scholarly journals The Role of Monitoring the Bcr-Abl Transcript Levels in the Management of Patients with Chronic Myeloid Leukemia

2013 ◽  
Vol 59 (2) ◽  
pp. 71-74
Author(s):  
Aliz-Beáta Tunyogi ◽  
I Benedek ◽  
Judit Beáta Köpeczi ◽  
Erzsébet Benedek ◽  
Enikő Kakucs ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Transcript Levels

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

Early Molecular Response Is Predictive Of Overall, Progression-Free and Event-Free Survival In Chronic Myeloid Leukemia Using Second-Generation Tyrosine Kinase Inhibitors After Imatinib Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1326-1326
Author(s):  
Beatriz F Ribeiro ◽  
Bruna Vergilio ◽  
Eliana C M Miranda ◽  
Maria Helena Almeida ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Disease Status ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Event Free Survival ◽  
Molecular Responses ◽  
Free Survival ◽  
Transcript Levels

Abstract Second-generation tyrosine kinase inhibitors (2G-TKI), nilotinib or dasatinib used after imatinib failure can induce complete cytogenetic response (CCR) in 50% of chronic myeloid leukemia (CML) patients. BCR-ABL transcript levels reduction in the initial months of treatment has been associated improved outcome. Aims to evaluate the predictive value of early molecular responses, at 3 and 6 months after treatment with 2G-TKI in CML patients with imatinib failure or intolerance; to correlate these responses with CCR, overall survival (OS), progression-free survival (PFS) and event free survival (EFS). Methods Between September 2007 and August 2012, 71 consecutive patients with CML resistant or intolerant to imatinib were treated with dasatinib (n= 50) or nilotinib (n=21). BCR-ABL transcripts were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) at 3 months intervals. 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). Cytogenetic analysis was performed at baseline, 3, 6, 12 and 18 months after starting therapy with 2G-TKI. BCR-ABL mutation analysis by direct sequencing was investigated in resistant patients. Probabilities of OS, PFS and EFS were calculated using Kaplan-Meier method. An event was defined as the loss of CHR, CCR, progression to advanced phases, death or 2G-TKI discontinuation. The CCR probabilities according to molecular responses were calculated by c2 method and cumulative incidence, considering as competitive event death or progression. Results 71 patients were analyzed, median age of 47 years (15-81); Disease status before 2G-TKI was: 50 (71%) CP; 13 (18%) AP and 8 (11%) BC. Responses: 59/71 (83%) obtained CHR; 38/55 (69%) CCR and 37/60 (62%) MMR. At 3 months of therapy, 81.5% (44/54) had a BCR-ABL ratio ≤10% and at 6 months 66% (33/50) had ≤ 1%. At 3 months, CCR was obtained 65% (19/29) pts with ≤10% RQ-PCR and 16% (1/6) with >10% RQ-PCR (p= 0.06). At 6 months, CCR was 100% (12/12) in pts with RQ-PCR ≤ 1% and 14% (1/7) in those with >1% (p< 0.0001). The probability to achieve RQ-PCR < 10% at 3 month was 43% (95% CI 32-54%). During treatment 3 (4%) progressed to AP and 5 (7%) to BC. The 5-year probability of OS was 78% (95% CI: 68-88%) albeit by disease status was 86% in CP, 92% in AP and 12% in BC (p< 0.0001). OS was inferior in pts with RQ-PCR > 10% at 3 months (60 vs 84%, p= 0.03) and >1% at 6 months (68 vs100%, p= 0.006). PFS was 68% in 5-year, and was lower in BC pts (p< 0.0001) and pts with RQ-PCR >1% at 6 months (p= 0.004). EFS was 53% and lower in BC pts (p< 0.0001), in pts with RQ-PCR > 10% at 3 months (p= 0.005) and > 1% at 6 months (p< 0.0001). RQ-PCR at 3 and 6 months were also predictive of a worse survival when patients in CP were analyzed separately. 2G-TKI was discontinued in 44% (31/71) due to: resistance (n=18), intolerance (n=5), death (n= 3), HSCT (n=3) and loss of follow-up (n=2). Eleven BCR-ABL mutations were detected in 36 pts; 3 previously 2G-TKI (L387M-1, E255K-1, M351T-1) and 9 after therapy (T315I-5, M244V-2, E255V-1, Y253H-1). OS by mutation was 45% with any mutation and 88% with no mutation (p= 0.05). Conclusion BCR-ABL transcript levels at 3 and 6 months can identify patients with worse prognosis and less chance to obtain CCR with 2G-TKI after imatinib treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. 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%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ponatinib as a Valid Alternative Strategy in Patients with Blast Crisis-Chronic Myeloid Leukemia Not Eligible for Allogeneic Stem Cells Transplantation and/or Conventional Chemotherapy: Report of a Case

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Cristina Bucelli ◽  
Daniele Cattaneo ◽  
Valeria Ferla ◽  
Manuela Zappa ◽  
Caterina de Benedittis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
T315i Mutation ◽  
Stem Cells Transplantation ◽  
One Year

Currently, imatinib and dasatinib are the only tyrosine-kinase inhibitors approved in the US and Europe for the treatment of blast crisis of chronic myeloid leukemia (BC-CML) at diagnosis, while ponatinib is the only inhibitor used in patients bearing T315I mutation. Here we report the case of a 61-year-old man diagnosed with B-cell lymphoid BC-CML, initially treated with imatinib 800 mg day and then with dasatinib 140 mg day because of intolerance. A complete cytogenetic response (CCyR) was achieved at three months; however, three months later a relapse was observed, and the T315I mutation was detected. Ponatinib 45 mg once daily was then started together with a short course of chemotherapy. Bone marrow evaluation after six months of therapy showed the regaining of CCyR, together with the achievement of a deep molecular response. However, one year from ponatinib start the patient experienced a new disease relapse; he was effectively treated with ponatinib and chemotherapy once again, but in the meanwhile an ischemic stroke was detected. This case report confirms the high efficacy of ponatinib monotherapy in BC-CML patients, representing a valid option for non-allogeneic stem cells transplantation eligible cases and the only one available for those carrying the T315I mutation.

Current Therapies for Chronic Myeloid Leukemia

2008 ◽  
Vol 21 (2) ◽  
pp. 116-125
Author(s):  
Laureen K. Kenealy ◽  
Courtney B. Christenson ◽  
Casey B. Williams
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Management Strategies ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Current Therapies

Management strategies for patients with chronic-phase chronic myeloid leukemia (CML) have changed dramatically since the introduction of imatinib into clinical trials in 1998. Imatinib is generally accepted, at present, to be the most appropriate initial therapy for newly diagnosed chronic-phase CML; however, a proportion of patients will not respond adequately. Many of these patients may benefit from alternative treatment strategies, including second- and third-generation BCR-ABL kinase inhibitors and allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, with continued improvements in molecular monitoring, it is much more clinically routine to measure ongoing treatment efficacy or characterize pending disease relapse via molecular analysis. The challenge is to now combine molecular monitoring information with timely treatment decisions to achieve the best possible outcomes. Additionally, unanswered questions about HSCT remain, and include (1) What is the role of allogeneic HSCT in CML? (2) What type of transplant, reduced-intensity or myeloablative, should be performed? The goal of this article is to provide an overview of where we stand in the treatment of CML in 2008.

The European Treatment and Outcome Study (EUTOS) for Chronic Myeloid Leukemia (CML). A Prospective, Population-Based European Registry.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4272-4272
Author(s):  
Michele Baccarani ◽  
Bengt Simonsson ◽  
Doris Lindörfer ◽  
Gianantonio Rosti ◽  
Antonio M Almeida ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Death Rate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Population Based ◽  
European Countries ◽  
Molecular Response ◽  
Outcome Study ◽  
Molecular Monitoring ◽  
Hematopoietic Stem

Abstract Abstract 4272 The incidence of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) in Europe is still difficult to estimate, due to insufficient information. Currently, it is believed to range between 8 and 22 cases per million people per year, age adjusted. Prior to the introduction of the tyrosine kinase inhibitor (TKI) imatinib the annual death rate was about 10% for the first 2 to 3 years, and about 20% from the 4th year on, with less than 10% of patients alive after 10 years. Interferon-alfa treatment and allogeneic hematopoietic stem cell transplantation were very effective treatments but only in a minority of patients. Following the introduction of IM, and of the second generation TKI nilotinib and dasatinib the annual death rate has decreased to less than 5%, and more than 75% of patients are projected to be alive 10 years after diagnosis. Based on these figures, the prevalence of the disease is expected to double every 5 years and the management of the disease will rapidly become an important social and pharmacoeconomic issue. To govern this progress it is necessary to improve the level of information on the epidemiology of CML, on the treatment of CML in clinical practice, and on the outcome of treatment outside prospective, controlled clinical trials on which current outcome estimates are based. With that purpose, the European Leukemia Network (ELN) has established a registry of all new cases of Ph+ CML. In a public private partnership with Novartis Oncology Europe this registry has been expanded to also include treatment and quality controlled outcome (European Treatment and Outcome Study [EUTOS] for CML). The infrastructure of the registry is based on a EUTOS Central Scientific Headquarter (Dpt. Hematology-Oncology “L. and A. Seràgnoli”, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy) and a EUTOS Central Data Center (Dpt. For Medical Informatics, Biometric and Epidemiology, University of Munich, Munich, Germany), interacting with each national hub. Registry is population-based, covers completely most European countries with less than 12 millions inhabitants (Portugal, Belgium, Sweden, Finland, Lithuania, Latvia, Estonia, Czech Republic, Slovakia, Slovenia, Croatia, Serbia, Hungary, Austria, Greece, Cyprus), and covers partially (for larger countries, only sub-regions with roughly 10 millions inhabitants have been selected) most of the countries with more than 12 millions inhabitants, including Spain, the United Kingdom, The Netherlands, Germany, Poland, France, Romania, Russia and Italy. About 2500 newly diagnosed cases are planned to be registered over one year and to be followed for treatment and outcome including cytogenetic response, molecular response, and BCR-ABL KD mutations. Moreover, flanking projects have been implemented in the EUTOS frame: a network of standardized laboratories across Europe, to provide a molecular monitoring with quality controlled data, a central facility for imatinib blood level testing, soon in many European countries, and an educational effort (symposia, training workshops, internet platform). The EUTOS registry joins epidemiological and outcome data: its implementation requires considerable efforts and resources, but in the long run CML could become a model for epidemiologi and management of other cancers. Disclosures: Hasford: Novartis Pharma: Research Funding.

scholarly journals Molecular monitoring in chronic myeloid leukemia—how low can you go?

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 156-163 ◽  
Author(s):  
Susan Branford
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Maintenance Phase ◽  
Transcript Level ◽  
Response Prediction ◽  
Molecular Technique ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Low Level

Abstract Molecular monitoring of BCR-ABL1 transcripts for patients with chronic myeloid leukemia (CML) is now used to assess response to tyrosine kinase inhibitors (TKIs), including treatment failure that mandates a change of therapy. Therefore, many centers have adopted the molecular technique for measuring BCR-ABL1 and rely on conversion of values to the international reporting scale for appropriate clinical interpretation. However, the technique has a degree of inherent variability despite standardized procedures, which means care should be taken by the clinician when assessing response based on BCR-ABL1 cutoff limits. The last few years have witnessed the emergence of a new molecular response target, which is the achievement and maintenance of a deep molecular response. The ability to achieve treatment-free remission for some patients has shifted the relevant boundary for molecular response. However, the definitive safe BCR-ABL1 transcript level and length of the maintenance phase after which treatment cessation can be attempted has not yet been determined. For patients with TKI resistance, BCR-ABL1 kinase domain mutation analysis remains an essential assessment to guide therapy. Furthermore, low-level mutation detection is clinically relevant for response prediction to subsequent TKI therapy for some patients. Multiple low-level mutations may be a biomarker of a clonally diverse disease with the propensity for resistance evolution. Overall, molecular monitoring, including low-level monitoring is a fundamental component of management for patients with CML.

Medication Adherence to Tyrosine Kinase Inhibitors: 2-Year Analysis of Medication Adherence to Imatinib Treatment for Chronic Myeloid Leukemia and Correlation with the Depth of Molecular Response

2016 ◽  
Vol 136 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Fiorenzo Santoleri ◽  
Ruggero Lasala ◽  
Elena Ranucci ◽  
Gaetano La Barba ◽  
Roberto Di Lorenzo ◽  
...  
Keyword(s):  
Medication Adherence ◽  
Chronic Myeloid Leukemia ◽  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Complete Response ◽  
Molecular Response ◽  
Imatinib Treatment

Objective: Adherence to tyrosine kinase inhibitor treatment is a significant factor in the achievement of a good clinical response in chronic myeloid leukemia (CML). The aim of this retrospective study is to investigate 1- and 2-year medication adherence to imatinib treatment, linking adherence rates with the clinical outcome, in accordance with European LeukemiaNet Recommendations for the management of CML. We have tried to find a cutoff value for adherence in order to achieve a good clinical outcome. Methods: The method used to calculate medication adherence was the ratio between the received and the prescribed daily dose. Results: We observed the levels of mean adherence for each of the following response groups (in years 1 and 2, respectively): complete response (0.96, 0.95), MR4.5 (1.00, -), MR4 (0.93, 0.91), major molecular responses (0.96, 0.97), warning (0.91, 0.89) and failure (0.79, 0.84). Conclusion: Results show that the higher the adherence, the lower the level of BCR-ABL1. Furthermore, using cutoffs ≥0.9, outcomes were significantly improved compared to those with cutoffs <0.90. This value of adherence is in line with previous publications.

scholarly journals Ramadan Fasting in a Patient with Chronic Myeloid Leukemia Receiving Nilotinib as Upfront

2020 ◽  
Vol 13 (2) ◽  
pp. 664-667
Author(s):  
Husam N. Al-Dubai ◽  
Mohammed A. Yassin ◽  
Mohammed A. Abdulla ◽  
Mahmood S. Aldapt ◽  
Rola S. Ghassoub
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Unmet Needs ◽  
Blast Crisis ◽  
Myeloproliferative Neoplasm ◽  
Intermittent Fasting ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Ramadan Fasting

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm classically described as triphasic disease: chronic, accelerated, and blast crisis. There are many unmet needs and unanswered questions about CML. Intermittent fasting in patients with CML on tyrosine kinase inhibitors is among these unmet needs. Here we report the effect of intermittent fasting on response to nilotinib as upfront in a 49-year-old female Muslim who fasted during Ramadan and took her medication once instead of twice daily and remained in major molecular response.

scholarly journals Assessment ofBCR-ABL1Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

2012 ◽  
Vol 30 (3) ◽  
pp. 232-238 ◽  
Author(s):  
David Marin ◽  
Amr R. Ibrahim ◽  
Claire Lucas ◽  
Gareth Gerrard ◽  
Lihui Wang ◽  
...  
Keyword(s):  
Relative Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Characteristic Curve ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Transcript Levels

PurposeWe studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.Patients and MethodsWe analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.ResultsPatients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).ConclusionA single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

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