Outcome of Patients with Chronic Myeloid Leukemia Who Recieved an Intermittent Imatinib Therapy.

Abstract Diagnosis of chronic myeloid leukemia (CML) is based on detection of the BCR-ABL gene or Philadelphia chromosome, and the BCR-ABL tyrosine kinase inhibitor imatinib has been the standard therapy for CML patients. Although imatinib therapy is effective in CML, it is still unclear whether imatinib can be safely discontinued without relapse. This study was designed to investigate the outcome of 26 CML patients after discontinuation of imatinib and to determine whether intermittent imatinib therapy can be employed in CML patients. Between May 2001 and Jun 2007, 555 patients have been treated with imatinib in St Mary’s Hospital of the Catholic University of Korea, and 26 patients discontinued imatinib when they achieved either complete cytogenetic response (CCyR) or complete molecular response (CMR). These 26 patients were diagnosed as Philadelphia positive (Ph+) CML between November 1995 and May 2002, and 22 patients were in chronic phase (CP) and 4 patients were in accelerated phase (AP) at diagnosis. The median age was 35 years (22–56), and 12 patients (46%) were female and 14 (54%) were male. Among 26 patients, 7 received interferon prior to imatinib therapy and 7 underwent SCT. Five patients received both interferon and SCT before imatinib therapy, and the remaining 7 patients received the imatinib as a front line therapy. Imatinib was started at oral dose of 400mg and 600mg daily for patients in CP and AP, respectively, and when they achieved CCyR or CMR, imatinib was discontinued after informed consent of the patient. In case of cytogenetic or molecular relapse, patients in all phases were retreated with imatinib at 400mg daily. Bone marrow (BM) or peripheral blood (PB) samples were obtained at regular intervals from diagnosis for hematologic response (HR), cytogenetic response (CyR) and molecular response (MR) monitorings. Eleven patients discontinued imatinib when they achieved CCyR, and 15 patients discontinued imatinib after achieving CMR. After the median duration of 7 month (4–48) observation without imatinib therapy, hematologic, cytogenetic and molecular relapses occurred in 4, 7 and 10 patients, respectively, and imatinib at oral dose of 400mg daily was reintroduced to all patients except 2 who continued to remain in CMR after imatinib discontinuation. Except 1 patient who expired and 2 patients who are in persistent molecular remission, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median duration of 38 months (16–58). In conclusion, although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of CML patients. Intermittent imatinib treatment should not be restricted to CP patients who achieve CMR, and AP patients or patients with CCyR also can be considered for intermittent imatinib treatment. We will continue the follow-up of the patients enrolled in this study, and long-term study of intermittent imatinib treatment with expanded pool of patients will enable us to determine the accurate consequences of discontinuation of imatinib and intermittent imatinib treatment.

Download Full-text

The Impact of Cytogenetic Response At 6 Months of Therapy in Global Survival of Patients with Chronic Myeloid Leukemia Treated with Imatinib in the South of Brazil

Blood ◽

10.1182/blood.v120.21.4453.4453 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4453-4453

Author(s):

Laura Fogliatto ◽

Marcelo Capra ◽

Mariza Schaan ◽

Mario Sérgio Fernandes ◽

Tito Vanelli Costa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Molecular Response ◽

Imatinib Treatment ◽

Major Molecular Response ◽

Global Survival ◽

The Impact

Abstract Abstract 4453 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 3 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Global survival (GS) was measured from the start of imatinib to the date of death from any cause. Results We analyzed data from 181 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 123 pts (68%) achieved CCyR, in this group the four year global survival was 97%. 58 (32%) were not in CCyR at 6 months of therapy, in this group the four year GS was 87%. This difference was significant (P=.024; Figure 1). The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and global survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Role of Early Cytogenetic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib and the Impact of Adherence and Comorbidities

Blood ◽

10.1182/blood.v118.21.4423.4423 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4423-4423

Author(s):

Laura Fogliatto ◽

Marcelo Capra ◽

Mariza Shaan ◽

Tito Vanelli Costa ◽

Mayde Seadi Torriani ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Molecular Response ◽

Imatinib Treatment ◽

Major Molecular Response ◽

Complete Cytogenetic Response

Abstract Abstract 4423 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 450 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 198 pts (44%) achieved CCyR. In this group, the four year cumulative incidence of events was 33 (17%) and the EFS was 75,5%. 252 (56%) were not in CCyR at 6 months of therapy. In this group, a greater proportion of cumulative of events was observed: 86 (34%), and the EFS was 62,3%. This difference was significant (P=0,03; Figure 1). In this group of pts, 63% achieved CCyR after 6 months any time during follow up and the median time for CCyR in these pts was 17 months. The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and event-free survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: A Study from the International Registry of Childhood CML

Cancers ◽

10.3390/cancers13164102 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4102

Author(s):

Frédéric Millot ◽

Meinolf Suttorp ◽

Stéphanie Ragot ◽

Guy Leverger ◽

Jean-Hugues Dalle ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Remission Rate ◽

Univariate Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Imatinib Treatment ◽

International Registry ◽

Treatment Free Remission

Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR4 was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR4 for at least two years.

Download Full-text

A Rare t(9;22;16)(q34;q11;q24) Translocation in Chronic Myeloid Leukemia for Which Imatinib Mesylate Was Effective: A Case Report

Leukemia Research and Treatment ◽

10.4061/2011/592519 ◽

2011 ◽

Vol 2011 ◽

pp. 1-3

Author(s):

Masahiro Manabe ◽

Yumi Yoshii ◽

Satoru Mukai ◽

Erina Sakamoto ◽

Hiroshi Kanashima ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Normal Karyotype ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Molecular Response ◽

Trisomy 8 ◽

Additional Chromosome

The t(9;22)(q34;q11) translocation is found in about 90% of chronic myeloid leukemia (CML) patients. About 5–10% of CML patients have complex variant translocations involving a third chromosome in addition to chromosomes 9 and 22. Herein, we describe a CML-chronic phase male with a complex translocation involving chromosome 16, t(9;22;16)(q34;q11;q24). First, he was treated with interferon-alpha and intermittent hydroxyurea, but only a partial cytogenetic response was attained. Subsequently, the patient was treated with imatinib mesylate because of an additional chromosome abnormality, trisomy 8. A major molecular response was obtained after one year's imatinib therapy, and the follow-up chromosomal analysis performed 4 years and 3 months after the initiation of imatinib therapy displayed a normal karyotype of 46,XY.

Download Full-text

Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.8154 ◽

2008 ◽

Vol 26 (20) ◽

pp. 3358-3363 ◽

Cited By ~ 387

Author(s):

Hugues de Lavallade ◽

Jane F. Apperley ◽

Jamshid S. Khorashad ◽

Dragana Milojkovic ◽

Alistair G. Reid ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Kinase Domain ◽

Molecular Response ◽

Imatinib Treatment ◽

Newly Diagnosed

Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded. Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated. Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR. Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

Download Full-text

Molecular Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib – Single Centre Experience

PRILOZI ◽

10.1515/prilozi-2015-0065 ◽

2015 ◽

Vol 36 (2) ◽

pp. 179-186

Author(s):

Marica Pavkovic ◽

Rosica Angelkovic ◽

Marija Popova-Simjanovska ◽

Sonja Genadieva-Stavric ◽

Lidija Cevreska ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Treatment Resistance ◽

Cytogenetic Response ◽

Molecular Response ◽

Poor Treatment ◽

Heavily Pretreated ◽

Pcr Method

Abstract Introduction of tyrosine kinase inhibitors (TKI) dramatically improves the treatment and survival of the patients with chronic myeloid leukemia (CML) in the last decade. Imatinib (IM) and other TKI induce larger percentage of complete cytogenetic response (CCyR) and major molecular response (MMR). Treatment resistance to TKIs still remains an important problem in the treatment of CML. The aim of our study was to analyze the molecular response (MR) in CML patients treated with Imatinib in our institution. We have analyzed 53 CML patients (pts), 28 females and 25 males, treated with IM as a front or second line treatment. Only 15 pts were treated with IM as a front-line therapy, while 38 pts were pretreated with hydroxyurea or/and interferon. Median duration of CML was 6 years (range: 1 year- 17 years). Median duration of IM treatment was 3 years (range: 1 year-10 years). MR was analyzed in one up to 8 time points with Real Time Quantitative RT-PCR method. Forty six pts (87%) had complete hematological response and 55% of pts had MMR, 13/53(24.5%) pts had MMR at 4.0-4.5 log and 16/53(30.2%) pts had MMR at 3.0-4.0 log. MMR was not achieved in 24/53(45.3%). Our results have shown smaller percentage of patients (55%) with MMR, mostly due to the fact that larger proportion of patients (38/53) were heavily pretreated with HU or/and Interferon for a prolonged period of time, before the IM treatment. This is a major risk factor for acquisition of additional molecular and cytogenetic abnormalities responsible for IM resistance and poor treatment response.

Download Full-text

Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy

Blood ◽

10.1182/blood-2008-07-166694 ◽

2009 ◽

Vol 113 (25) ◽

pp. 6315-6321 ◽

Cited By ~ 104

Author(s):

Alfonso Quintás-Cardama ◽

Hagop Kantarjian ◽

Dan Jones ◽

Jianqin Shan ◽

Gautam Borthakur ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

High Dose ◽

Molecular Response ◽

Major Molecular Response ◽

Increased Risk ◽

Risk Of Progression

AbstractPatients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.

Download Full-text

The Hasford Score Correlates with the Long-Term Molecular Response to Imatinib Treatment for Chronic Myeloid Leukemia Patients and May be Useful for Differentiating Low and Intermediate Risk Patients: A Single Institution Experience

Blood ◽

10.1182/blood.v124.21.3152.3152 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3152-3152

Author(s):

Jaroslaw Dybko ◽

Ewa Medras ◽

Olga Haus ◽

Bozena Jazwiec ◽

Tomasz Wrobel ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Intermediate Risk ◽

Risk Patients ◽

Eutos Score

Abstract BACKGROUND: Since the beginning of the tyrosine-kinase inhibitor (TKI) era in the treatment of chronic myeloid leukemia (CML), there have been attempts to stratify patients for optimal management. An essential requirement for perfect stratification was the identification of factors capable of predicting long-term response [1]. The Sokal and Hasford scores were developed in the chemotherapy and interferon alfa eras, respectively [2]. The EUTOS score was found to predict probability of complete cytogenetic response (CCyR) within 18 months of Imatinib initiation and progression-free survival (PFS) for patients receiving Imatinib [3]. However, the usefulness of the EUTOS score in predicting survival and outcome in patients with early chronic phase CML treated with TKI was questioned [4]. The Hasford score failed to differentiate patients who achieved low and intermediate risk scores according to CCyR, MMR, and 5 years EFS [5] and in our study we found Hasford score correlated with the long-term molecular response. PATIENTS AND RESULTS: We analyzed a cohort of 88 patients (F/M:42/46, median age 51 (21-83)) receiving standard dose Imatinib treatment for first chronic phase of CML. As assessed by Hasford risk analysis, the group comprised 57 low risk and 31 intermediate risk patients. In the initial group of patients, there were 5 high risk patients who were excluded from the study. No additional chromosomal abnormalities were identified at diagnosis. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) at time points defined by the European Leukemia Net (ELN). Of these, 42 patients lost MMR in a median time of 47 months. Within this group we identified 20 low risk (LR) and 22 intermediate risk (IR) patients. There was a significant difference in maintenance of the MMR between IR and LR patients (p=0.03, Figure 1). This analysis revealed that all intermediate risk patients lost MMR after approximately 85 months of Imatinib treatment, while 62% of the low risk patients maintained MMR throughout this time frame. During analysis, all 42 patients were switched to second generation TKI. After 3 months of second generation TKI treatment, median bcr-abl transcript levels in the LR group were 0.01 (0.000-0.295) but in the IR group bcr-abl levels were 0.301 (0.000-44.5) (p=0.0006, Figure 2). CONCLUSIONS: As the Hasford metric was designed for assessing patients treated with interferon alpha, we found our results to be interesting, and to be relevant to the discussion on optimizing scoring systems in chronic myeloid leukemia patients. If the observed difference between low and intermediate risk patients in maintaining MMR on Imatinib is confirmed, IR patients will become candidates for different first line treatment. Despite clinical studies, the choice between Imatinib and second generation TKI as the first line treatment remains an issue. Our results (if confirmed) promise to directly impact treatment decisions affecting IR patients. References: 1. Breccia M, Alimena G. Bringing prognostic scores for chronic myeloid leukemia patients up to date. Expert Rev Hematol. 2011 Aug;4(4):373-5. 2. Hu B1, Savani BN. Impact of risk score calculations in choosing front-line tyrosine kinase inhibitors for patients with newly diagnosed chronic myeloid leukemia in the chronic phase. Eur J Haematol. 2014 Apr 26. 3. Hasford J1, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, Guilhot F, Porkka K, Ossenkoppele G, Lindoerfer D, Simonsson B, Pfirrmann M, Hehlmann R. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011 Jul 21;118(3):686-92 4. Jabbour E, Cortes J, Nazha A, O'Brien S, Quintas-Cardama A, Pierce S, Garcia-Manero G, Kantarjian H. 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. 2012 May 10;119(19):4524-6. 5. Yahng SA, Jang EJ, Choi SY, Oh YJ, Bang JH, Park JE, Jeon HL, Lee SE, Kim SH, Byun JY, Kim DW. Comparison of Sokal, Hasford and EUTOS Scores in Terms of Long-Term Treatment Outcome According to the Risks in Each Prognostic Model: A Single Center Data Analyzed in 255 Early Chronic Phase Chronic Myeloid Leukemia Patients Treated with Frontline Imatinib Mesylate. Blood 2012;120:Abstract 2794 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Multicenter Retrospective Study on the Development of Peripheral Lymphocytosis During Second-Line Dasatinib Therapy for Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.2275.2275 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2275-2275

Author(s):

Ha Yeon Lee ◽

Su Jin Lee ◽

Boram Ha ◽

Jun Ho Yi ◽

Chul Won Jung ◽

...

Keyword(s):

Retrospective Study ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Second Line ◽

Major Molecular Response ◽

The Republic

Abstract Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Impact of Drug Transporters ABCB1 and ABCG2 and Regulators of Xenobiotic Transport and Metabolism Pxr and CAR Gene Polymorphisms on Clinical Efficacy of Imatinib in Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood.v124.21.5222.5222 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5222-5222

Author(s):

Anna Stepien ◽

Alessandro Martino ◽

Federico Canzian ◽

Daniele Campa ◽

Angelika Stein ◽

...

Keyword(s):

Treatment Outcome ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Drug Transporters ◽

Pregnane X Receptor ◽

Imatinib Therapy ◽

Molecular Response ◽

Imatinib Treatment ◽

Primary Resistance ◽

Allelic Variants

Abstract Background: Inherited background in mechanisms regulating cellular uptake, elimination and metabolism of imatinib and other BCR-ABL tyrosine kinase inhibitors may influence treatment outcome in chronic myeloid leukemia (CML). Despite good efficacy of imatinib in CML therapy, a proportion of patients show suboptimal responses or even primary resistance. Imatinib is a well-established substrate of ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). However, the results of published studies regarding impact of ABCB1 and ABCG2 single nucleotide polymorphisms (SNPs) on imatinib treatment outcome have shown discrepant results. Moreover, little is known on the potential role of polymorphisms of regulators of xenobiotic transport and metabolism, pregnane X receptor (PXR, NR1|2) and constitutive androstane receptor (CAR, NR1|3) in imatinib efficacy. Aim: In this study we verified whether 61 tagging SNPs in drug transporters genes (ABCB1 and ABCG2) and regulators of xenobiotic transport and metabolism gene (PXR and CAR) genes affect imatinib therapy outcomes in CML. Methods: Genotyping was performed in 256 patients of Polish Caucasian origin (141 men and 117 women) treated with imatinib as first line treatment (229; 89.5%) or after second-line after interferon therapy (27; 10.5%). Tagging SNP approach was used to select the genetic variants and resulted in a selection of 61 tagging SNPs including 26 SNPs for ABCB1, 17 SNPs for ABCG2, 11 SNPs for PXR and 7 SNPs for CAR gene. Complete clinical data on imatinib treatment outcome were assessable for analyses of associations with tested SNPs. The influence of SNPs on imatinib outcomes including achievement of complete cytogenetic response (CCyR) at 12 months, achievement of major molecular response (MMR) at 18 months, progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. Three inheritance models (co-dominant, dominant and recessive) were tested for all allelic variants. Results: In this study we found that carriers of minor allele of CAR rs4073054A>C SNP significantly associated with shorter TTF on imatinib therapy (OR=2.42, 95%CI 1.41 - 4.17; p=0.0014; Bonferroni corrected p=0.048). In contrast, no impact of other tested allelic variants in ABCB1, ABCG2, PXR and CAR genes on proportion of patients who achieved CCyR at 12 months, MMR at 18 months as well as on probability of PFS, TTF and OS was observed. Conclusion: Our data suggest that inherited variants in the regulator of xenobiotic transport and metabolism CAR gene may modify results of imatinib therapy in CML patients. In contrast, the results of this relatively large study indicate that polymorphic variants in ABCB1, ABCG2 and PXR genes do not seem to play major role as determinants of response to imatinib in CML. Disclosures Robak: MorphoSys AG: Research Funding.

Download Full-text