Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

Authors:
Jerald P. Radich
Search for other papers by Jerald P. Radich in
Current site
Google Scholar
PubMed
Close
 MD
,
Michael Deininger
Search for other papers by Michael Deininger in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Camille N. Abboud
Search for other papers by Camille N. Abboud in
Current site
Google Scholar
PubMed
Close
 MD
,
Jessica K. Altman
Search for other papers by Jessica K. Altman in
Current site
Google Scholar
PubMed
Close
 MD
,
Ellin Berman
Search for other papers by Ellin Berman in
Current site
Google Scholar
PubMed
Close
 MD
,
Ravi Bhatia
Search for other papers by Ravi Bhatia in
Current site
Google Scholar
PubMed
Close
 MD
,
Bhavana Bhatnagar
Search for other papers by Bhavana Bhatnagar in
Current site
Google Scholar
PubMed
Close
 DO
,
Peter Curtin
Search for other papers by Peter Curtin in
Current site
Google Scholar
PubMed
Close
 MD
,
Daniel J. DeAngelo
Search for other papers by Daniel J. DeAngelo in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Jason Gotlib
Search for other papers by Jason Gotlib in
Current site
Google Scholar
PubMed
Close
 MD, MS
,
Gabriela Hobbs
Search for other papers by Gabriela Hobbs in
Current site
Google Scholar
PubMed
Close
 MD
,
Madan Jagasia
Search for other papers by Madan Jagasia in
Current site
Google Scholar
PubMed
Close
 MD
,
Hagop M. Kantarjian
Search for other papers by Hagop M. Kantarjian in
Current site
Google Scholar
PubMed
Close
 MD
,
Lori Maness
Search for other papers by Lori Maness in
Current site
Google Scholar
PubMed
Close
 MD
,
Leland Metheny
Search for other papers by Leland Metheny in
Current site
Google Scholar
PubMed
Close
 MD
,
Joseph O. Moore
Search for other papers by Joseph O. Moore in
Current site
Google Scholar
PubMed
Close
 MD
,
Arnel Pallera
Search for other papers by Arnel Pallera in
Current site
Google Scholar
PubMed
Close
 MD
,
Philip Pancari
Search for other papers by Philip Pancari in
Current site
Google Scholar
PubMed
Close
 MD
,
Mrinal Patnaik
Search for other papers by Mrinal Patnaik in
Current site
Google Scholar
PubMed
Close
 MD
,
Enkhtsetseg Purev
Search for other papers by Enkhtsetseg Purev in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Michal G. Rose
Search for other papers by Michal G. Rose in
Current site
Google Scholar
PubMed
Close
 MD
,
Neil P. Shah
Search for other papers by Neil P. Shah in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
B. Douglas Smith
Search for other papers by B. Douglas Smith in
Current site
Google Scholar
PubMed
Close
 MD
,
David S. Snyder
Search for other papers by David S. Snyder in
Current site
Google Scholar
PubMed
Close
 MD
,
Kendra L. Sweet
Search for other papers by Kendra L. Sweet in
Current site
Google Scholar
PubMed
Close
 MD, MS
,
Moshe Talpaz
Search for other papers by Moshe Talpaz in
Current site
Google Scholar
PubMed
Close
 MD
,
James Thompson
Search for other papers by James Thompson in
Current site
Google Scholar
PubMed
Close
 MD
,
David T. Yang
Search for other papers by David T. Yang in
Current site
Google Scholar
PubMed
Close
 MD
,
Kristina M. Gregory
Search for other papers by Kristina M. Gregory in
Current site
Google Scholar
PubMed
Close
 RN, MSN, OCN
, and
Hema Sundar
Search for other papers by Hema Sundar in
Current site
Google Scholar
PubMed
Close
 PhD
Full access

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Chronic myeloid leukemia (CML) accounts for 15% of adult leukemias. The median age of disease onset is 67 years; however, CML occurs in all age groups (SEER statistics). In 2018, an estimated 8,430 people will be diagnosed with CML in the United States, and 1,090 people will die of the disease.1

CML is defined by the presence of Philadelphia chromosome (Ph) in a patient with a myeloproliferative neoplasm (MPN). Ph results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene; the product of this fusion gene is a protein with deregulated tyrosine kinase activity (p210) that plays a central role in the pathogenesis of CML.2 Another fusion protein, p190, is also produced, usually in the setting of Ph-positive acute lymphoblastic leukemia. p190 is detected only in 1% of patients with CML.3

CML occurs in 3 different phases (chronic, accelerated, and blast phases) and is usually diagnosed in the chronic phase. Untreated chronic phase CML (CP-CML) will eventually progress to advanced phase in 3 to 5 years.4 Gene expression profiling has shown a close correlation of gene expression between accelerated phase CML (AP-CML) and blast phase CML (BP-CML). The bulk of the genetic changes in progression occur in the transition from CP-CML to AP-CML.5 The activation of beta-catenin signaling pathway in CML granulocyte-macrophage progenitors (which enhances the self-renewal activity and leukemic potential of these cells) may also be a key pathobiologic event in the evolution to BP-CML.6

The NCCN Guidelines for CML discuss the clinical management of CML in all 3 phases (chronic, accelerated, and blast). Evaluation for diseases other than CML, as outlined in the NCCN Guidelines for MPN, is recommended for all patients with BCR-ABL1–negative MPN (to view the most recent version of these guidelines, visit NCCN.org).

Diagnosis and Workup

Initial evaluation should consist of a history and physical exam, including palpation of spleen,

F1

NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 9; 10.6004/jnccn.2018.0071

F2

NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 9; 10.6004/jnccn.2018.0071

F3

NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 9; 10.6004/jnccn.2018.0071

F4

Chronic Myeloid Leukemia, Version 1.2019

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 9; 10.6004/jnccn.2018.0071

CBC with differential, chemistry profile, and hepatitis panel. Bone marrow aspirate and biopsy for morphologic and cytogenetic evaluation and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to establish the presence of quantifiable BCR-ABL1 mRNA transcripts at baseline are recommended to confirm the diagnosis of CML (see CML-1; page 1110).

Bone marrow cytogenetics should be done at initial workup to detect additional chromosomal abnormalities in Ph-positive cells (ACA/Ph+), also known as clonal cytogenetic evolution.7 The prognostic significance of ACA/Ph+ is related to the specific chromosomal abnormality and often other features of accelerated phase.812 The presence of “major route” ACA/Ph+ (trisomy 8, isochromosome 17q, second Ph, and trisomy 19) at diagnosis may have a negative prognostic impact on survival and disease progression to accelerated or blast phase.1315 However, in a more recent analysis that evaluated the outcomes of patients with CP-CML (with or without ACA) treated with tyrosine kinase inhibitors (TKIs) in prospective studies, the presence of ACA/Ph+ at the time of diagnosis was not associated with worse prognosis.16 Patients with ACA/Ph+ at diagnosis should be watched carefully for evidence of therapy failure. Clonal cytogenetic evolution in Ph-negative cells has also been reported in a small subset of patients during the course of imatinib therapy.1722 The most common abnormalities include trisomy 8 and loss of Y chromosome. Previous work suggested that the overall prognosis of Ph-negative CML with clonal evolution is good and is dependent on response to imatinib therapy.21 Recently, however, the presence of chromosome abnormalities other than loss of Y chromosome has been associated with decreased survival in patients with CP-CML treated with various TKIs, suggesting that closer follow-up is indicated until definitive data are available.23 Progression to myelodysplastic syndromes (MDS) and acute myeloid leukemia have been reported in patients with monosomy 7.24,25

If bone marrow evaluation is not feasible, fluorescence in situ hybridization (FISH) on a peripheral blood specimen with dual probes for BCR and ABL1 genes is an acceptable method to confirm the diagnosis of CML. Interphase FISH is performed on peripheral blood but is associated with a background level of 1%–5% depending on the specific probe used in the assay.26 Hypermetaphase FISH is more sensitive and can analyze up to 500 metaphases at a time, but it is applicable only to dividing cells in the bone marrow.27 Double-fusion FISH is also associated with low false-positive rates and can detect all variant translocations of the Ph-chromosome.28

Quantitative RT-PCR (qPCR) should be performed at initial workup to establish the presence of quantifiable BCR-ABL1 mRNA transcripts at baseline. qPCR, usually performed on peripheral blood, is the most sensitive assay available for the measurement of BCR-ABL1 mRNA and it can detect 1 CML cell in a background of ≥100,000 normal cells. qPCR results can be expressed in various ways, for instance as the ratio of BCR-ABL1 transcript numbers to the number of control gene transcripts.29 An international scale (IS) has been proposed to standardize molecular monitoring with qPCR across different laboratories with the use of 1 of 3 control genes (BCR, ABL1, or GUSB) and a qPCR assay with a sensitivity of at least 4-log reduction from the standardized baseline.30 In recent years, IS has become the gold standard of expressing qPCR values. More details on qPCR monitoring using IS are provided on MS-10 (in these guidelines, at NCCN.org).

BCR-ABL1 transcripts in the peripheral blood at very low levels (1–10 of 108 peripheral blood leukocytes) can also be detected in approximately 30% of normal individuals, and the incidence of BCR-ABL1 transcripts increases with advancing age in healthy individuals.31,32 TKI therapy is not indicated, as the risk of developing CML for these individuals is extremely low.

Management of Chronic Phase CML

Risk Stratification

Sokal and Euro scoring systems have been used for the risk stratification of patients into 3 risk groups (low, intermediate, and high) in clinical trials evaluating TKIs (see CML-A; available online, in these guidelines, at NCCN.org).33,34 The Sokal score is based on the patient's age, spleen size, platelet count, and percentage of blasts in the peripheral blood.33 The Euro score includes eosinophils and basophils in the peripheral blood in addition to the same clinical variables used in the Sokal score.34

European Treatment and Outcome Study (EUTOS) score is based only on the percentage of basophils in the blood and spleen size. The predictive value of EUTOS score was validated in a cohort of 2,060 patients enrolled in studies of first-line treatment with imatinib-based regimens.35 EUTOS score was better than Sokal and Euro score in predicting the probability of achieving a complete cytogenetic response (CCyR) at 18 months and 5-year progression-free survival (PFS). However, the predictive value of EUTOS score has not been confirmed in subsequent studies by other investigators, and additional studies are needed to validate the EUTOS score.3638

Determination of risk score using either the Sokal or Hasford (Euro) scoring systems before initiation of TKI therapy is recommended for patients diagnosed with CP-CML (see CML-1; page 1110).

Primary Treatment

Long-term efficacy data from randomized phase III studies for first-line TKI therapy in patients with newly diagnosed CP-CML are summarized in Table 1.3942 In summary, (1) all TKIs are highly effective in newly diagnosed CP-CML, with long-term overall survival (OS) approaching that of aged-matched controls; (2) second-generation TKIs, compared with imatinib, generally result in faster cytogenetic and molecular responses, with less progression to advanced phase CML; and (3) yet, in randomized clinical trials, there are no differences in OS between imatinib and second-generation TKIs.

The selection of first-line TKI therapy (bosutinib, dasatinib, imatinib, or nilotinib) in a given patient should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. Allogeneic hematopoietic cell transplantation (HCT) is no longer recommended as a first-line treatment option for patients with CP-CML.

Imatinib, 800 mg, is not recommended as initial therapy, given the recent data showing superior efficacy of second-generation TKIs (dasatinib, nilotinib, and bosutinib) in newly diagnosed CP-CML. Data from randomized phase III studies that have evaluated high-dose imatinib as first-line therapy for CP-CML suggest that imatinib, 800 mg, was not associated with lower rates of disease progression than imatinib, 400 mg, in any of these studies, despite improved early responses (Table 2).4345 Imatinib, 800 mg, was also associated with higher rates of dose interruption, reduction, or discontinuation

Table 1.

First-Line TKI Therapy for CP-CML: Long-Term Follow-Up Data From Phase III Studies

Table 1.
Table 2.

High-Dose Imatinib as First-Line Therapy for CP-CML: Long-Term Follow-Up Data From Phase III Studies

Table 2.
due to grade 3 or 4 adverse events in all of the studies. However, patients who can actually tolerate the higher dose of imatinib experience better response rates than those receiving standard-dose imatinib.

The prospective studies evaluating imatinib, 800 mg, daily found that increased toxicity of that dose forced decreasing dose to approximately 600 mg, daily when considering the actually administered dose intensity.4345 Additionally, the French SPIRIT trial reported superior major molecular response (MMR) rates in patients treated with imatinib, 600 mg daily compared with 400 mg daily.46 These data suggest that imatinib, 600 mg, daily may be closer to the optimal dose than 400 mg.

Clinical Considerations for The Selection of First-Line Therapy

Risk Stratification: Imatinib (400 mg daily) and second-generation TKIs (dasatinib, 100 mg once daily; nilotinib, 300 mg twice daily; and bosutinib, 400 mg daily) are all appropriate options for first-line TKI therapy for patients with CP-CML across all risk scores (see CML-2; page 1112).3942

Disease progression is more frequent in patients with intermediate- or high-risk score, and prevention of disease progression to AP-CML or BP-CML is the primary goal of TKI therapy in patients with CP-CML. Second-generation TKIs are associated with lower risk of disease progression than imatinib and are therefore preferred for patients with an intermediate- or high-risk Sokal or Euro score.

Second-generation TKIs also result in quicker molecular responses and higher rates of deep molecular responses (MMR [BCR-ABL1 ≤0.1% IS] and MR4.5 [≥4.5-log reduction in BCR-ABL1 transcripts from baseline]) in patients with CP-CML across all risk scores (Table 3), which may facilitate subsequent discontinuation of TKI therapy in selected patients.4042 Therefore, second-generation TKIs may be preferred over imatinib for younger patients, particularly women, because the achievement of a deep and rapid molecular response may allow eventual discontinuation of TKI therapy for fertility purposes. Imatinib may be preferred for older patients with comorbidities, especially cardiovascular.

Toxicity Profile: All of the TKIs are fairly well tolerated. Because bosutinib, dasatinib, and nilotinib have very good efficacy in the upfront setting, differences in their potential toxicity profiles may inform the selection of either of these TKIs as initial therapy. Nilotinib or bosutinib may be preferred for patients with a history of lung disease or deemed to be at risk of developing pleural effusions. Dasatinib or bosutinib may be preferred in patients with a history of arrhythmias, heart disease, pancreatitis, or hyperglycemia.

Adverse events of first-line TKI therapy in patients with CP-CML reported in phase III randomized

Table 3.

First-Line TKI Therapy for CP-CML: MR Rates According to Sokal or Euro Risk Score

Table 3.
studies are discussed subsequently and are also summarized in Table 4. See CML-F (available online, in these guidelines, at NCCN.org) for the management of toxicities associated with TKI therapy.

Imatinib: Chronic fatigue (mostly correlated with musculoskeletal pain and muscular cramps) is a major factor reducing quality of life.47 Hypophosphatemia and decrease in bone mineral density has been noted in a small group of patients, suggesting that monitoring bone health should be considered for patients taking imatinib.48,49 Skin hypopigmentation has also been reported as a side effect of imatinib and is reversible on discontinuation or dose reduction.50,51

Dasatinib: In the DASISION study, the incidences of grade 3/4 hematologic toxicities (anemia, neutropenia, and thrombocytopenia) were higher for dasatinib than imatinib. Nonhematologic adverse events such as muscle spasms, peripheral edema, and hypophosphatemia were more frequent with imatinib. Discontinuation of therapy because of drug-related adverse events occurred in 16% and 7% of patients in the dasatinib and imatinib arms, respectively.40 Dasatinib is also associated with significant but reversible inhibition of platelet aggregation that may contribute to bleeding in some patients, especially if accompanied by thrombocytopenia.52

Pleural effusion was more common with dasatinib (28%) than with imatinib (<1%).40 The occurrence of pleural effusion is significantly reduced with dasatinib, 100 mg once daily compared with 70 mg twice daily.53 Patients with prior cardiac history, hypertension, and those receiving twice-daily dosing of dasatinib at 70 mg are at increased risk of developing pleural effusions. Close monitoring and timely intervention are necessary for patients at risk of developing pleural effusions.

Reversible pulmonary arterial hypertension has been reported as a rare but serious side effect of dasatinib.54,55 In the DASISION study, pulmonary hypertension was reported in 5% of patients compared with 0.4% of patients treated with imatinib.40 Evaluation for signs and symptoms of underlying cardiopulmonary disease before starting and during treatment with dasatinib is recommended. If pulmonary arterial hypertension is confirmed, dasatinib must be permanently discontinued.

The recommended starting dose of dasatinib is 100 mg once daily for patients with CP-CML. Limited data available from small cohorts of patients suggest that lower doses of dasatinib may potentially have similar efficacy.56,57 Treatment interruption of dasatinib at standard dose and reintroduction of dasatinib at a lower dose of 40 mg twice daily also resolved all pulmonary complications without recurrence.58 However, the minimum effective dose has not been established in randomized clinical trials. Reintroduction of dasatinib at 50 mg (20 mg with careful monitoring in selected patients) should be considered for patients with clinically significant intolerance to dasatinib at 100 mg once daily to avoid serious adverse events necessitating the discontinuation of dasatinib (eg, pleural effusion, myelosuppression).

Table 4.

Adverse Events of First-Line TKI Therapy in CP-CML

Table 4.

Nilotinib: In the ENESTnd study, nonhematologic adverse events such as nausea, diarrhea, vomiting, muscle spasm, and peripheral edema of any grade were higher for patients receiving imatinib.41 Conversely, rash and headache were higher with nilotinib. Grade 3 or 4 neutropenia was more frequent in the imatinib group, whereas thrombocytopenia and anemia were similar in both groups. Electrolyte abnormalities and elevations in lipase, glucose, and bilirubin were more frequent with nilotinib than with imatinib. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase levels. The overall incidences of adverse events leading to discontinuation of therapy were comparable in the nilotinib, 300 mg, twice daily arm and imatinib arms (12% and 14%, respectively) and slightly higher in the nilotinib, 400 mg, twice daily arm (20%).

Nilotinib labeling contains a black box warning regarding the risk of QT interval prolongation, and sudden cardiac death has been reported in patients receiving nilotinib. QT interval prolongation could be managed with dose reduction. Electrolyte abnormalities should be corrected before start of treatment with nilotinib, and electrolytes should be monitored periodically. Drugs that prolong QT interval should be avoided. Electrocardiogram should be obtained to monitor the QT interval at baseline, 7 days after start of nilotinib, and periodically thereafter, and after any dose adjustments. Patients with cardiovascular risk factors should be referred to a cardiologist.

Nilotinib is associated with an increased risk of peripheral arterial occlusive disease (PAOD).5961 Patients should be evaluated for pre-existing PAOD and vascular risk factors before starting and during treatment with nilotinib. If PAOD is confirmed, nilotinib should be permanently discontinued.

Bosutinib: In the BFORE study, diarrhea, increased alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were more common with bosutinib, whereas muscle spasms and peripheral edema were more common with imatinib. Grade 3/4 thrombocytopenia was higher with bosutinib and grade 3/4 neutropenia was higher with imatinib. Grade 3/4 anemia was similar in both groups. Discontinuation of therapy because of drug-related adverse events occurred in 14% of patients in the bosutinib group compared with 11% in the imatinib group. Increased ALT (5%) and increased AST increase (2%) were the most common adverse events leading to discontinuation of bosutinib. However, no hepatotoxicity-related fatalities occurred during the study.42

Management of Hematologic Toxicities of TKI Therapy: Cytopenias (anemia, neutropenia, and thrombocytopenia) should be managed with transient interruptions of TKI therapy and dose modifications. Please see the package insert for full prescribing information, available at www.fda.gov, for the recommended dose modifications of specific TKI therapy.

Assessment of reticulocyte count, ferritin, iron saturation, vitamin B12, and folate and correction of nutritional deficiencies if present is recommended for patients with grade 3/4 anemia. Red blood cell transfusions are indicated in symptomatic patients. Myeloid growth factor support can be used in combination with TKI therapy for the management of neutropenia.62,63 The use of erythropoiesis-stimulating agents (ESAs) did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate in patients with CP-CML.64 Recent guidelines from the Centers for Medicare & Medicaid Services (CMS) and the FDA do not support the use of ESAs in patients with myeloid malignancies.

Monitoring Response to TKI Therapy

Response to TKI therapy is determined by the measurement of hematologic (normalization of peripheral blood counts), cytogenetic (decrease in the number of Ph-positive metaphases using bone marrow cytogenetics), and molecular responses (decrease in the amount of BCR-ABL1 chimeric mRNA using qPCR). The criteria for hematologic, cytogenetic, and molecular response are summarized in CML-D (page 1115).

Conventional bone marrow cytogenetics is the standard method for monitoring cytogenetic responses, and clinical trial response analyses are most often based on conventional bone marrow cytogenetics. If conventional bone marrow cytogenetics showed no analyzable metaphases, cytogenetic response can be evaluated by FISH; however, it has a false-positive rate of 1% to 10%.65,66 Although some investigators have reported that interphase FISH can be used to monitor CCyR, end points for TKI failure have not been defined on the basis of FISH analysis.67,68 The panel feels that FISH has been inadequately studied for monitoring response to TKI therapy. Therefore, FISH is not generally recommended for monitoring response if conventional cytogenetics or qPCR are available.

qPCR is the only tool capable of monitoring responses after the patient has experienced CCyR, because BCR-ABL1 transcripts typically remain detectable after CCyR is achieved. A major advantage of qPCR is the strong correlation between the results obtained from the peripheral blood and the bone marrow, allowing molecular monitoring without bone marrow aspirations.69,70

Standardization of Molecular Monitoring Using the IS: In the IS, the standardized baseline (defined as the average expression of BCR-ABL1 transcripts in 30 patients treated on the IRIS trial) is set to 100%. Molecular response is expressed as log-reduction from 100%. For example, ≥3-log reduction (≤0.1% BCR-ABL1 IS) is referred to as MMR or MR3.0).30,71,72 A 2-log reduction generally correlates with CCyR (≤1% BCR-ABL1 IS).

The sensitivity of a qPCR assay depends not only on the performance of the assay, but also on the quality of a given sample. As such the term “complete molecular response” to denote undetectable BCR-ABL1 transcripts (a negative qPCR test) should be abandoned, because it may refer to very different levels of response, dependent on the quality of the sample. Laboratories can use their individual assays, but the BCR-ABL1 transcripts obtained in a given laboratory should be converted to the IS by applying a laboratory-specific conversion factor.30,73

Recommendations for Monitoring Response to TKI Therapy: qPCR (IS) is the preferred method to monitor response to TKI therapy. qPCR assays with a sensitivity of ≥4.5-log reduction from the standardized baseline are recommended for the measurement of BCR-ABL1 transcripts. In patients with prolonged myelosuppression who may not be in complete hematologic response due to persistent cytopenias or unexplained drop in blood counts during therapy, bone marrow cytogenetics is indicated to confirm response to TKI therapy and exclude other pathology, such as MDS or the presence of chromosomal abnormalities other than Ph.

Monitoring with qPCR (IS) every 3 months is recommended for all patients after initiating TKI therapy, including those who meet response milestones at 3, 6, and 12 months (≤10% BCR-ABL1 IS at 3 and 6 months, ≤1% BCR-ABL1 IS at 12 months, and ≤0.1% BCR-ABL1 IS at >12 months). After CCyR (≤1% BCR-ABL1 IS) has been achieved, molecular monitoring is recommended every 3 months for 2 years and every 3 to 6 months thereafter (see CML-C; page 1114).

Frequent molecular monitoring with qPCR (IS) can help to identify nonadherence to TKI therapy early in the treatment course.74 Because adherence to TKI therapy is associated with better clinical outcomes, frequent molecular monitoring is essential if there are concerns about the patient's adherence to TKI therapy after CCyR has been achieved. In patients with deeper molecular responses (MMR and better) and who are adherent with TKI therapy, the frequency of molecular monitoring can be reduced, though the optimal frequency is unknown.

Prognostic Significance of Cytogenetic and Molecular Response

Early molecular response (≤10% BCR-ABL1 IS at 3 and 6 months) after first-line TKI therapy has emerged as an effective prognosticator of favorable long-term PFS and OS, regardless of TKI used (Table 5).40,41,45,75 Some reports suggest that early molecular response at 3 months has a superior prognostic value and support the use of early intervention strategies based on the BCR-ABL1 transcript level at 3 months.76,77 However other studies yielded partially conflicting results regarding the predictive value of BCR-ABL1 transcript levels at 3-months.78 From a practical perspective, it is important to consider these data points within the clinical context. For instance, if BCR-ABL1 transcript level is minimally above the 10% cutoff (11% at 3 months), it is reasonable to reassess at 6 months before considering major changes to the treatment strategy.

Recently, studies have suggested that the rate of decline in BCR-ABL1 transcripts correlates with longer-term response.7982 Among patients with >10% BCR-ABL1 IS after 3 months of treatment with imatinib, those with a faster decline in BCR-ABL1 (BCR-ABL1 halving time <76 days) had a superior outcome compared with those with a slower decline (4-year PFS rate was 92% vs 63%, respectively).79 A rapid initial BCR-ABL1 decline also identifies a subgroup of Sokal high-risk patients with outcomes similar to those of Sokal low-risk patients.80 Among Sokal high-risk patients, a BCR-ABL1 halving time of ≤11 days was associated with significantly improved FFS (4-year FFS rate was 79% for patients with halving time of ≤11 days vs 53% for those with halving time of >11 days; P=.03). In the German CML IV study, lack of a half-log reduction of BCR-ABL1 transcripts at 3 months was associated with a higher risk of disease progression on imatinib therapy.81 The results of the D-First study also showed that in patients treated with dasatinib, BCR-ABL1 halving time of ≤14 days was a significant predictor of MMR by 12 months and deep molecular response (BCR-ABL1 <0.01% IS) by 18 months.82

Achievement of CCyR (≤1% BCR-ABL1 IS) within 12 months after first-line TKI therapy is an established prognostic indicator of long-term survival.83,84 In the IRIS study, the estimated 6-year PFS rate was 97% for patients achieving a CCyR at 6 months compared with 80% for patients with no cytogenetic response at 6 months.83 In an analysis of patients with newly diagnosed CP-CML treated with imatinib or second-generation TKIs, the 3-year event-free survival and OS rates were 98% and 99% for patients who experienced CCyR at 12 months compared with 67% and 94% in patients who did not experience a CCyR.84

The prognostic significance of MMR (0.1% BCR-ABL1 IS) after first-line imatinib has also been evaluated in several studies.69,8589 In all of these studies, the analyses were done for different outcomes measures at multiple time points, but failed to adjust for multiple comparisons, thereby reducing the validity of the conclusions. The synoptic conclusion from these studies is that MMR is moderately superior to CCyR in predicting long-term PFS and OS. However, with longer

Table 5.

Early Molecular Response (≤10% BCR-ABL1 IS at 3 mo) After First-Line TKI Therapy and Survival Outcomes

Table 5.
follow-up, CCyR becomes an ever stronger indicator of MMR. The achievement of MMR is also not a significant prognosticator of long-term outcome in patients who are in stable CCyR after first-line treatment with dasatinib or nilotinib.90,91 These findings suggest that MMR may not be of prognostic significance in patients who have achieved CCyR and absence of MMR in the presence of a CCyR is not considered a treatment failure. Achievement of MMR (0.1% BCR-ABL1 IS) at 12 months, however, is associated with a very low probability of subsequent disease progression and a high likelihood of achieving a subsequent deep molecular response (MR4.0; ≤0.01% BCR-ABL1 IS) which may facilitate discontinuation of TKI therapy. TKI de-escalation has also been shown to be feasible in patients who had received TKI therapy for ≥3 years with either a stable MMR or MR4.0 for ≥12 months.92

Response Milestones after First-Line TKI Therapy

The goal of TKI therapy is to achieve a CCyR (≤1% BCR-ABL1 IS) within 12 months after first-line TKI therapy and to prevent disease progression to AP-CML or BP-CML. The guidelines emphasize that achievement of response milestones must be interpreted within the clinical context, before making drastic changes to the treatment strategy.

The panel has included ≤10% BCR-ABL1 IS at 3 and 6 months and ≤1% BCR-ABL1 IS at 12 and 15 months as response milestones after first-line TKI therapy (see CML-3; page 1112). Patients who experience these response milestones are considered to have TKI-sensitive disease, and continuation of the same dose of TKI and assessment of BCR-ABL1 transcripts with qPCR (IS) every 3 months is recommended for this group of patients.

In patients with a >10% BCR-ABL1 IS at 3 months and >1% BCR-ABL1 IS at 12 months, clinical judgement should be used, considering problems with adherence (which can be common given drug toxicity at start of therapy), rate of decline in BCR-ABL1 (the faster, the better), and how far from the 10% cutoff the BCR-ABL1 value falls. That being said, failure to experience ≤10% BCR-ABL1 IS at 3 months or ≤1% BCR-ABL1 IS at 12 months is associated with a higher risk for disease progression.

Patients with >10% BCR-ABL1 IS at 3 months or >1% BCR-ABL1 IS at 12 months can continue the same dose of dasatinib or nilotinib or bosutinib for another 3 months. Mutational analysis and evaluation for allogeneic HCT should considered. Bone marrow cytogenetics should be considered to assess for MCyR at 3 months or CCyR at 12 months.

Patients with >10% BCR-ABL1 IS at ≥6 months and those with BCR-ABL1 IS >1% at 15 months are considered to have TKI-resistant disease. Evaluation for allogeneic HCT (that is, a discussion with a transplant specialist, which might include HLA testing) is recommended. Alternate treatment options should be considered as described subsequently.

Second-Line Therapy

Long-term efficacy data from phase II/III studies on second-line TKI therapy for CP-CML are summarized in Table 6.9396

Early molecular response (≤10% BCR-ABL1 IS at 3 and 6 months) after second-line TKI therapy with dasatinib or nilotinib has also been reported to be a prognosticator of OS and PFS (Table 7). Patients who do not experience cytogenetic or molecular responses at 3, 6, or 12 months after second-line and subsequent TKI therapy should be considered for alternative therapies or allogeneic HCT if deemed eligible.

Table 6.

Second-line and Subsequent TKI Therapy for CP-CML: Long-Term Follow-Up Data From Phase II/III Studies

Table 6.

Management of Patients With Inadequate Response to Imatinib: Switching to an alternate TKI is recommended for patients with disease that is resistant to imatinib 400 mg daily. Dasatinib, nilotinib, and bosutinib are active against many of the imatinib-resistant BCR-ABL1 kinase domain mutants, except T315I, and are effective treatment options for patients with CP-CML intolerant to imatinib or those with CP-CML resistant to imatinib.93-95

Dose escalation of imatinib up to 800 mg daily has been shown to overcome some of the primary resistance and is particularly effective in patients with cytogenetic relapse who had achieved cytogenetic response with imatinib, 400 mg daily, although the duration of responses has typically been short.97100 However, it is unlikely to benefit patients with hematologic failure or those who never had a cytogenetic response with imatinib 400 mg daily. Switching to nilotinib has been shown to result in higher rates of cytogenetic and molecular response than dose escalation of imatinib in patients with inadequate response to imatinib, 400 mg.101,102 In the TIDEL-II study, the cohort of patients with >10% BCR-ABL1 IS at 3 months after imatinib, 400 mg, who were switched directly to nilotinib had higher rates of MMR and CMR at 12 months (but not at 24 months) than the cohort of patients who received dose escalation of imatinib before switching to nilotinib.101 Although dose escalation of imatinib has been shown to be beneficial for patients in CCyR with no MMR, no randomized studies have shown that a change of therapy would improve PFS or event-free survival in this group of patients.103,104

Management of Patients with Inadequate Response to Dasatinib, Nilotinib or Bosutinib: Switching to an alternate TKI (other than imatinib) in the second-line setting could be considered for patients with disease that is resistant to dasatinib, nilotinib, or bosutinib. However, no clear evidence supports that switching to alternate TKI therapy would improve long-term clinical outcome for this group of patients.

Ponatinib is an option for patients with T315I mutation and for those with disease that has not responded to several TKIs.96 Long-term efficacy data from phase II/III studies evaluating bosutinib or ponatinib in patients with pretreated CP-CML are summarized in Table 6.

In the PACE trial, serious arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular) and venous thromboembolic events occurred in 31% and 6% of patients, respectively.96 Cardiovascular occlusion, cerebrovascular occlusion, and peripheral arterial occlusive events were reported in 16%, 13%, and 14% of patients, respectively. Ponatinib labeling contains a black box warning regarding vascular occlusion, heart failure, and hepatotoxicity. Cardiovascular risk factors (eg, diabetes mellitus, hypertension, hyperlipidemia, smoking, estrogen use) should be identified and controlled before starting ponatinib. Patients should be monitored

Table 7.

Early Molecular Response (≤10% BCR-ABL1 IS) After Second-Line TKI Therapy and Survival Outcomes

Table 7.
for high blood pressure, evidence of arterial occlusive or thromboembolic events, and reduced cardiac function. Ponatinib should be interrupted or stopped immediately for vascular occlusion and for new or worsening heart failure. Patients with cardiovascular risk factors should be referred to a cardiologist.

The recommended initial dose of ponatinib is 45 mg once daily. High dose intensity of ponatinib is significantly associated with increased risk of adverse events.105 Therefore, dose modifications may be necessary for the management of adverse events. In a post hoc analysis of the PACE trial that assessed the clinical impact of dose modification and dose intensity on outcomes of patients with CP-CML, substantial responses were seen at lower dose levels and the rates of maintenance of MCyR and MMR were high irrespective of dose-reductions.96 Thus, an initial dose of 30 mg may be a safer and effective dose for patients with cardiovascular risk factors. Safety and efficacy of ponatinib at initial doses lower than 45 mg are being evaluated in a randomized clinical trial.

Omacetaxine is an option for patients with the T315I mutation and in those with CML that is resistant to ≥2 TKIs.106108 In the CML 202 study, among 62 evaluable patients with T315I and CP-CML resistant to prior TKI therapy, MCyR, CCyR, and MMR were achieved in 23%, 16%, and 17% of patients, respectively, and the T315I clone declined to below detection limits in 61% of patients.106 After a median follow-up of 19 months, the median PFS was 8 months and the median OS had not yet been reached. In the cohort of 46 patients with CP-CML that is resistant to ≥2 TKIs (CML 203 study), MCyR and CCyR were achieved in 22% and 4% of patients, respectively. Median PFS and OS were 7 months and 30 months, respectively.107 Omacetaxine had an acceptable toxicity profile, and the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%).108

Clinical Considerations For The Selection Of Second-Line Therapy

BCR-ABL kinase domain mutation analysis (see subsequent section), evaluation of drug interactions, and compliance to therapy are recommended before the start of second-line TKI therapy.

Drug Interactions: Bosutinib, dasatinib, imatinib, and nilotinib are metabolized in the liver by cytochrome P450 (CYP) enzymes. Drugs that are CYP3A4 or CYP3A5 inducers may decrease the therapeutic plasma concentration of TKIs, whereas CYP3A4 inhibitors and drugs that are metabolized by the CYP3A4 or CYP3A5 enzyme might result in increased plasma levels of TKIs.109 In addition, imatinib is also a weak inhibitor of the CYP2D6 and CYP2C9 isoenzymes and nilotinib is a competitive inhibitor of CYP2C8, CYP2C9, CYP2D6, and UG-T1A1, potentially increasing the plasma concentrations of drugs eliminated by these enzymes.

Concomitant use of drugs that are metabolized by these enzymes requires caution, and appropriate alternatives should be explored to optimize treatment outcome. If coadministration cannot be avoided, dose modification should be considered.

Concomitant use of H2 blockers or proton pump inhibitors (PPIs) is not recommended in patients receiving dasatinib. If their use is inevitable, they should be administered 12 hours before the next dasatinib dose. Concomitant use of PPI is not recommended in patients receiving bosutinib. The use of short-acting antacids or H2 blockers should be considered instead of PPIs.

Adherence to Therapy: Treatment interruptions and nonadherence to therapy may lead to undesirable clinical outcomes.110112 In the ADAGIO study, non-adherence to imatinib was associated with poorer response. Patients with suboptimal response missed significantly more imatinib doses (23%) than did those with optimal response (7%).110 Adherence to imatinib therapy has been identified as the only independent predictor for achieving complete molecular response (CMR) on standard-dose imatinib.111 Poor adherence to imatinib therapy has also been identified as the most important factor contributing to cytogenetic relapse and imatinib failure.112 Patients with adherence of ≤85% had a higher probability of losing CCyR at 2 years than those with adherence of >85% (27% and 2%, respectively). Poor adherence to therapy has also been reported in patients receiving dasatinib and nilotinib after imatinib failure.113,114

Patient education on adherence to therapy and close monitoring of patient's adherence is critical to achieving optimal responses. In a significant proportion of patients with TKI-induced toxicities, responses have been observed with doses well below their determined maximum tolerated doses.115 Short interruptions or dose reductions, when medically necessary, may not have a negative impact on disease control or other outcomes. Adequate and appropriate management of side effects and scheduling appropriate follow-up visits to review side effects may be helpful to improve patient adherence to therapy.116 Switching to an alternate TKI because of intolerance might be beneficial for selected patients with acute grade 3/4 nonhematologic toxicities or in those with low-grade, chronic, and persistent adverse events that are not manageable with adequate supportive care measures.117

Resistance to TKI Therapy: Aberrant expressions of drug transporters118120 and plasma protein binding of TKI121123 could contribute to primary resistance by altering the intracellular and plasma concentration of TKI. Monitoring imatinib plasma levels may be useful in determining patient adherence to therapy. However, there are no data to support that change of therapy based on plasma imatinib levels will affect treatment outcomes. Pretreatment levels of organic cation transporter 1 (OCT1) have been reported as the most powerful predictor of response to imatinib.124 Conversely, cellular uptake of dasatinib or nilotinib seems to be independent of OCT1 expression, suggesting that patients with low hOCT1 expression might have better outcomes with dasatinib or nilotinib than with imatinib.125128

BCR-ABL Kinase Domain Mutation Analysis: Point mutations in the BCR-ABL1 kinase domain are a frequent mechanism of secondary resistance to TKI therapy and are associated with poor prognosis and higher risk of disease progression.129134 Among the BCR-ABL1 kinase domain mutations, the T315I mutation confers the complete resistance to imatinib, dasatinib, nilotinib, and bosutinib.135,136

F317L and V299L mutants are resistant to dasatinib and Y253H, E255K/V, and F359V/C mutants are resistant to nilotinib.137140 E255K/V, F359C/V, Y253H, and T315I mutants are most commonly associated with disease progression and relapse.140 Bosutinib has demonstrated activity in patients with BCR-ABL1 mutants resistant to dasatinib (F317L) and nilotinib (Y253H, E255K/V, and F359C/I/V).95 T315I, G250E, and V299L mutants are resistant to bosutinib. Ponatinib is active against other BCR-ABL1 mutants resistant to dasatinib or nilotinib, including E255V, Y253H, and F359V, in addition to T315I.96,141 Response rates based on BCR-ABL mutation status are listed in Table 8.

BCR-ABL kinase domain mutational analysis is helpful in the selection of subsequent TKI therapy for patients with inadequate initial response to first- or second-line TKI therapy.142 Treatment options based on BCR-ABL1 mutation status are outlined on CML-5 (page 1113). BCR-ABL mutational analysis provides additional guidance in the selection of subsequent TKI therapy only in patients with identifiable mutations. In patients with no identifiable mutations, the selection of subsequent TKI therapy should be based on the toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. Adverse events of second-line TKI therapy in patients with CP-CML are summarized in Table 9.

The use of an alternate second-generation TKI after treatment failure with 2 prior TKIs, including a second-generation TKI, is not associated with durable responses, except in occasional patients with CP-CML.143 The guidelines recommend BCR-ABL1 mutational analysis for patients who do not experience response milestones, for those with any sign of loss of response (hematologic or cytogenetic relapse), and if there is a 1-log increase in BCR-ABL1 level with loss of MMR.

Rising BCR-ABL1 Transcript Levels: Rising BCR-ABL1 transcript levels are associated with an increased

Table 8.

Responses Based on BCR-ABL1 Mutations Status

Table 8.
likelihood of detecting BCR-ABL1 kinase domain mutations and cytogenetic relapse.144148 In patients who had achieved very low levels of BCR-ABL1 transcripts, emergence of BCR-ABL1 mutations was more frequent in those who had more than a 2-fold increase in BCR-ABL1 levels compared with those with stable or decreasing BCR-ABL1.144 A serial rise has been reported to be more reliable than a single ≥2-fold increase in BCR-ABL1 transcripts.145,146 Among patients in CCyR with a ≥0.5-log increase in BCR-ABL1 transcripts on at least 2 occasions, the highest risk of disease progression was associated with loss of MMR and a more than 1-log increase in BCR-ABL1 transcripts.146

The precise increase in BCR-ABL1 transcripts that warrants a mutation analysis depends on the performance characteristics of the qPCR assay.148 Some laboratories have advocated a 2- to 3-fold range,88,147,148 whereas others have taken a more conservative approach (5- to 10-fold).146 Obviously, some common sense must prevail, because the amount of change in absolute terms depends on the level of molecular response. For example, a finding of any BCR-ABL1 after achieving a deep molecular response (MR4.5; ≤0.0032% BCR-ABL1 IS) is an infinite increase in BCR-ABL1 transcripts. However,

Table 9.

Adverse Events of Second-Line and Subsequent TKI Therapy in CP-CML

Table 9.
a change in BCR-ABL1 transcripts from a barely detectable level to MR4.5 is clearly different from a 5-fold increase in BCR-ABL1 transcripts after achieving MMR.

Currently there are no specific guidelines for changing therapy based on rising BCR-ABL1 levels as detected by qPCR. Changes of therapy based solely on rising BCR-ABL1 levels should be done only in the context of a clinical trial.

Discontinuation of TKI Therapy

The feasibility of discontinuation of TKI therapy (with close monitoring) in carefully selected patients who have experienced and maintained deep molecular response (≥MR4.0; ≤0.01% BCR-ABL1 IS) for ≥2 or more years has been evaluated in several clinical studies. Limited longer-term follow-up data from the TKI discontinuation trials are summarized in Table 10.

The possibility of treatment-free remission (TFR) after discontinuation of imatinib was first evaluated in the Stop Imatinib (STIM1) study in 100 patients with a CMR for at least 2 years (5-log

Table 10.

Summary of Limited Longer-Term Follow-Up Data From the TKI Discontinuation Trials

Table 10.
reduction in BCR-ABL1 levels and undetectable minimal residual disease on qPCR with a sensitivity of ≥4.5-log reduction from the standardized baseline).149,150 With a median follow-up of 77 months after discontinuation of imatinib, the molecular recurrence-free survival was 43% at 6 months and 38% at 60 months.150 Other subsequent studies that have evaluated discontinuation of imatinib have also reported similar findings.151156

More recent studies have also confirmed the feasibility of TFR after discontinuation of dasatinib or nilotinib, in patients with CP-CML who have achieved and maintained MR4.5 for 12 months after ≥2 years of TKI therapy in the first-line or second-line setting (TFR rates ranging from 44% to 54%; Table 10).156160 The feasibility of TFR after discontinuation of bosutinib or ponatinib has not yet been evaluated in clinical studies. In the EURO-SKI study that evaluated TFR after discontinuation of any first-line TKI therapy (imatinib, dasatinib, or nilotinib) in eligible patients, the type of first-line TKI therapy did not significantly affect molecular relapse-free survival.156 Therefore, it is reasonable to assume that the likelihood of TFR after discontinuation would be similar irrespective of TKI in patients who have experienced and maintained deep molecular response (MR4.0; ≤0.01% BCR-ABL1 IS) for ≥2 years.

The results of the RE-STIM study demonstrated the safety of a second TKI discontinuation after a first unsuccessful attempt.161 The rate of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months after second TKI discontinuation was higher for patients who remained in deep molecular response within the first 3 months after the first TKI discontinuation (72% vs 32% for other patients).

Approximately 40% to 60% of patients who discontinue TKI therapy after achieving deep molecular response experience recurrence within 6 months of treatment cessation, in some cases as early as 1 month after discontinuation of TKI therapy. Resumption of TKI therapy immediately after recurrence results in the achievement of undetectable disease in almost all patients.149160 TKI withdrawal syndrome (aggravation or new development of musculoskeletal pain and/or pruritus after discontinuation of TKI therapy) has been reported during the TFR period in some TKI discontinuation studies,155,158,159 and the occurrence of imatinib withdrawal syndrome was associated with a lower rate of molecular relapse in the KID study.155

In the STIM study, molecular relapse (trigger to resume TKI therapy) was defined as positivity for BCR-ABL1 transcripts by qPCR confirmed by a 1-log increase in BCR-ABL1 transcripts between 2 successive assessments or loss of MMR at one point.149,150 The results of the A-STIM study showed that loss of MMR (≤0.1% BCR-ABL1 IS) could be used as a practical criterion for restarting therapy. The estimated probability of MMR loss was 35% at 12 months and 36% at 24 months after discontinuation of imatinib.153 Several factors may help predict the risk of relapse after discontinuation of TKI therapy (eg, a higher Sokal risk score, female sex, lower natural killer cell counts, suboptimal response or resistance to imatinib, duration of TKI therapy, and deep molecular response prior to TKI discontinuation).149,150,156160,162 However, only the duration of TKI therapy and deep molecular response before TKI discontinuation therapy have been associated with TFR with a high level of consistency.149,156 In the EURO-SKI study, duration of treatment with imatinib (≥ 6 years) and deep molecular response duration (MR4.0 for 3 years) were significantly associated with MMR maintenance at 6 months after discontinuation of imatinib.156

Based on the available evidence from clinical studies that have evaluated the feasibility of TFR, the panel members feel that discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected patients (in early CP-CML) who have achieved and maintained a deep molecular response (≥MR4.0) for ≥2 years. Clinical studies that have evaluated the safety and efficacy of discontinuation of TKI have employed strict eligibility criteria and have mandated more frequent molecular monitoring than typically recommended for patients on TKI therapy. Access to a reliable qPCR (IS) with a sensitivity of detection of at least MR4.5 (BCR-ABL1 ≤ 0.0032% IS) and the availability of test results within 2 weeks is one of the key requirements to monitor patients after TKI discontinuation and ascertain their safety.

The criteria for the selection of patients suitable for discontinuation of TKI therapy are outlined in CML-E (page 1116). The guidelines emphasize that discontinuation of TKI therapy outside of a clinical trial should be considered only if all the criteria included in the list are met. The panel acknowledges that more frequent molecular monitoring is essential after discontinuation of TKI therapy for the early identification of loss of MMR. Frequency of molecular monitoring has varied substantially among different studies, and the optimal frequency of molecular monitoring in patients with a loss of MMR after discontinuation of TKI therapy has not been established. The panel recommendations for molecular monitoring in TFR phase are outlined in CML-E (page 1116).

Individual Disclosures for Chronic Myeloid Leukemia

T11

References

  • 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:730.

  • 2.

    Faderl S, Talpaz M, Estrov Z et al.. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164172.

  • 3.

    Verma D, Kantarjian HM, Jones D et al.. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood 2009;114:22322235.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:13301340.

  • 5.

    Radich JP, Dai H, Mao M et al.. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:27942799.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Jamieson CHM, Ailles LE, Dylla SJ et al.. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657667.

  • 7.

    Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 1993;11 Suppl 1:1115.

  • 8.

    Cortes JE, Talpaz M, Giles F et al.. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101:37943800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    O'Dwyer ME, Mauro MJ, Blasdel C et al.. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004;103:451455.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Wang W, Cortes JE, Lin P et al.. Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. Blood 2015;126:16991706.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wang W, Tang G, Cortes JE et al.. Chromosomal rearrangement involving 11q23 locus in chronic myelogenous leukemia: a rare phenomenon frequently associated with disease progression and poor prognosis. J Hematol Oncol 2015;8:32.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Wang W, Cortes JE, Tang G et al.. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood 2016;127:27422750.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Verma D, Kantarjian H, Shan J et al.. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 2010;116:26732681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Fabarius A, Kalmanti L, Dietz CT et al.. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol 2015;94:20152024.

  • 15.

    Fabarius A, Leitner A, Hochhaus A et al.. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011;118:67606768.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Alhuraiji A, Kantarjian H, Boddu P et al.. Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol 2018;93:8490.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Bumm T, Muller C, Al-Ali H-K et al.. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:19411949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Feldman E, Najfeld V, Schuster M et al.. The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol 2003;31:702707.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Medina J, Kantarjian H, Talpaz M et al.. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:19051911.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Terre C, Eclache V, Rousselot P et al.. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia 2004;18:13401346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Deininger MW, Cortes J, Paquette R et al.. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007;110:15091519.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Jabbour E, Kantarjian HM, Abruzzo LV et al.. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2007;110:29912995.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Issa GC, Kantarjian HM, Gonzalez GN et al.. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood 2017;130:2084.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Karimata K, Masuko M, Ushiki T et al.. Myelodysplastic syndrome with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment for chronic myeloid leukemia. Intern Med 2011;50:481485.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Navarro JT, Feliu E, Grau J et al.. Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol 2007;82:849851.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Douet-Guilbert N, Morel F, Le Charpentier T et al.. Interphase FISH for follow-up of Philadelphia chromosome-positive chronic myeloid leukemia treatment. Anticancer Res 2004;24:25352539.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Seong DC, Kantarjian HM, Ro JY et al.. Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 1995;86:23432349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Dewald GW, Wyatt WA, Juneau AL et al.. Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood 1998;91:33573365.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Kantarjian HM, Talpaz M, Cortes J et al.. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003;9:160166.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Hughes T, Deininger M, Hochhaus A et al.. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:2837.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Biernaux C, Loos M, Sels A et al.. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995;86:31183122.

  • 32.

    Bose S, Deininger M, Gora-Tybor J et al.. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 1998;92:33623367.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Sokal J, Cox E, Baccarani M et al.. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789799.

  • 34.

    Hasford J, Pfirrmann M, Hehlmann R et al.. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850858.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Hasford J, Baccarani M, Hoffmann V et al.. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118:686692.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Marin D, Ibrahim AR, Goldman JM. European Treatment and Outcome Study (EUTOS) score for chronic myeloid leukemia still requires more confirmation. J Clin Oncol 2011;29:39443945.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Jabbour E, Cortes J, Nazha A et al.. 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;119:45244526.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Yamamoto E, Fujisawa S, Hagihara M et al.. European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients. Cancer Sci 2014;105:105109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Hochhaus A, Larson RA, Guilhot F et al.. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 2017;376:917927.

  • 40.

    Cortes JE, Saglio G, Kantarjian HM et al.. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:23332340.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Hochhaus A, Saglio G, Hughes TP et al.. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:10441054.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cortes JE, Gambacorti-Passerini C, Deininger MW et al.. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol 2018;36:231237.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Baccarani M, Druker BJ, Branford S et al.. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol 2014;99:616624.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Deininger MW, Kopecky KJ, Radich JP et al.. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 2014;164:223232.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Hehlmann R, Lauseker M, Saussele S et al.. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia 2017;31:23982406.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Preudhomme C, Guilhot J, Nicolini FE et al.. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:25112521.

  • 47.

    Efficace F, Baccarani M, Breccia M et al.. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 2013;27:15111519.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Berman E, Nicolaides M, Maki RG et al.. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:20062013.

  • 49.

    Berman E, Girotra M, Cheng C et al.. Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors. Leuk Res 2013;37:790794.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Tsao AS, Kantarjian H, Cortes J et al.. Imatinib mesylate causes hypopigmentation in the skin. Cancer 2003;98:24832487.

  • 51.

    Aleem A. Hypopigmentation of the skin due to imatinib mesylate in patients with chronic myeloid leukemia. Hematol Oncol Stem Cell Ther 2009;2:358361.

  • 52.

    Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261263.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Porkka K, Khoury HJ, Paquette RL et al.. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer 2010;116:377386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Montani D, Bergot E, Gunther S et al.. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:21282137.

  • 55.

    Orlandi EM, Rocca B, Pazzano AS, Ghio S. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res 2012;36:e46.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Serpa M, Sanabani SS, Bendit I et al.. Efficacy and tolerability after unusually low doses of dasatinib in chronic myeloid leukemia patients intolerant to standard-dose dasatinib therapy. Clin Med Insights Oncol 2010;4:155162.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Naqvi K, Jabbour E, Skinner J et al.. Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2018;124:27402747.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Bergeron A, Rea D, Levy V et al.. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 2007;176:814818.

  • 59.

    Aichberger KJ, Herndlhofer S, Schernthaner G-H et al.. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011;86:533539.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Tefferi A, Letendre L. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol 2011;86:610611.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Giles FJ, Mauro MJ, Hong F et al.. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013;27:13101315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Quintas-Cardama A, Kantarjian H, O'Brien S et al.. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004;100:25922597.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Quintas-Cardama A, De Souza Santos FP, Kantarjian H et al.. Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer 2009;115:39353943.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Santos FP, Alvarado Y, Kantarjian H et al.. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer 2011;117:982991.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Landstrom AP, Ketterling RP, Knudson RA, Tefferi A. Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia. Leuk Lymphoma 2006;47:20552061.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Muhlmann J, Thaler J, Hilbe W et al.. Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment. Genes Chromosomes Cancer 1998;21:90100.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Testoni N, Marzocchi G, Luatti S et al.. Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood 2009;114:49394943.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68.

    Lima L, Bernal-Mizrachi L, Saxe D et al.. Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer 2011;117:12451252.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Hughes T, Hochhaus A, Branford S et al.. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010;116:37583765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Akard LP, Cortes JE, Albitar M et al.. Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the rationale and insight for Gleevec high-dose therapy study. Arch Pathol Lab Med 2014;138:11861192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Branford S, Cross NCP, Hochhaus A et al.. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006;20:19251930.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009;22:355365.

  • 73.

    Branford S, Fletcher L, Cross NC et al.. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008;112:33303338.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74.

    Guerin A, Chen L, Dea K et al.. Association between regular molecular monitoring and tyrosine kinase inhibitor therapy adherence in chronic myelogenous leukemia in the chronic phase. Curr Med Res Opin 2014;30:13451352.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75.

    Hanfstein B, Muller MC, Hehlmann R et al.. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012;26:20962102.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Marin D, Ibrahim AR, Lucas C et al.. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 2012;30:232238.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Neelakantan P, Gerrard G, Lucas C et al.. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood 2013;121:27392742.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78.

    Nazha A, Kantarjian H, Jain P et al.. Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months. Haematologica 2013;98:16861688.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79.

    Branford S, Yeung DT, Parker WT et al.. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014;124:511518.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80.

    Branford S, Yeung DT, Ross DM et al.. The adverse effect of high sokal risk for first line imatinib treated patients is overcome by a rapid rate of BCR-ABL decline measured as early as 1 month of treatment [abstract]. Blood 2014;124:Abstract 816.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81.

    Hanfstein B, Shlyakhto V, Lauseker M et al.. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 2014;28:19881992.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82.

    Iriyama N, Fujisawa S, Yoshida C et al.. Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: results of the D-first study of Kanto CML study group. Am J Hematol 2015;90:282287.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83.

    Hochhaus A, O'Brien SG, Guilhot F et al.. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:10541061.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84.

    Jabbour E, Kantarjian H, O'Brien S et al.. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 2011;118:45414546.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85.

    Druker BJ, Guilhot F, O'Brien SG et al.. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

  • 86.

    Press RD, Galderisi C, Yang R et al.. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res 2007;13:61366143.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 87.

    de Lavallade H, Apperley JF, Khorashad JS et al.. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:33583363.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 88.

    Marin D, Milojkovic D, Olavarria E et al.. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008;112:44374444.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 89.

    Hehlmann R, Lauseker M, Jung-Munkwitz S et al.. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29:16341642.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 90.

    Jabbour E, Kantarjian HM, O'Brien S et al.. Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response? J Clin Oncol 2011;29:42604265.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91.

    Jabbour E, Kantarjian HM, Saglio G et al.. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494500.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92.

    Clark RE, Polydoros F, Apperley JF et al.. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol 2017;4:e310e316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93.

    Shah NP, Rousselot P, Schiffer C et al.. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol 2016;91:869874.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94.

    Giles FJ, le Coutre PD, Pinilla-Ibarz J et al.. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 2013;27:107112.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95.

    Cortes JE, Khoury HJ, Kantarjian HM et al.. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol 2016;91:12061214.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 96.

    Cortes JE, Kim DW, Pinilla-Ibarz J et al.. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood 2018.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 97.

    Kantarjian HM, Talpaz M, O'Brien S et al.. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473475.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98.

    Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood 2003;102:27022704.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99.

    Jabbour E, Kantarjian HM, Jones D et al.. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009;113:21542160.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100.

    Kantarjian HM, Larson RA, Guilhot F et al.. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009;115:551560.

  • 101.

    Yeung DT, Osborn MP, White DL et al.. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015;125:915923.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102.

    Cortes JE, De Souza CA, Ayala M et al.. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol 2016;3:e581e591.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 103.

    Cervantes F, López-Garrido P, Montero MI et al.. Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica 2010;95:13171324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 104.

    Kantarjian H, Cortes J. Considerations in the management of patients with Philadelphia chromosome-positive chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:15121516.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105.

    Dorer DJ, Knickerbocker RK, Baccarani M et al.. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res 2016;48:8491.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 106.

    Cortes J, Lipton JH, Rea D et al.. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012;120:25732580.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 107.

    Cortes J, Digumarti R, Parikh PM et al.. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013;88:350354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 108.

    Cortes JE, Nicolini FE, Wetzler M et al.. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk 2013;13:584591.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 109.

    Haouala A, Widmer N, Duchosal MA et al.. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117:e7587.

  • 110.

    Noens L, van Lierde M-A, De Bock R et al.. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:54015411.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111.

    Marin D, Bazeos A, Mahon F-X et al.. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:23812388.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 112.

    Ibrahim AR, Eliasson L, Apperley JF et al.. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:37333736.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 113.

    Wu EQ, Guerin A, Yu AP et al.. Retrospective real-world comparison of medical visits, costs, and adherence between nilotinib and dasatinib in chronic myeloid leukemia. Curr Med Res Opin 2010;26:28612869.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114.

    Yood MU, Oliveria SA, Cziraky M et al.. Adherence to treatment with second-line therapies, dasatinib and nilotinib, in patients with chronic myeloid leukemia. Curr Med Res Opin 2012;28:213219.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 115.

    Quintas-Cardama A, Cortes JE, Kantarjian H. Practical management of toxicities associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Clin Lymphoma Myeloma 2008;8 Suppl 3:S8288.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116.

    Cornelison M, Jabbour EJ, Welch MA. Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner. J Support Oncol 2012;10:1424.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 117.

    Cortes JE, Lipton JH, Miller CB et al.. Evaluating the impact of a switch to nilotinib on imatinib-related chronic low-grade adverse events in patients with CML-CP: the ENRICH study. Clin Lymphoma Myeloma Leuk 2016;16:286296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 118.

    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:37393745.

  • 119.

    Mahon FX, Hayette S, Lagarde V et al.. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res 2008;68:98099816.

  • 120.

    Hegedus C, Ozvegy-Laczka C, Apati A et al.. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 2009;158:11531164.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 121.

    Picard S, Titier K, Etienne G et al.. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:34963499.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122.

    Larson RA, Druker BJ, Guilhot F et al.. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:40224028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 123.

    Bouchet S, Titier K, Moore N et al.. Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory. Fundam Clin Pharmacol 2013;27:690697.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 124.

    White DL, Radich J, Soverini S et al.. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomised to high-dose imatinib achieve better responses, and lower failure rates, than those randomized to standard-dose. Haematologica 2012;97:907914.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 125.

    Giannoudis A, Davies A, Lucas CM et al.. Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood 2008;112:33483354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 126.

    Hiwase DK, Saunders V, Hewett D et al.. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008;14:38813888.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 127.

    Davies A, Jordanides NE, Giannoudis A et al.. Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia 2009;23:19992006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 128.

    White DL, Saunders VA, Dang P et al.. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006;108:697704.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 129.

    Branford S, Rudzki Z, Walsh S et al.. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102:276283.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 130.

    Soverini S, Martinelli G, Rosti G et al.. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005;23:41004109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 131.

    Nicolini FE, Corm S, Le QH et al.. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006;20:10611106.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 132.

    Soverini S, Colarossi S, Gnani A et al.. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006;12:73747379.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 133.

    Khorashad JS, de Lavallade H, Apperley JF et al.. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol 2008;26:48064813.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 134.

    Soverini S, Gnani A, Colarossi S et al.. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood 2009;114:21682171.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 135.

    Nicolini FE, Hayette S, Corm S et al.. Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. Haematologica 2007;92:12381241.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 136.

    Jabbour E, Kantarjian H, Jones D et al.. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008;112:5355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 137.

    Soverini S, Colarossi S, Gnani A et al.. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 2007;92:401404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 138.

    Jabbour E, Kantarjian HM, Jones D et al.. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 2008;112:48394842.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 139.

    Muller MC, Cortes JE, Kim D-W et al.. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009;114:49444953.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 140.

    Hughes T, Saglio G, Branford S et al.. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009;27:42044210.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 141.

    Deininger MW, Hodgson JG, Shah NP et al.. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood 2016;127:703712.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 142.

    Soverini S, Branford S, Nicolini FE et al.. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res 2014;38:1020.

  • 143.

    Garg RJ, Kantarjian H, O'Brien S et al.. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 2009;114:43614368.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 144.

    Branford S, Rudzki Z, Parkinson I et al.. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004;104:29262932.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 145.

    Wang L, Knight K, Lucas C, Clark R. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006;91:235239.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 146.

    Kantarjian HM, Shan J, Jones D et al.. Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol 2009;27:36593663.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 147.

    Marin D, Khorashad JS, Foroni L et al.. Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? Br J Haematol 2009;145:373375.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 148.

    Press RD, Willis SG, Laudadio J et al.. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood 2009;114:25982605.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 149.

    Mahon FX, Rea D, Guilhot J et al.. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010:10291035.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 150.

    Etienne G, Guilhot J, Rea D et al.. Long-term follow-up of the french stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol 2017;35:298305.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 151.

    Ross DM, Branford S, Seymour JF et al.. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515522.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 152.

    Thielen N, van der Holt B, Cornelissen JJ et al.. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013;49:32423246.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 153.

    Rousselot P, Charbonnier A, Cony-Makhoul P et al.. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol 2014;32:424430.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 154.

    Mori S, Vagge E, le Coutre P et al.. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol 2015;90:910914.

  • 155.

    Lee SE, Choi SY, Song HY et al.. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica 2016;101:717723.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 156.

    Saussele S, Richter J, Guilhot J et al.. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol 2018;19:747757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 157.

    Rea D, Nicolini FE, Tulliez M et al.. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood 2017;129:846854.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 158.

    Ross DM, Masszi T, Gomez Casares MT et al.. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol 2018;144:945954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 159.

    Mahon FX, Boquimpani C, Kim DW et al.. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, pPhase 2, open-label study. Ann Intern Med 2018;168:461470.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 160.

    Okada M, Imagawa J, Tanaka H et al.. Final 3-year results of the dasatinib discontinuation trial in patients with chronic myeloid leukemia who received dasatinib as a second-line treatment. Clin Lymphoma Myeloma Leuk 2018;18:353360 e351.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 161.

    Legros L, Nicolini FE, Etienne G et al.. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer 2017;123:44034410.

  • 162.

    Ilander M, Olsson-Stromberg U, Schlums H et al.. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia 2017;31:11081116.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand
  • NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

    Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

    Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2019

    Version 1.2019, 08-01-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • Chronic Myeloid Leukemia, Version 1.2019

    Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

  • 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:730.

  • 2.

    Faderl S, Talpaz M, Estrov Z et al.. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164172.

  • 3.

    Verma D, Kantarjian HM, Jones D et al.. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood 2009;114:22322235.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:13301340.

  • 5.

    Radich JP, Dai H, Mao M et al.. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:27942799.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Jamieson CHM, Ailles LE, Dylla SJ et al.. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657667.

  • 7.

    Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 1993;11 Suppl 1:1115.

  • 8.

    Cortes JE, Talpaz M, Giles F et al.. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101:37943800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    O'Dwyer ME, Mauro MJ, Blasdel C et al.. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004;103:451455.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Wang W, Cortes JE, Lin P et al.. Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. Blood 2015;126:16991706.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wang W, Tang G, Cortes JE et al.. Chromosomal rearrangement involving 11q23 locus in chronic myelogenous leukemia: a rare phenomenon frequently associated with disease progression and poor prognosis. J Hematol Oncol 2015;8:32.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Wang W, Cortes JE, Tang G et al.. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood 2016;127:27422750.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Verma D, Kantarjian H, Shan J et al.. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 2010;116:26732681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Fabarius A, Kalmanti L, Dietz CT et al.. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol 2015;94:20152024.

  • 15.

    Fabarius A, Leitner A, Hochhaus A et al.. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011;118:67606768.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Alhuraiji A, Kantarjian H, Boddu P et al.. Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol 2018;93:8490.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Bumm T, Muller C, Al-Ali H-K et al.. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:19411949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Feldman E, Najfeld V, Schuster M et al.. The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol 2003;31:702707.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Medina J, Kantarjian H, Talpaz M et al.. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:19051911.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Terre C, Eclache V, Rousselot P et al.. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia 2004;18:13401346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Deininger MW, Cortes J, Paquette R et al.. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007;110:15091519.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Jabbour E, Kantarjian HM, Abruzzo LV et al.. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2007;110:29912995.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Issa GC, Kantarjian HM, Gonzalez GN et al.. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood 2017;130:2084.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Karimata K, Masuko M, Ushiki T et al.. Myelodysplastic syndrome with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment for chronic myeloid leukemia. Intern Med 2011;50:481485.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Navarro JT, Feliu E, Grau J et al.. Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol 2007;82:849851.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Douet-Guilbert N, Morel F, Le Charpentier T et al.. Interphase FISH for follow-up of Philadelphia chromosome-positive chronic myeloid leukemia treatment. Anticancer Res 2004;24:25352539.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Seong DC, Kantarjian HM, Ro JY et al.. Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 1995;86:23432349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Dewald GW, Wyatt WA, Juneau AL et al.. Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood 1998;91:33573365.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Kantarjian HM, Talpaz M, Cortes J et al.. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003;9:160166.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Hughes T, Deininger M, Hochhaus A et al.. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:2837.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Biernaux C, Loos M, Sels A et al.. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995;86:31183122.

  • 32.

    Bose S, Deininger M, Gora-Tybor J et al.. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 1998;92:33623367.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Sokal J, Cox E, Baccarani M et al.. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789799.

  • 34.

    Hasford J, Pfirrmann M, Hehlmann R et al.. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850858.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Hasford J, Baccarani M, Hoffmann V et al.. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118:686692.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Marin D, Ibrahim AR, Goldman JM. European Treatment and Outcome Study (EUTOS) score for chronic myeloid leukemia still requires more confirmation. J Clin Oncol 2011;29:39443945.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Jabbour E, Cortes J, Nazha A et al.. 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;119:45244526.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Yamamoto E, Fujisawa S, Hagihara M et al.. European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients. Cancer Sci 2014;105:105109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Hochhaus A, Larson RA, Guilhot F et al.. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 2017;376:917927.

  • 40.

    Cortes JE, Saglio G, Kantarjian HM et al.. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:23332340.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Hochhaus A, Saglio G, Hughes TP et al.. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:10441054.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cortes JE, Gambacorti-Passerini C, Deininger MW et al.. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol 2018;36:231237.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Baccarani M, Druker BJ, Branford S et al.. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol 2014;99:616624.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Deininger MW, Kopecky KJ, Radich JP et al.. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 2014;164:223232.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Hehlmann R, Lauseker M, Saussele S et al.. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia 2017;31:23982406.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Preudhomme C, Guilhot J, Nicolini FE et al.. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:25112521.

  • 47.

    Efficace F, Baccarani M, Breccia M et al.. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 2013;27:15111519.