukemia (CML) patients, but whether its effects of imatinib can be considered a cure remains controversial. This is because primitive, quiescent, Philadelphia-positive stem cells from patients with CML are insensitive to imatinib in vitro. Nonetheless, it was recently recognized that some patients with a complete molecular response (CMR) could sustain that response after discontinuation of imatinib. In a non-randomized prospective study, Mahon et al. reported that among patients with CMR lasting at least 2 years, CMR was sustained in 41% after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase CML patients who discontinued imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated CML patients, 50 (1.5%) were identified who discontinued imatinib therapy for at least 6 months; of those, 43 were analyzed further. Molecular recurrence was detected in 19 patients, and the complete molecular response (CMR) rate was estimated to be 47% following imatinib discontinuation. Notably, the durations of imatinib therapy and CMR before cessation of therapy were significantly longer, and imatinib dose intensity and the frequency of prior IFN-a administration were significantly higher, in patients sustaining CMR for 12 months after cessation than in those with molecular recurrence. No significant correlations were detected between molecular recurrence and age, sex, Sokal risk, imatinib daily dose, combination with IFN-a, or time to achieve CMR. Moreover, we found a significant difference in estimated CMR rate following discontinuation between patients who had sustained CMR for greater than 24 months prior to imatinib discontinuation and those with less than 24 months (78% vs. 15%, p =0.0002 by Log-rank test, Figure). Based on multivariate regression analysis, only imatinib dose intensity and prior IFN-a administration were independently predictive of molecular recurrence within 12 months (p =0.0035, p =0.0060). The identified prediction formula was: Y= −0.0061 x dose intensity of imatinib(g)-3.17171 x prior IFN-a(Yes=1/No=0) +4.0124. If 1/(1+exp(-1 × Y)) > 0.5, molecular recurrence was predicted; the total accuracy rate of the formula was 82.5%. Although the depth of the molecular response should be a factor influencing long-term sustained CMR after discontinuation of imatinib, other factors, for example an immunological mechanism modified by IFN-a, might control quiescent CML stem cells. To increase the “cure” rate among CML patients, it will be necessary to establish a treatment strategy on the basis of large prospective study of imatinib discontinuation. This should entail the use of a highly sensitive and strict method for monitoring minimal residual disease over the course of a long follow-up period. Disclosures: No relevant conflicts of interest to declare.

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