NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia
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 myelogenous leukemia (CML) accounts for 15% of adult leukemias. The median age of disease onset is 67 years; however, SEER statistics show that CML occurs in all age groups. In 2010, an estimated 4870 cases were diagnosed in the United States, and 440 patients died of the disease.1
CML is a hematopoietic stem cell disease, characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome (Ph). This translocation t(9;22) results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 at band q11 and the Abelson murine leukemia (ABL) gene located on chromosome 9 at band q34.2 The product of the fusion gene (BCR-ABL) is believed to play a central role in the initial development of CML.
The BCR-ABL gene encodes a protein (p210BCR-ABL), with deregulated tyrosine kinase activity. This protein contains NH2-terminal domains of BCR and the COOH-terminal domains of ABL. Another fusion protein, p190, may be produced, but this is usually in the setting of Ph-positive acute lymphocytic leukemia (ALL). The oncogenic potential of the BCR-ABL fusion proteins has been validated by their ability to transform hematopoietic progenitor cells in vitro and in vivo.
The mechanisms through which p210BCR-ABL promotes the transition from a benign to a malignant state are not entirely understood. However, attachment of the BCR sequences to ABL results in 3 critical functional changes: 1) the ABL protein becomes constitutively active as a protein tyrosine kinase enzyme, 2) the DNA protein binding activity of ABL is attenuated, and 3) the binding of ABL to cytoskeletal actin microfilaments is enhanced. These effects increase proliferation, affect differentiation, and block apoptosis.
CML occurs in 3 different phases (chronic, accelerated, and blast) and is usually diagnosed in the chronic phase. However, gene expression profiling has shown a close correlation of gene expressions between the accelerated and blast phase. Most of the genetic changes in progression occur during the transition from chronic to accelerated phase.3 Untreated chronic phase CML (CP-CML) will eventually progress to advanced-phase disease in 3 to 5 years.4 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 evolution to blast phase CML.5
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 2:2012
Version 2.2012, 07-22-11 ©2012 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 10, 1; 10.6004/jnccn.2012.0009
Sokal6 and Hasford7 are the 2 prognostic scoring systems available for risk stratification of patients with CML. The Sokal score was developed in the chemotherapy era and is based on patient age, spleen size, platelet count, and the percentage of blasts in the peripheral blood.6 The Hasford model is applicable to patients treated with interferon. It includes eosinophils and basophils in the peripheral blood in addition to the same clinical variables used in the Sokal model.7 The scoring systems stratify patients into 3 risk groups: low, intermediate, and high (see Table 1, Calculation of Risk Score, available online, in these guidelines, at www.NCCN.org). The Sokal scoring system has been used to stratify patients according to risk in all of the imatinib clinical trials.
These guidelines discuss the clinical management of chronic phase, disease progression to accelerated or blast phase, and monitoring response to treatment.
Tyrosine Kinase Inhibitor Therapy for CML
Imatinib Mesylate
Imatinib mesylate is a selective inhibitor of the BCR-ABL tyrosine kinase.8,9 Initial trials with imatinib showed a marked effect as a second-line therapy in patients in chronic phase for whom interferon therapy failed or those with more advanced-stage disease (accelerated phase or blast crisis).10 At 5-year followup, complete cytogenetic response (CCyR) was seen in 41% of patients, and 44% of patients remain on imatinib. Estimated rates of freedom from progression (FFP) to accelerated or blast phase and overall survival at 6 years were 61% and 76%, respectively.11
Newly diagnosed patients were evaluated in the IRIS (International Randomized Study of Interferon and ST1571) trial. In this trial, 1106 patients were randomized to receive initial therapy with either 400 mg of daily imatinib or interferon-alpha plus low-dose cytarabine.12 Crossover was allowed for treatment failure or intolerance. With a median follow-up of 19 months, the major cytogenetic response (MCyR) rate at 18 months was 87.1% in the imatinib group versus 34.7% in the control group. The estimated rate of CCyR was 76.2% with imatinib and 14.5% with interferon (P < .001). The estimated rate of FFP to more advanced-stage disease was 96.7% in the imatinib arm and 91.5% in the interferon-based arm (P < .001). In addition to its significantly greater efficacy, imatinib was also much better tolerated than the combination of interferon plus cytarabine.
In May 2001, the FDA first approved imatinib mesylate for the advanced stages of CML. In December 2002, based on the results of the IRIS study, the FDA approved imatinib for the first-line treatment of patients with CML.
Long-term follow-up data of the IRIS trial are now available.13,14 With a median follow-up of 60 months, estimated cumulative rates of CCyR among patients receiving imatinib were 69% at 12 months and 87% at 60 months. Only 7% of patients had progressed to accelerated or blast phase CML. Overall survival was 89% at 60 months for patients who received imatinib as initial treatment.13 Estimated 8-year event-free survival, FFP to accelerated or blast phase, and overall survival rates were 81%, 92%, and 85%, respectively.14 Major molecular response (MMR) increased from 24% at 6 months and 39% at 12 months to the best-observed MMR rate of 86% with 8-year followup. None of the patients with documented MMR at 12 months progressed to accelerated phase blast crisis. These results show that continuous treatment of CP-CML with imatinib induces durable responses in a large proportion of the patients with a decreasing rate of relapse. These data confirm the high durable response rates with imatinib in a large proportion of patients. However, because of the high rate of crossover (90%) from interferon-alpha to imatinib mesylate within a year of study, survival benefit for imatinib mesylate versus interferon could not be shown in the IRIS trial. In historical comparisons, survival benefit was significantly better for imatinib than with interferon.15,16 Recently, Guilhot et al.17 reported the safety and efficacy of imatinib in 359 patients who crossed over from interferon-alpha plus cytarabine to imatinib in the IRIS study. After a median follow-up of 54 months on imatinib, 93% achieved a complete hematologic response (CHR); MCyR and CCyR were observed in 86% and 81% of patients, respectively. Estimated rates of FFP to accelerated or blast phase and overall survival were 91% and 89%, respectively, at 48 months after starting imatinib.
Imatinib mesylate is generally well tolerated. Frequently reported grade 3 or 4 toxicities include neutropenia and thrombocytopenia. Most frequently reported adverse events include gastrointestinal disturbances, edema, rash, and musculoskeletal complaints, but none of these led to discontinuation of treatment.18 Hypophosphatemia, with associated changes in bone and mineral metabolism, has been noted in a small group of patients.19 Hematologic and nonhematologic toxicities caused by imatinib, and specific panel-recommended interventions, are summarized in the algorithm. Erythropoietin and filgrastim has been shown to be effective in patients who develop imatinib-induced anemia and neutropenia, respectively.20,21 In a recent report, use of erythropoietin-stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate in the cohort of patients with CP-CML treated at MD Anderson Cancer Center.22 Recent guidelines from the Centers for Medicare & Medicaid Services and the FDA do not support the use of erythropoietic stimulating agents in myeloid malignancies. See Management of Imatinib Toxicity on page 73.
Cardiotoxicity
In a recent trial, long-term imatinib treatment was associated with congestive heart failure (CHF) and cardiotoxicity.23 However, this seems to be rare, as shown by the recent analysis of 1276 patients treated with imatinib at MD Anderson Cancer Center.24 After a median follow-up of 47 months, 22 (1.7%) patients were found to have CHF during imatinib therapy. Of these patients, 13 had received prior treatment with cardiotoxic drugs. The authors concluded that CHF is uncommon among patients receiving imatinib and its incidence rates are similar to those that occur in the general population. Patients with previous cardiac history should be monitored carefully. Aggressive medical therapy is recommended for symptomatic patients.
High-Dose Imatinib
Most patients retain variable levels of residual molecular disease at the 400-mg dose of imatinib. Several studies have evaluated the efficacy of high-dose imatinib in patients with newly diagnosed CML.25-27 Imatinib dosed at 600 or 800 mg daily was well tolerated and associated with superior cytogenetic and molecular response rates.25,26
In a phase II multicenter study (Rationale and Insight for Gleevec High-Dose Therapy [RIGHT]), newly diagnosed patients (n = 115; 70% Sokal low risk) treated with 400 mg of imatinib twice daily experienced rapid and deep responses.27 CHR at 6, 12, and 18 months was achieved and maintained in 93%, 94%, and 93% of evaluable patients, respectively. The rates of MCyR at 12 and 18 months were 90% and 96%, respectively, and the corresponding CCyR rates were 85% and 83%, respectively. MMR rates were 48% and 54% at 6 and 12 months, respectively. The response rates were also higher in this trial compared with historic controls who received 400 mg daily in the IRIS trial. At 12 months, MMR was 54% for patients in the RIGHT trial compared with an estimated 39% for the historical control group. At 18 months, MCyR and CCyR rates were 90% and 85%, respectively, in the RIGHT trial compared with an estimated 85% and 69%, respectively, in the historical control group.
The investigators of the TIDEL (Therapeutic Intensification in De Novo Leukemia) trial also reported superior responses (MMR at 12 and 24 months were 55% and 77%, respectively) in patients receiving 600 mg of imatinib as the initial dose compared with those receiving less than 600 mg (MMR at 12 and 24 months were 32% and 53%, respectively).25
The efficacy of high-dose (800 mg) imatinib as front-line therapy in patients with intermediate and high Sokal risk with CP-CML has been evaluated by the GIMEMA CML working party and the European LeukemiaNet study group, respectively.28,29 The results of the phase II trial by the GIMEMA CML working party indicated that high-dose imatinib is effective in inducing rapid cytogenetic and molecular responses in patients with intermediate Sokal risk.28 The response rates at 12 months were better than those documented in the IRIS study for intermediate-risk patients treated with 400 mg of imatinib. The European LeukemiaNet Study, which randomized patients with high Sokal risk to receive 800 mg or 400 mg of imatinib, did not show a significant benefit for high-dose imatinib.29 The CCyR rate at 1 year was 64% and 58% for high- and standarddose imatinib, respectively. No differences were detectable in CCyR rates at 3 and 6 months or in the molecular response rates at any time.
The TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) study is an open-label phase III randomized trial comparing the efficacy of high-dose imatinib and standard-dose imatinib in patients with newly diagnosed CP-CML.30 This trial randomized 476 patients to receive either high-dose imatinib (800 mg; 400 mg twice daily) or standard-dose imatinib (400 mg once daily). High-dose imatinib was well tolerated in most patients and was also associated with more rapid responses than the standard dose. However, MMR and CCyR rates at 12 months were comparable between arms (MMR, 46% vs. 40%, respectively; CCyR, 70% vs. 66%, respectively). In patients with high Sokal risk scores, MMR rates at 12 months were 51% for high-dose imatinib compared with 31% for standard-dose. The MMR rate also correlated with average dose intensity. At 12 months, MMR was observed in 83 (62%) of 134 patients with an average dose intensity of 600 to 799 mg/d, and it was observed in 26 (38%) of 69 patients with an average dose intensity of 400 to 599 mg/d.
The German CML IV study also reported significantly faster response rates with imatinib, 800 mg, compared with imatinib, 400 mg, with or without interferon.31 The incidence of MMR at 12 months was also significantly higher with imatinib, 800 mg/d (59% vs. 44% and 46% for imatinib, 800 mg; imatinib, 400 mg; and imatinib, 400 mg, with interferon, respectively). More rapid achievement of MMR with imatinib, 800 mg, was observed in low- and intermediate-risk patients, but not in high-risk patients. At 3 years, the over-all and progression-free survival rates (95% and 94%, respectively) for all patients were not different between treatment arms.
In newly diagnosed patients, high-dose imatinib induces higher and faster CCyR and MMR than standard-dose imatinib early on, but no difference in response rates was seen between the arms at 12 months. Imatinib, 800 mg, has not been shown to have lower rates of disease progression than standard-dose imatinib in any of the studies, despite improved early responses. High-dose imatinib is associated with higher rates of dose interruption, reduction, and discontinuation in a substantial number of patients because of grade 3 or 4 adverse events. However, data suggest that patients who can actually tolerate the higher dose of imatinib have better response rates than those receiving standard-dose imatinib. High-dose imatinib currently has only a limited role in first-line therapy.
Dasatinib
Dasatinib is a potent, orally available ABL kinase inhibitor, similar to imatinib but with the added advantage that it can bind to both the active and the inactive conformation of the ABL kinase domain. As a result, dasatinib is active against nearly all imatinib-resistant BCR-ABL mutations in vitro.32
In a phase I dose-escalation study, dasatinib induced hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who could not tolerate or were resistant to imatinib.33 This result led to the initiation of several phase II studies (SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib [START]) of dasatinib in patients with imatinib-resistant or imatinib-intolerant Ph-positive leukemias. Resistance to imatinib was defined as failure to experience a CHR within 3 to 6 months, absence of an MCyR by month 12, or progression of disease after prior response. Dasatinib was administered at 70 mg twice daily on a continuous basis. Interruption of treatment and dose modifications were allowed for the management of disease progression or toxicity after one cycle of treatment.
In the START-C trial, patients with imatinib-resistant or imatinib-intolerant CP-CML were treated with dasatinib (70 mg twice daily).34 Initial results of this study in 186 patients showed CHR in 90% of patients. Dasatinib also induced MCyR in 52% of the patients, with only 2% of these patients subsequently experiencing progression or dying. After a followup of 8 months, the progression-free survival rate was 92%. Extended 2-year follow-up data confirmed that dasatinib induces durable cytogenetic responses in patients with CP-CML.35 After a follow-up of 24 months, CHR, MCyR, CCyR, and MMR were observed in 91%, 62%, 53%, and 47% of patients, respectively. Overall and progression-free survival rates at 24 months were 94% and 80%, respectively.35
Follow-up data reported by Baccarani et al.36 confirmed the durability of cytogenetic responses with dasatinib. At 2 years of follow-up among patients with imatinib-resistant CML, median time to MCyR and CCyR was 2.9 and 5.5 months, respectively. Among imatinib-intolerant patients, median times to MCyR and CCyR were both 2.8 months. Most patients with imatinib-resistant and imatinib-intolerant CML had maintained their responses at 24 months (MCyR, 84% and 97%, respectively; CCyR, 86% and 98%, respectively).36
The START-A trial evaluated the safety and efficacy of dasatinib (70 mg twice daily) in patients with imatinib-resistant or imatinib-intolerant accelerated phase CML (AP-CML).37 At 8-month followup (for the first 107 patients enrolled in the study), major hematologic response (MaHR) was achieved in 64% of patients and MCyR was achieved in 33% of the treated population, and 76% of patients remained progression-free. Follow-up data from the full patient cohort of 174 patients have confirmed the efficacy and safety of dasatinib in patients with imatinib-resistant or imatinib-intolerant AP-CML.38 The 12-month progression-free and overall survival rates were 66% and 82%, respectively.
The efficacy of dasatinib in patients with imatinib-resistant or imatinib-intolerant CML in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) was evaluated in the START-B and START-L trials, respectively.39 In patients with MBC-CML, 32% had achieved an MaHR at 6-month followup, which increased to 34% at 8-month follow-up, and this rate was maintained at 12-month followup.40 MCyR was achieved in 31% of patients. In the LBC-CML group, 31% achieved an MaHR at 6-month follow-up, and this rate increased to 35% at 12-month follow-up.40 After a minimum follow-up of 12 months, MCyR was attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and CCyR was attained in 26% and 46% of patients, respectively. Median progression-free and overall survivals for patients in MBC were 6.7 and 11.8 months, respectively. In patients with LBC, the corresponding survivals were 3.0 and 5.3 months, respectively.40
Dasatinib induced cytogenetic and hematologic responses in a significant number of patients with imatinib-resistant CML (all phases), and was also well tolerated in all of these studies. Dasatinib was associated with significant but reversible inhibition of platelet aggregation that may contribute to bleeding in some patients receiving the drug.41 Nonhematologic adverse events were mild to moderate, and cytopenias, although more common, were manageable with dose modification. See Management of Dasatinib Toxicity on page 75.
In June 2006, based on the favorable results of the above-mentioned 5 single-arm phase II studies, the FDA approved dasatinib (70 mg twice daily) for patients with CML who are resistant or intolerant to imatinib.
Pleural effusion can be an adverse effect of dasatinib. Recently, Quintas-Cardama et al.42 from MD Anderson Cancer Center analyzed patients with CML treated with varying doses of dasatinib in phase I and II studies. Pleural effusion occurred in 29% of patients with CP-CML, 50% of patients with AP-CML, and 33% of patients with blast phase CML (BP-CML). Pleural effusion led to dose interruption in 83% of patients, and dose reduction was necessary in 71% of patients with pleural effusion. A history of cardiac disease, hypertension, and use of twice-daily dosing of dasatinib at 70 mg are associated with increased risk for development of pleural effusion. Close monitoring and timely intervention are necessary for patients who are at risk.
Lymphocytosis from the clonal expansion of natural killer (NK)/T cells has been reported during dasatinib treatment in patients with all stages of CML resistant or intolerant to imatinib, and has been associated with increased incidence of pleural effusion.43 Cytogenetic response rates to dasatinib were higher in this group of patients.44,45 Similar effects were also observed among patients treated with dasatinib as first-line therapy in the Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients (DASISION) study.46 Further studies are needed to confirm these preliminary findings.
In a recent dose-optimization randomized study (CA180-034), dasatinib dosed at 100 mg once daily was equally as effective as 70 mg twice daily in patients (n = 167) with CP-CML resistant or intolerant to imatinib.47,48 At 24 months, patients who received dasatinib at 100 mg once daily and those who received dasatinib at 70 mg twice daily had comparable rates of CCyR (50% vs. 54%) and MCyR (63% vs. 61%), progression-free survival (80% vs. 76%), and overall survival (91% vs. 88%).48 The incidences of grade 3 or 4 pleural effusion (2% vs. 5%) and grade 3 or 4 thrombocytopenia (23% vs. 38%) were also lower with the 100-mg daily dose, and fewer patients required dose interruption (62% vs. 77%), dose reduction (39% vs. 62%), and toxicity-related discontinuation (16% vs. 23%). Based on the results of this study, the FDA approved 100 mg once daily as the starting dose. Five-year follow-up data of dasatinib at 100 mg once daily confirmed the long-term safety and durability of cytogenetic responses in responding patients with CP-CML resistant or intolerant to imatinib.49 At 60 months, the rates of MMR, progression-free survival, and overall survival were 44%, 57%, and 78%, respectively. The rate of progression to accelerated or blast phase was 5% (n = 8). Patients who experienced CCyR or MMR at 6 or 12 months had improved progression-free survival at 60 months compared with those with a partial or no cytogenetic response.
Kantarjian et al.50 recently reported that once-daily dosing of dasatinib at 140 mg has similar efficacy to twice-daily dosing at 70 mg, with an improved safety profile in patients with AP-CML. Recently, 2-year follow-up data from a phase III trial showed that dasatinib at 140 mg once daily shows equivalent efficacy and improved safety as 70 mg twice daily in patients with BP-CML.51
The recommended starting dose of dasatinib is 100 mg once daily for patients with CP-CML resistant or intolerant to imatinib and 140 mg once daily for patients with disease progression to AP-CML or BP-CML.
The efficacy and safety of dasatinib as first-line therapy in previously untreated patients with CP-CML was first confirmed in a phase II trial.52 Fifty patients with newly diagnosed early CP-CML were randomly assigned to dasatinib at 100 mg once daily or 50 mg twice daily as initial therapy. With a median follow-up of 24 months, 98% of evaluable patients had achieved CCyR and 82% achieved MMR. In historical comparison, the CCyR rates at 3, 6, and 12 months were comparable to those achieved with high-dose imatinib, and better than those achieved with standard-dose imatinib.52 No significant differences were seen in response rate and toxicity between the arms, and the median dose at 12 months was 100 mg.
The efficacy and safety of dasatinib (100 mg once daily) and imatinib (400 mg once daily) among patients with newly diagnosed CP-CML were compared in the multinational randomized DASISION study, in which 519 patients with newly diagnosed CP-CML were randomized to receive dasatinib (100 mg once daily; 259 patients) or imatinib (400 mg once daily; 260 patients).53 After a minimum follow-up of 12 months, the rates of confirmed CCyR (77% vs. 66%, respectively) and of MMR (46% vs. 28%, respectively) were higher and responses were achieved in a shorter time with dasatinib. The rates of CCyR at 3, 6, and 9 months after initiation of therapy were 54%, 73%, and 78%, respectively, for dasatinib, compared with 31%, 59%, and 67%, respectively, for imatinib. The rates of MMR at 3, 6, and 9 months after dasatinib treatment were 8%, 27%, and 39%, respectively, compared with 0.4%, 8%, and 18%, respectively, for imatinib. Although a trend was seen favoring dasatinib, progression to the accelerated or blast phase was not statistically different between the groups, with 5 patients on dasatinib (2%) and 9 patients on imatinib (3.5%) meeting the definition of progression. The safety profiles were similar in both treatment arms.
In October 2010, the FDA approved dasatinib (100 mg once daily) for the treatment of adult patients with newly diagnosed Ph-positive CP-CML. Twenty-four-month follow-up data confirmed that dasatinib induces higher CCyR and higher and faster MMR over imatinib in patients with newly diagnosed CP-CML.54 At 24-months, CCyR rates were 86% and 82%, respectively, for dasatinib and imatinib. MMR rates were significantly higher for dasatinib compared with imatinib (64% and 46%, respectively; P < .0001). Fewer patients experienced transformation to accelerated or blast phase (6 patients on dasatinib [2%] and 13 patients on imatinib [5%]). Longer-term follow-up is ongoing.
In the Intergroup phase II randomized trial (S0325), dasatinib at 100 mg induced deeper molecular responses (3-log reductions in BCR-ABL transcript level) at 12 months (59%) than imatinib at 400 mg (43%) in patients with newly diagnosed CP-CML.55 Follow-up is ongoing to evaluate whether the short-term deeper molecular response will translate into improved long-term outcomes.
Nilotinib
Nilotinib is a new, orally available, highly selective inhibitor of BCR-ABL tyrosine kinase that is more potent than imatinib (20-50 times more potent in imatinib-resistant cell lines and 3-7 times more potent in imatinib-sensitive cell lines). In a phase I study, nilotinib was found to be active in imatinib-resistant CML, with a favorable safety profile.56
After this study, a phase II open-label trial evaluated the safety and efficacy of nilotinib in patients with imatinib-resistant or imatinib-intolerant CP-CML and AP-CML. Nilotinib was administered at 400 mg twice daily. The efficacy end point for CP-CML was MCyR, and the end point for AP-CML was MaHR. The results were reported recently from an interim analysis conducted at 6-month follow-up on 280 patients with CP-CML.57 MCyR was observed in 48% of patients and CCyR was observed in 31% of patients. Two-year follow-up results from this study confirmed that these responses are durable, with no change in safety profile.58 The overall MMR, MCyR, and CCyR rates were 28%, 59%, and 44% of patients, respectively, and the responses were durable, with 84% maintaining CCyR and 77% maintaining MCyR at 24 months.58 The estimated overall progression-free and overall survival rates at 24 months were 64% and 87%, respectively. MCyR, MMR, and progression-free survival rates were higher among patients with CHR than those without CHR at study entry (73%, 38%, and 77%, respectively, vs. 52%, 22%, and 56%, respectively).
In patients with AP-CML, hematologic response was observed in 47% of patients and MCyR in 29% of patients.59 The overall survival rate among the 119 patients after 12 months of follow-up was 79%. Non-hematologic adverse events were mostly mild to moderate. Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively. Long-term follow-up results confirmed that nilotinib induces rapid and durable responses, with a favorable risk/benefit profile in patients with AP-CML intolerant or resistant to prior imatinib.60 Median duration of treatment was 272 days. Confirmed hematologic response was observed in 56% of patients, and 31% had CHR (30% of patients with imatinib-resistant CML and 37% of patients with imatinib-intolerant CML achieved CHR). Median time to first hematologic response was 1 month and was durable at 24 months in 54% of patients. MCyR and CCyR were achieved in 32% and 20% of patients, respectively. Cytogenetic responses were also durable, with 70% of patients maintaining MCyR at 24 months and 83% of patients maintaining CCyR at 12 months. Estimated overall survival at 24 months was 67%.
Nilotinib was rarely associated with fluid retention, edema, or muscle cramps. Neutropenia and thrombocytopenia (grade 3 or 4) were reported only in 29% of patients with CP-CML. Grade 3 or 4 elevations in lipase, bilirubin, hypophosphatemia, and hyperglycemia were observed in 17%, 8%, 16%, and 12% of patients with CP-CML, respectively. However, these abnormalities were transient and clinically asymptomatic. See Management of Nilotinib Toxicity on page 74.
QTc prolongation was a nonhematologic adverse reaction associated with nilotinib, which could be managed with dose reduction. Nilotinib labeling contains a black box warning regarding the risk of QT prolongation, and sudden cardiac death has been reported in patients receiving nilotinib. Electrolyte abnormalities should be corrected before treatment with nilotinib is initiated, and should be monitored periodically. Drugs that prolong QT interval should be avoided. Electrocardiograms should be obtained at baseline, periodically thereafter, and after any dose adjustment to monitor QTc. See Important Considerations With Nilotinib on page 74.
In October 2007, the FDA approved nilotinib (400 mg twice daily) for the treatment of adult patients with chronic phase and accelerated phase Ph-positive CML resistant to or intolerant of prior therapy with imatinib.
Nilotinib has also shown activity in a group of patients with BP-CML. In a phase II study of 136 patients (82% imatinib-resistant and 18% imatinib-intolerant), nilotinib induced CHR in 13% of patients. MCyR was seen in 38% of patients with MBC and 52% of patients with LBC.61 CCyR was seen in 30% of patients with MBC and 32% with LBC, respectively. The overall survival rates at 12 and 24 months were 42% and 27%, respectively. However, the responses were not durable. The duration of MCyR was 11 months for patients with MBC and 3 months for those with LBC. Nilotinib is not yet approved by the FDA for the treatment of patients with BP-CML.
The efficacy and safety of nilotinib as first-line therapy in patients with early CP-CML were initially evaluated in 2 separate phase II studies.62,63 Nilotinib at a dose of 400 mg twice daily induced high rates of CCyR and MMR, with most patients reaching these responses early during their therapy.
In a phase III, randomized, open-label, multi-center trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients [EN-ESTnd]), the efficacy and safety of nilotinib (300 mg twice daily; n = 282, or 400 mg twice daily; n = 281) were compared with those of imatinib (400 mg once daily; n = 283) in patients with newly diagnosed CP-CML.64 At 12 months, the rates of MMR (the primary endpoint) were 44% for the 300-mg dose and 43% for the 400-mg dose versus 22% for imatinib. The rates of CCyR by 12 months (80% for the 300-mg dose and 78% for the 400-mg dose vs. 65% for imatinib) were also higher for nilotinib. Patients receiving nilotinib at either of the 2 dose levels had a significant improvement in time to progression to accelerated phase or blast crisis, compared with those receiving imatinib. The rate of progression to accelerated or blast phase was 4% with imatinib and less than 1% with nilotinib (P = .01 for the 300 mg, and P = .004 for the 400 mg). Superior rates of CCyR and MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups. Among patients with a high Sokal risk receiving 300 mg of nilotinib, 400 mg of nilotinib, and imatinib, CCyR rates were 74%, 63%, and 49%, respectively, and MMR rates were 41%, 32%, and 17%, respectively, at 12 months. Among the 3 study groups, the 300-mg dose of nilotinib had the lowest rate of discontinuation because of adverse events or laboratory abnormalities. Additional follow-up data will provide more information about the potential long-term effects of nilotinib as first-line therapy. Based on the results of this study, in June 2010 the FDA approved nilotinib (300 mg twice daily) for the treatment of adult patients with newly diagnosed Ph-positive CP-CML. Twenty-four-month followup data confirmed that nilotinib induces superior MMR and complete molecular response (CMR), and significantly fewer progressions to accelerated or blast phase.65 At 24 months, MMR rates were 71% and 67% for nilotinib at 300 and 400 mg twice daily, respectively (P ≤ .0001), compared with 44% for imatinib at 400 mg once daily. Among patients with high Sokal risk, the MMR rates at 24 months were 65%, 56%, and 32% for patients receiving 300 mg of nilotinib, 400 mg of nilotinib, and imatinib, respectively. The rates of progression to accelerated or blast phase were 0.7% (2 patients; P = .0059) with 300 mg of nilotinib, 1.1% (3 patients; P = .016) with 400 mg of nilotinib, and 4% (12 patients) with imatinib. The estimated 24-month progression-free survival rates were 98%, 97.7%, and 95%, respectively, for the 3 treatment groups.
Tyrosine Kinase Inhibitor Therapy and Conception
Imatinib has been shown to be teratogenic and embryotoxic in animal studies. Some reports indicate that patients who receive imatinib at conception may have normal pregnancies.66-73 Pye et al.72 recently reported the outcome of pregnancies in 180 women exposed to imatinib during pregnancy. Of the pregnancies with known outcome, 50% were normal and 10% had fetal abnormalities; 18 pregnancies ended in spontaneous abortion. In another report by Ault et al.,68 of the 10 women who discontinued imatinib because of pregnancy, 6 had an increase in Ph-positive metaphases. Only 3 women had CCyR at 18 months after resuming therapy. Imatinib is not known to be a genotoxic. However, spermatogenesis was impaired in animal studies. In the clinical experience, male fertility seems to be preserved in patients receiving imatinib.72,73 However, there are isolated reports of oligospermia in men receiving imatinib therapy.74
Dasatinib and nilotinib are known to cause embryonic or fetal toxicities in animals. There have been isolated reports in literature regarding the outcome of pregnancy in patients receiving dasatinib75-77 or nilotinib.78 In a report from Cortes et al.75 involving 16 patients, among the 8 patients who became pregnant while on dasatinib, induced or spontaneous abortion was reported in 3 and 2, respectively, and the outcome and pregnancy course in the other 3 patients were normal.75 Among the 8 male patients treated with dasatinib whose partners became pregnant during treatment, normal pregnancy was reported in 7, with the outcome unknown in 1.75
Sufficient evidence is not currently available to favor the continuation of imatinib, dasatinib, or nilotinib during pregnancy. Potential benefit of tyrosine kinase inhibitor (TKI) therapy for the mother or its potential risk to the fetus must be carefully evaluated on an individual basis before either agent is administered to a pregnant woman. Men desiring conception should consider sperm cryopreservation before initiation of TKI therapy.
Drug Interactions
Imatinib: Imatinib is predominantly metabolized in the liver by the cytochrome P450 enzymes, CYP3A4 or CYP3A5.79 Drugs that induce CYP3A4/5 enzyme levels may decrease therapeutic levels of imatinib. CY3A4/5-inducing drugs, such as anticonvulsants and steroids, should be used with caution in patients receiving imatinib, and appropriate alternatives should be explored to maximize treatment outcome. Conversely, drugs that inhibit CYP3A4 enzyme activity and those that are metabolized by the CY3A4/5 enzyme might result in increased plasma levels of imatinib. Imatinib is also a weak inhibitor of the CYP2D6 and CYP2C9 isoenzymes; therefore, drugs metabolized by these enzymes (e.g., warfarin) should be used with caution. Full prescribing information and drug interactions can be found on the package insert (www.fda.gov).
Dasatinib: Dasatinib is extensively metabolized in the liver, primarily by CYP3A4. CYP3A4 inducers may decrease plasma concentration of dasatinib. CYP3A4 inhibitors and drugs that are metabolized by this enzyme may increase the concentration of dasatinib. Therefore, concomitant administration with CYP3A4 inhibitors or inducers should be avoided. If coadministration cannot be avoided, a dose adjustment and close monitoring for toxicity should be considered. In addition, the solubility of dasatinib is pH-dependent, and long-term suppression of gastric acid secretion reduces dasatinib exposure. Concomitant use with H2 blockers or proton pump inhibitors is not recommended. Full prescribing information and drug interactions can be found on the package insert (www.fda.gov).
Nilotinib: Nilotinib is also metabolized by the CYP3A4 isoenzyme, and drugs that induce CYP3A4 may decrease nilotinib plasma concentrations. If nilotinib needs to be administered with a CYP3A4 inducer, a dose increase should be considered. Concomitant administration of strong inhibitors of CYP3A4 may increase the concentration of nilotinib. If coadministration cannot be avoided, nilotinib should be interrupted or a dose reduction should be considered. In addition, nilotinib is a competitive inhibitor of CYP2C8, CYP2C9, CYP2D6, and UGT1A1, potentially increasing the concentrations of drugs eliminated by these enzymes. Full prescribing information and drug interactions can be found on the package insert (www.fda.gov).
CP-CML
Initial Workup
The panel recommends the following tests as part of the initial evaluation of patients with CP-CML:
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History and physical, including spleen size by palpation
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CBC
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Platelet count
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Chemistry profile
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Bone marrow aspirate and biopsy
Bone marrow cytogenetics and measurement of BCR-ABL transcript levels using quantitative reverse transcriptase polymerase chain reaction (QPCR) is recommended before initiation of treatment and for assessing response to therapy.80 Conventional bone marrow cytogenetics should be performed during initial workup, because it not only provides a morphologic review but also detects chromosomal abnormalities other than Philadelphia chromosome that are not detectable using peripheral blood. If bone marrow collection is not feasible, fluorescence in situ hybridization (FISH) on a peripheral blood specimen with dual probes for BCR and ABL genes is an acceptable method for confirming the diagnosis of CML.
Patients who are BCR-ABL-negative do not have CML, and have a significantly worse prognosis than those with BCR-ABL-positive disease.81 Therefore, further evaluation for other diseases is warranted for patients with BCR-ABL-negative disease. Patients whose cells are BCR-ABL-positive (determined using karyotype analysis, FISH, or molecular techniques) are the focus of these guidelines.
Primary Treatment
Imatinib is recommended for patients with newly diagnosed Ph-positive or BCR-ABL-positive CP-CML. Based on the recent FDA approval of nilotinib and dasatinib, the guidelines also include nilotinib or dasatinib for newly diagnosed patients. Imatinib (400 mg once daily), nilotinib (300 mg twice daily), or dasatinib (100 mg once daily) are listed as category 1 recommendations for initial treatment of CML. Given the recent data showing superior efficacy of nilotinib and dasatinib in newly diagnosed patients, high-dose imatinib is currently not recommended as initial therapy for patients with newly diagnosed CML.
Preliminary data from DASISION53,54 and EN-ESTnd64,65 studies suggest that intermediate-risk and high-risk patients (based on Sokal or Hasford score) may preferentially benefit from a second-generation TKI because these agents are associated with a lower risk of disease progression in this patient population. Therefore, the guidelines recommend determining risk status as part of initial workup (see Table 1, Calculation of Risk Score, available online, in these guidelines, at www.NCCN.org). Longer-term follow-up is needed to determine whether second-generation TKIs should be implemented as standard first-line therapy in such a risk-adapted fashion.
Because both dasatinib and nilotinib have very good efficacy in the upfront setting, differences in their potential toxicity profiles may be helpful when choosing a second-generation TKI over imatinib as first-line therapy.82 In general, the choice of first-line therapy in a given patient may depend on diseased risk score, age, ability to tolerate therapy, the presence of comorbid conditions, and physician experience. For example, based on the toxicity profile, nilotinib may be preferred for patients deemed to be at risk for developing pleural effusions. Alternatively, dasatinib may be preferred in patients with a history of pancreatitis or hyperglycemia. The NCCN Member Institutions believe that interferon should no longer be considered as initial therapy for CML, given the excellent long-term results with imatinib. In patients treated with interferon, 10% to 15% achieved a CCyR with a median survival of more than 10 years, and some of them may actually be cured. However, given this small percentage, most of the panel members believed that these data for interferon did not outweigh the significant benefits seen with imatinib. In rare patients who are not able to tolerate TKI therapy, interferon or pegylated interferon therapy, allogeneic hematopoietic stem cell transplant (HSCT), or participation in a clinical can be considered. In phase II/III studies, pegylated interferon alpha-2a and alpha-2b have been shown to be active as initial treatment in patients with CP-CML.83,84
Resistance to Imatinib
Primary Resistance: Primary hematologic resistance to imatinib therapy (i.e., failure to achieve hematologic remission within 3-6 months of initiation of treatment) is rare in patients with newly diagnosed Ph-positive CP-CML, whereas primary cytogenetic resistance (i.e., failure to achieve any level of cytogenetic response at 6 months, MCyR at 12 months, or CCyR at 18 months) is evident in 15% to 25% of patients.
Imatinib Plasma Levels: Available data indicate that inadequate plasma concentration of imatinib may be one of the causes for primary resistance.85-87 Gambacorti-Passerini et al.85 observed that excessive binding of imatinib to plasma protein alpha-1-glycoprotein may reduce the therapeutic effect of imatinib. Picard et al.87 also observed that trough plasma levels of imatinib were significantly higher in patients achieving CCyR and MMR at 12 months. In a subanalysis of the IRIS study, plasma levels of imatinib after the first month of treatment proved to be a significant prognostic factor for long-term clinical response.86 However, other investigators have suggested that plasma levels of imatinib in patients receiving different dose schedules had no correlation with response to therapy.88,89
The clinical value of monitoring plasma levels of imatinib remains to be defined. Monitoring imatinib plasma levels may be useful in determining patient adherence to therapy. However, no data currently support that changing therapy based on plasma imatinib levels will affect treatment outcomes. Therefore, the panel does not recommend routine imatinib plasma level testing.
Intracellular Concentration of Imatinib: Aberrant expressions of drug transporters also contribute to resistance through altering the intracellular concentration of imatinib. Overexpression of the multidrug resistance gene (MDR1) decreases the intracellular concentration of imatinib, which may confer resistance to imatinib.90 Pretreatment levels of human organic cation transporter-1 (hOCT1) have been reported as being the most powerful predictor of response to imatinib.91 White et al.92 recently reported that most patients with suboptimal response to imatinib have low hOCT1 activity. In the updated analysis of patients enrolled in the TIDEL study, MMR rate at 60 months was higher for patients with high hOCT1 activity than for those with low hOCT1 activity (89% vs. 55%, respectively). Low hOCT1 activity was also associated with a significantly lower overall survival (87% vs. 96%) and event-free survival rates (48% vs. 74%) and a higher kinase domain mutation rate (21% vs. 4%). These differences were highly significant in patients who averaged less than 600 mg/d of imatinib.93 On the other hand, cellular uptake of dasatinib or nilotinib seems to be independent of hOCT1 expression.94-97 Thus, preliminary findings suggest that patients with low hOCT1 expression might have better outcomes with dasatinib or nilotinib.
Secondary Resistance: The most common mechanism for secondary resistance is the reactivation of BCR-ABL activity. This occurs most often through mutations in the ABL tyrosine kinase domain of the BCR-ABL gene (resulting in conformational changes in the fusion protein that affect the binding site of imatinib on the tyrosine kinase) and, less frequently, through BCR-ABL gene amplification, or increased BCR-ABL gene expression.98-100 In the START-C study, 46% of patients with imatinib-resistant CP-CML did not carry BCR-ABL mutations, confirming that secondary resistance to imatinib is multifactorial. Other mechanisms that are independent of BCR-ABL include activation of the Src family of kinases or cytogenetic clonal evolutions characterized by additional chromosomal abnormalities in the Ph-positive cells.99,101
Point mutations in the ABL kinase domain are emerging as the most frequent mechanism of resistance. In a large study of 319 patients with CP-CML, Khorashad et al.102 found that kinase domain mutations were the only independent predictor for loss of CCyR and a higher risk for progression (3.8- and 3.7-fold, respectively) than in patients without a mutation. Phosphate-binding loop (P-loop) mutations were associated with a particularly high risk of progression. Other studies also report that mutations in the ATP P-loop are associated with poor prognosis and high risk of progression among patients treated with imatinib.103-106 However, Jabbour et al.107 could not confirm these findings. In the START trials, dasatinib induced similar rates of major hematologic and cytogenetic responses irrespective of the presence of P-loop or other mutations in patients with imatinib-resistant AP-CML or BP-CML.37,39 Branford et al.103 observed that, although a higher incidence of P-loop mutations was seen in the accelerated phase, the difference in the frequency of mutation was significant between the early chronic phase and accelerated phase, compared with between the late chronic phase and accelerated phase.
Among the mutations in the ABL kinase domain, the presence of T315I mutation confers the highest resistance to imatinib, dasatinib, and nilotinib. Some reports have suggested that T315I is associated with disease progression and poor survival.108,109 Jabbour et al.108 reported that survival of patients with T315I is dependent on the stage of the disease, with many patients with CP-CML having an indolent course. Patients with CP-CML had a 2-year survival rate of 87%. Among patients in accelerated and blast phases, survival rates were similarly poor irrespective of their T315I mutational status.
Clonal evolutions are considered to be a feature of AP-CML. In patients with AP-CML, clonal evolution resulted in lower response rates and a shorter time to treatment failure. However, in a subset of patients, clonal evolution was associated with a better prognosis when it was considered the only criterion for accelerated phase disease.110 With a median follow-up of 12 months, the MCyR and CCyR rates were 73% (11 of 15) and 60% (9 of 15), respectively. In a subsequent report, among 141 patients treated with imatinib after treatment with interferon failed, O'Dwyer et al.111 identified clonal evolution, an elevated platelet count, and failure to achieve MCyR by 6 months to be adverse prognostic factors for hematologic relapse.
In a study from MD Anderson Cancer Center (before the use of imatinib), Majlis et al.112 analyzed patients who developed cytogenetic clonal evolution on interferon therapy. They concluded that the prognostic significance of clonal evolution is not uniform, but is related to the specific chromosomal abnormality and the presence of other features of accelerated phase. In this study, presence of chromosome 17 abnormality, predominance of abnormal metaphases (≥ 36%), and the other accelerated features were identified as the worst prognostic factors. In a large trial of 498 patients in chronic or accelerated phase, cytogenetic clonal evolution was not an important factor for achieving MCyR or CCyR with imatinib, but it was an independent poor prognostic factor for survival in both chronic and accelerated phases of CML.113 In patients with CP-CML for whom imatinib failed and who were treated with second-generation TKIs, the hematologic and cytogenetic response rates, overall survival, and event-free survival were not different between patients in chronic phase with clonal evolution and those with no clonal evolution.114 However, clonal evolution had a significant adverse impact when associated with other features of accelerated phase. Patients with cytogenetic abnormalities, including trisomy 8, chromosome 17, and complex abnormalities, had the worst outcome, regardless of the number of metaphases involved.
Taken in full, the data suggest that mutational analysis would be helpful for identifying a subgroup of patients who demand careful monitoring because they are at a higher risk of progression. Mutational analysis would also be helpful to identify the subset of patients who will be eligible for allogeneic HSCT.
Management of Resistance
Dose escalation of imatinib up to 800 mg daily has been shown to overcome some of the primary resistance, but the duration of responses has typically been short.115-117 Jabbour et al.118 assessed the long-term efficacy of imatinib dose escalation after hematologic or cytogenetic failure in 84 patients with CP-CML. After a median follow-up of 61 months, the estimated 2- and 3-year event-free and overall survival rates were 57% and 47%, and 84% and 76%, respectively. Responses were also durable; 88% of patients with MCyR sustained their response beyond 2 years. Dose escalation was particularly effective in patients with cytogenetic relapse who had achieved cytogenetic response with standard-dose imatinib. In this group of patients, CCyR and MCyR rates were 73% and 87%, respectively, compared with 52% and 60% for the overall group of patients with cytogenetic failure. These results indicate that dose escalation of imatinib is unlikely to benefit patients with hematologic failure or those who never had a cytogenetic response with standard-dose imatinib. Kantarjian et al.119 performed a retrospective analysis of 106 patients with newly diagnosed CP-CML from the IRIS trial who received imatinib at 400 mg daily and subsequently underwent dose escalation to either 600 or 800 mg daily. At 3 years after dose increase, the rates of FFP to accelerated or blast phase and overall survival were 89% and 84%, respectively. The results of this retrospective analysis also supported that dose escalation of imatinib is an appropriate option for patients in chronic phase who were experiencing suboptimal cytogenetic response or cytogenetic relapse.
Dasatinib34,48 and nilotinib58 have been effective in patients with imatinib-resistant or imatinib-intolerant CP-CML. The efficacy of high-dose imatinib and dasatinib was evaluated in a phase II trial (START-R) in which 150 patients with imatinib-resistant CP-CML were randomized to receive 140 mg (70 mg twice daily) of dasatinib or 800 mg of imatinib.120,121 In the initial report from the START-R trial, dasatinib was clearly superior to 800 mg of imatinib if treatment with 600 mg of imatinib had already failed, whereas response rates were equivalent for high-dose imatinib and dasatinib in patients for whom treatment with 400 mg of imatinib failed.120 However, the 2-year follow-up data suggested that dasatinib is clearly superior to 800 mg of imatinib in patients resistant to imatinib at doses of 400 or 600 mg daily.121 At a minimum follow-up of 2 years, dasatinib showed higher rates of CHR (93% vs. 82%), MCyR (53% vs. 33%), and CCyR (44% vs. 18%) than high-dose imatinib. MMR was also more frequent with dasatinib than with high-dose imatinib (29% vs. 12%), and the estimated progression-free survival also favored dasatinib, indicating that dasatinib is an effective treatment for patients with CP-CML resistant to standard-dose and high-dose imatinib.121 Dose escalation of imatinib might be beneficial for patients with suboptimal response to imatinib at 400 mg daily (see Suboptimal Response, page 94).
Several new agents under clinical development have shown promising results in the management of patients with T315I mutation.122 Recently, some studies have reported the clinical activity of omacetaxine (homoharringtonine) in patients with CML after imatinib failure, including those with BCR-ABL kinase domain mutations.123,124 In 2 long-term phase II studies, omacetaxine induced hematologic and cytogenetic responses in patients with T315I mutation whose disease had failed to respond to imatinib (CML-202; n = 81)125 and in patients who were intolerant or resistant to 2 or more TKIs (CML-203; n = 89).126 Preliminary results of CML-202 showed that among 44 evaluable patients, the T315I clone was reduced to below detection limits in 64% of patients. In patients with CP-CML, CHR and CCyR were seen in 80% and 16% of patients and 28%, respectively. Median duration of CHR and CCyR was 12 and 5 months, respectively. The estimated 2-year progression-free survival rate was 70%.
Monitoring Response to Imatinib
Disease monitoring to assess the response to therapy and to detect early relapse is one of the key management strategies of CML.127-129 There are 3 different types of responses in CML: hematologic, cytogenetic, and molecular response (see Criteria for Cytogenetic, Hematologic, and Molecular Response on page 76). A widely accepted goal of CML therapy is to achieve CCyR within 18 months of initiation of therapy.
Hematologic Response: CHR is defined as complete normalization of peripheral blood counts with no immature blood cells, leukocyte count less than 10 × 109/L, and platelet count less than 450 × 109/L. Patients are free of signs and symptoms of the disease, with the disappearance of splenomegaly. Partial hematologic response indicates the presence of immature blood cells and/or a platelet count less than 50% of pretreatment count but more than 450 × 109/L, and/or persistent splenomegaly (but < 50% of pretreatment).
Cytogenetic Response: Cytogenetic response is determined by the decrease in the number of Ph-positive metaphases, as determined by bone marrow aspirate and cytogenetic evaluation. Cytogenetic monitoring is the most widely used technique for monitoring response in patients with CML. CCyR indicates that no Ph-positive metaphases are present. MCyR indicates that 0% to 35% of the cells still have Ph-positive metaphases, and partial cytogenetic response indicates that 1% to 34% of the cells have Ph-positive metaphases.
Conventional cytogenetics for Ph-positive metaphases is the standard for monitoring cytogenetic responses in CML, and clinical trial response analyses are most often based on standard cytogenetics. It is widely available and reliable. However, the sensitivity is approximately 5% if only 20 metaphases are examined. If conventional cytogenetics showed no analyzable metaphases, cytogenetic response can be further evaluated using more-sensitive techniques, such as FISH, although end points for failure of imatinib therapy have been defined based on FISH analysis.130,131 FISH uses 5′-BCR and 3′-ABL probes and has a false-positive rate of 1% to 10%. Interphase or hypermetaphase FISH can be performed on peripheral blood specimens or marrow aspirates, respectively. Interphase FISH does not require cell division. It is applicable to a larger number of cells but is associated with a background level of 1% to 5% (depending on the specific probe used in the assay).132 Hypermetaphase FISH is applicable only to dividing cells in the bone marrow. Hypermetaphase FISH is more sensitive and can analyze up to 500 metaphases at a time.133 Techniques such as double-FISH can detect all variant translocations of the Ph-chromosome and are also associated with low false-positive rates.134 FISH can be used complimentary to conventional cytogenetics until FISH levels are less than 5% to 10%. This technique is no longer useful for monitoring further reduction in Ph levels. At this point, more sensitive techniques are required.
Cytogenetic responses are indicative of treatment effectiveness. In the IRIS study, progression-free survival was significantly better for patients who achieved any cytogenetic response at 6 months and an MCyR at 12 months, compared with those with no cytogenetic response at 6 months or less than an MCyR at 12 months. At the median follow-up of 60 months, the progression-free survival rate was better for patients who achieved a CCyR or a partial cytogenetic response at 12 months compared with those who did not have an MCyR at 12 months (97%, 93%, and 81%, respectively).13 At 8 years, of the 456 patients who achieved CCyR on imatinib, only 15 (3%) had experienced progression to accelerated or blast phase during study treatment.14 de Lavallade et al.135 also identified cytogenetic response after 1 year of imatinib therapy as the major prognostic factor for overall and progression-free survival. In the retrospective analysis of data from phase II studies of dasatinib in patients with imatinib-resistant CP-CML, event-free survival was higher for those who started taking dasatinib after losing MCyR on imatinib than for those who received dasatinib after the loss of both MCyR and CHR (89% and 29%, respectively).136
The updated results of the IRIS trial confirmed that a minor cytogenetic response at 3 months, partial cytogenetic response at 6 and 12 months, and CCyR at 18 months were associated with stable CCyR over the observation period. Patients with minor to partial cytogenetic response at 3 months and those with partial cytogenetic response at 6 and 12 months were more likely to achieve a stable CCyR than to have an event.14
Jabbour et al.137 recently reported that the achievement of an early CCyR remains a major prognostic factor for outcome in patients with newly diagnosed early CP-CML, regardless of the TKI (imatinib at 400 mg, imatinib at 800 mg, or second-generation TKI). Patients with CCyR at 3, 6, and 12 months had significantly better rates of 3-year event-free survival (98%, 97%, and 98%, respectively) and overall survival (99%, 99%, and 99%, respectively) than patients who did not achieve a CCyR at these time points (83%, 72%, and 67%; and 95%, 90%, and 94%, respectively).
Clonal cytogenetic abnormalities in Ph-negative cells have also been reported in a small subset of patients during the course of imatinib therapy.138-141 The significance of these chromosomal abnormalities is unclear, but one of the most common abnormalities is trisomy 8, which is an aberration frequently seen in myelodysplastic syndromes (MDS). Only rare cases of MDS or acute myeloid leukemia (AML) have been reported in patients with these abnormalities, usually in those who had received interferon and prior chemotherapy. Some of these abnormalities may persist only in a small percentage of metaphases, or they may be transient and disappear with continued therapy in patients who have achieved a CCyR. In a recent report, Deininger et al.142 concluded that the overall prognosis for patients with Ph-negative CML and clonal cytogenetic evolution was good and dependent on response to imatinib therapy. Among patients with newly diagnosed CP-CML treated with imatinib, chromosomal abnormalities in Ph-negative cells appeared in 9%.143 Loss of Y chromosome was most common. The significance of loss of Y chromosome in this setting is unclear. This phenomenon has been reported to be common in aging men.
Molecular Response: Molecular response is determined by the decrease in the amount of BCR-ABL chimeric mRNA. CMR indicates that no detectable BCR-ABL chimeric mRNA is present based on reverse transcriptase polymerase chain reaction (RT-PCR) analysis. MMR indicates that there is a reduction (3-log reduction or greater) of BCR-ABL chimeric mRNA.
RT-PCR is the most sensitive assay available for the BCR-ABL chimeric mRNA. This assay measures the levels of BCR-ABL transcripts in the peripheral blood or the bone marrow, and can detect one CML cell in a background of 100,000 or more normal cells. Most patients initially treated with imatinib or allogeneic HSCT will experience a CCyR; however, a smaller percentage will achieve a CMR identified by the absence of BCR-ABL mRNA transcripts. The BCR-ABL mRNA transcripts typically decrease slowly after complete cytogenetic remission is reached. Therefore, RT-PCR assays are useful to establish a baseline BCR-ABL for monitoring molecular responses after patients have achieved a CCyR.
Qualitative RT-PCR technique is reported as either positive or negative; it is rarely used in the context of monitoring patients because it is only a “yes or no” answer. In contrast, a QPCR assay reports the actual percentage of BCR-ABL mRNA transcripts.144 A major advantage of QPCR testing is the strong correlation between results obtained from the peripheral blood and the bone marrow, allowing molecular monitoring without needing bone marrow aspirations. Among institutions and laboratories that perform this test, differences exist in techniques and the use of various internal controls that make quantification of the assay variable. A substantial effort has been made to standardize BCR-ABL testing and reporting across academic and private laboratories.145-148
In the QPCR assay, results are expressed as the ratio of BCR-ABL transcript numbers to the number of control gene transcripts. Thus, the choice of an appropriate control gene is important for generating reliable and reproducible data. BCR, ABL, β-glucuronidase (GUSB), and β2-microglobilin are the 4 control genes that have been widely studied for BCR-ABL quantification. In 2006, the National Institute of Health Consensus group proposed an international scale (IS) for BCR-ABL measurement.148 This group recommended the use of 1 of 3 control genes: BCR, ABL, or GUSB. In the IRIS trial, BCR was used as the control gene and the standardized baseline was calculated by measuring the level of BCR-ABL/BCR in the peripheral blood collected from 30 patients with newly diagnosed CP-CML before treatment was initiated.149 The same 30 samples were assayed in the 3 laboratories. The median value was used as the standardized baseline at each laboratory, and at least a 3-log reduction from this baseline was defined as the MMR. Thus, MMR is defined as a 3-log reduction in the BCR-ABL transcript levels from the standardized baseline, and not a reduction from the actual baseline level in an individual patient.
Several studies have reported that MMR is associated with durable long-term remission rates and progression-free survival after treatment with imatinib.13,150-152 The 5-year follow-up of the IRIS trial showed that no patient who had a CCyR and an MMR at 12 months had progressed to the accelerated or blast phase.13 The estimated progression-free survival rate at 24 months was 100% for patients with a CCyR and at least a 3-log reduction in the BCR-ABL transcript level at 12 months, compared with 95% for those with a CCyR and a less than 3-log reduction of BCR-ABL at 12 months. The 7-year follow-up of the IRIS study also showed that progression is rare in patients who achieved an MMR (BCR-ABL [IS] ≤ 0.1%) at any time point during imatinib therapy.152 The estimated event-free survival rate at 84 months was 95% for patients who had an MMR at 18 months compared with 86% in those with less than an MMR at this time point (86% for those with BCR-ABL [IS] > 0.1% to ≤ 1.0%; P = .01, and 65% for those with BCR-ABL [IS] > 1.0%).152 Press et al.150 also reported that failure to achieve at least a 2-log reduction in BCR-ABL mRNA at the time of CCyR or a 3-log reduction any time thereafter is associated with a significantly shorter progression-free survival, and that a minimal half-log increase in the BCR-ABL or a loss of MMR predicts shorter relapsefree survival in patients who were in complete cytogenetic remission on imatinib therapy.151
Molecular responses also predict the duration of CCyR.152-155 Cortes et al.153 reported that a significantly lower portion of patients (5% with an MMR and 4% with complete molecular remission) lost their CCyR compared with 37% who did not reach these levels of molecular response. In the 7-year follow-up of the IRIS study, the probability of loss of CCyR by 7 years was only 3% for patients with an MMR at 18 months compared with 26% for those with a CCyR but not an MMR.152 The GIMEMA study group reported similar findings.154,155 Patients with a stable MMR have a significantly lower risk of losing their CCyR than patients with an unstable MMR (4% vs. 21%, respectively; P = .03) and those with no MMR (4% vs. 33%, respectively; P < .0001).155
Although early molecular response has been shown to be a predictor of durable long-term remission rates and progression-free survival in patients with CP-CML, some studies suggest that early MMR does not predict a long-term survival advantage.135,156 de Lavallade et al.135 reported that in patients achieving a CCyR at 12 or 18 months, achievement of molecular response at these time points did not affect progression-free or overall survivals. Marin et al.156 also confirmed that among patients with a CCyR, even though those who did not have an MMR at 18 months had a higher chance of losing CCyR, this did not translate into a difference in progressionfree survival. Recently, Hehlmann et al.31 from the German CML Study Group reported that, independent of the treatment approach, MMR at 12 months was associated with better progression-free (99% vs. 94%; P = .0023) and overall survivals (99% vs. 93%; P = .0011) at 3 years when compared with greater than 1% (IS) or no MMR.31 However, no difference was seen in progression-free and overall survivals compared with the 0.1% to 1% IS group (which closely correlates with CCyR). The 3-year survival rates for MMR at 12 months and 0.1% to 1% IS at 12 months were 99% and 98%, respectively, implying that MMR may not be of prognostic significance in patients who have achieved CCyR at 12 months.
Although achievement of MMR is associated with a lower rate of disease progression, and some investigators have reported that dose escalation might benefit patients who have a CCyR with no MMR,157 no randomized studies have shown that a change of therapy would improve survival, progression-free survival, or event-free survival in this group of patients.158
Rising BCR-ABL Levels: Several studies have shown that a rising BCR-ABL level may be associated with an increased risk of BCR-ABL mutations in the future.159-162 Branford et al.159 reported that in patients who had achieved very low levels of BCR-ABL transcripts, emergence of BCR-ABL mutations was more frequent in those who had more than a 2-fold increase in BCR-ABL levels compared with those with stable or decreasing BCR-ABL. In contrast, Wang et al.160 reported that a serial rise is more reliable than a single 2-fold or greater rise in BCR-ABL transcript levels. In an analysis of 258 patients with CP-CML on imatinib therapy, Kantarjian et al.163 studied 116 patients in CCyR who experienced an increase in BCR-ABL transcript levels of a half-log or more on at least 2 occasions. Of these patients, 11 (9%) experienced CML progression. The patients with the highest risk were those who lost MMR with a greater than 1-log increase in BCR-ABL, or those who never achieved a MMR and had a 1-log rise in BCR-ABL.
The amount of BCR-ABL increase that warrants concern and should trigger mutation testing is unknown. Some laboratories have advocated a 2- to 3-fold range,156,162 whereas others have taken a more conservative approach (0.5- to 1-log).163 Obviously, some common sense must prevail, because the amount of change in absolute terms depends on the MMR level. For example, a finding of any BCR-ABL compared with CMR is an infinite increase in BCR-ABL level, though a change from CMR to a barely detectable level is clearly different from a 5-fold increase in a case hovering at the MMR level.
Currently no specific guidelines exist for changing therapy based on rising BCR-ABL transcripts detected using QPCR. Changes of therapy based solely on rising BCR-ABL transcripts should occur only in the context of a clinical trial.
Mutational Analysis
Dasatinib and nilotinib are active against many of the imatinib-resistant BCR-ABL kinase domain mutations, except T315I. Available clinical evidence indicates that, in addition to T315I, the mutations F317L and V299L are resistant to dasatinib, and mutations Y253H, E255, and F359 are resistant to nilotinib.164,165
Muller et al.166 recently reported the results of the largest analysis of clinical response to dasatinib after imatinib failure in 1043 patients with CP-CML according to the preexisting BCR-ABL mutations. The presence of T315I and F317L mutations at baseline was associated with less favorable responses. A few responses (CHR and MCyR) were observed in patients with T315I mutation but no CCyRs. Patients with an F317L mutation had a high rate of CHR (93%) but low rates of MCyR and CCyR (14% and 7%, respectively), whereas favorable CCyR rates were achieved in patients with highly imatinib-resistant mutations, such as E255K/V (38%) and L248V (40%). Other studies have also reported similar findings in patients with F317 mutations at baseline.167,168 In one study, T315L and/or F317L mutations were associated with resistance to dasatinib.168 In another study, patients with an F317L mutation had similar survival to patients with other mutations, with outcome dependent on the CML phase, and this mutation was sensitive to other TKIs.167
Hughes et al.169 assessed the occurrence and impact of baseline BCR-ABL mutations on nilotinib therapy in patients with imatinib-resistant CP-CML. Patients with Y253H, E255V/K, and F359V/C mutations achieved less-favorable MCyR rates (13%, 43%, and 9%, respectively), and none of them achieved CCyR within 12 months of therapy. E255K/V, F359C/V, Y253H, and T315I mutations were most commonly associated with disease progression. Consistent with these findings, F359V, Y253H, and E255K/V mutations were associated with relapse on nilotinib in the study reported by Soverini et al.170
Branford et al.164 studied a large sample of imatinib-resistant patients with BCR-ABL mutations, and found that clinically relevant mutations less sensitive to nilotinib (Y253H, E255K/V, and F359V/C), dasatinib (F317L and V299L), or both (T315I) occurred in 43% of patients with mutations, including 14% with T315I.
Identification of mutations supports the diagnosis of imatinib resistance. Patient mutation status at the time of loss of response to a first-generation TKI may be helpful in selecting subsequent TKI therapy (see Table 2, Treatment Options Based on BCR-ABL Kinase Domain Mutation Status, available online, in these guidelines, at www.NCCN.org).
NCCN Recommendations
Monitoring Response to First-Line TKI Therapy and Mutational Analysis: Most patients receiving TKI therapy will achieve a CHR at 3 months and CCyR at 6, 12, or 18 months. If no hematologic and cytogenetic response occurs at these intervals, mutational analysis should be considered and patient compliance to TKI therapy should be evaluated.
Bone marrow cytogenetics is recommended at 6, 12, and 18 months after imatinib therapy. The panel recommends considering bone marrow cytogenetics for patients with less than a CHR at 3 months because it may be useful to confirm response to TKI therapy, especially in patients with prolonged myelosuppression who may not be in CHR because of persistent cytopenias. If a persistent, unexplained decrease in blood counts occurs during therapy, it may be reasonable to perform a bone marrow cytogenetics to look for non-Ph clonal changes and evidence of myelodysplasia. QPCR to monitor BCR-ABL transcript levels is recommended every 3 months when a patient is experiencing response to treatment. Hughes et al.152 reported that routine monitoring of BCR-ABL transcripts, in conjunction with cytogenetic evaluation, provides important information about long-term disease control in patients with CML. Some investigators have reported that interphase FISH can be used to monitor CCyR.171,172 However, the panel feels that FISH has not been adequately studied for monitoring response to TKI therapy. Therefore, FISH is not recommended for monitoring response.
The optimal guidelines for monitoring response to TKI therapy and mutational analysis are outlined in Table 3. Because no data exist regarding the time points for monitoring response to dasatinib or nilotinib, the panel currently believes that the same evaluation points recommended for monitoring response to imatinib could also be applied to dasatinib or nilotinib.
Recommendations for Monitoring Response to Tyrosine Kinase Inhibitor Therapy and Mutational Analysis
Follow-up Therapy: Patients with CML not responding to first-line therapy with a second-generation TKI should be switched to the other second-generation TKI (that they have not received before) for second-line therapy. Participation in a clinical trial or allogeneic HSCT are reasonable treatment options for patients with a T315I mutation, because this mutation is associated with resistance to imatinib, dasatinib, and nilotinib. The recommendations for follow-up therapy are outlined in Table 4.
Recommendations for Follow-Up Therapy
Suboptimal Response: In the European Leukemia-Net guidelines, suboptimal response is defined as no cytogenetic response at 3 months, less than a partial cytogenetic response at 6 months, a partial cytogenetic response at 12 months, and less than an MMR at 18 months.145 Suboptimal response to imatinib could result from many factors, including poor compliance to imatinib therapy, individual variation in drug metabolism, aberrant expression of drug transporters, and differences in the intrinsic biology of the disease, which might result in clonal competition between clones highly sensitive to imatinib and those resistant.82 The prognostic implications of suboptimal response may also be different depending on the time point of suboptimal response. Thus, the outcomes of patients with suboptimal response at 6 and 12 months are more similar to those of patients who meet the criteria for failure, and the outcomes of patients with a suboptimal response at 18 months are very similar to those of patients with an optimal response.156 However, other investigators suggest that patients experiencing a suboptimal response at 12 months have an outcome closer to that of patients with an optimal response, with a similar transformation-free survival but worse event-free survival.173 A few early reports have suggested that dose escalation of imatinib to 800 mg as tolerated173-176 or switching to dasatinib48,177 or nilotinib176,178,179 are effective treatment option in patients with suboptimal response to standard-dose imatinib.
These guidelines have incorporated patients who meet the European LeukemiaNet criteria for suboptimal response: minor cytogenetic response at 6 months and partial cytogenetic response at 12 months. The panel currently feels that no strong evidence exists to recommend a definite treatment option for this group of patients, but agree that patients with suboptimal response represent a subgroup who require careful monitoring and may benefit from alternative treatment options. Continuation of TKI therapy with dasatinib or nilotinib at the same dose, imatinib dose escalation to 800 mg as tolerated, or a change of therapy to an alternate second-generation TKI are included as options for these patients. The NCCN supports trials that study whether intervention for suboptimal response or molecular relapse affects short- and long-term outcomes.
Monitoring Response to Second-Line TKI Therapy
Early cytogenetic response to second-line TKIs can predict survival and guide subsequent therapy.180,181 Tam et al.180 reported that in patients receiving dasatinib or nilotinib, those achieving a MCyR after 12 months of treatment had a significant advantage over those achieving a minor cytogenetic response or CHR. Milojkovic et al.181 also reported that among patients with CP-CML who were resistant to imatinib and were treated with dasatinib or nilotinib, those who had a minimal cytogenetic response at 3 months, partial cytogenetic response at 6 months, and CCyR at 12 months had significantly better outcomes than those with lesser degrees of cytogenetic response. At the 12-month landmark analysis, patients with a CCyR at 12 months had significantly superior rates of event-free and overall survival probabilities compared with those who did not achieve a CCyR (97% vs. 80% and 100% vs. 85%, respectively). No significant differences were seen in progression-free survival. More recently, Shah et al.182 reported that, at 6 and 12 months, response to dasatinib at a dose of 100 mg once daily was predictive of progression-free survival at 48 months. The progression-free survival rate after 48 months was higher for patients who achieved CCyR at 6 months than for those who achieved a partial cytogenetic response (93% and 67%, respectively).182 Similarly, the progression-free survival rate was 87% for those with a CCyR (with or without MMR) at 12 months compared with 78% and 45%, respectively, for those with a partial cytogenetic response or no cytogenetic response at 12 months.
The BCR-ABL transcript level at 3 months after second-line TKI therapy has also been reported to be predictive of response, and may provide further information about the value of continuing treatment with the second-generation TKIs.181,183,184 In imatinib-resistant and imatinib-intolerant patients receiving nilotinib, BCR-ABL % (IS) at 3 months correlated with MCyR, MMR, and event-free survival rates regardless of baseline mutation.184 Patients whose BCR-ABL % (IS) levels decreased below 10% at 3 months have a high probability of achieving MMR and MCyR at 24 months. Similarly, patients who achieve early molecular response may also have an increased probability of improved long-term outcomes on nilotinib therapy, whereas patients with BCR-ABL % (IS) levels greater than 10% at 3 months may have a poorer prognosis.
Milojkovic et al.181 identified low Sokal risk score at diagnosis, best cytogenetic response on imatinib, neutropenia at any time during imatinib therapy requiring dose reduction despite growth factor support, and time from detection of imatinib failure to start of second-line TKI as predictive factors for achievement of cytogenetic response on second-line TKI therapy.181 Recently, Jabbour et al.185 identified a lack of any cytogenetic response to imatinib therapy and a poor performance status as independent poor predictive factors of outcome with second-line TKIs.
The use of a second-generation TKI after failure of 2 prior TKIs may induce responses in some patients, but these are not durable except in occasional patients in chronic phase.186 Investigational therapies or allogeneic HSCT should be considered for these patients.
Currently, no definite recommendations have been made for specific time points to switch patients to allogeneic HSCT based on the response to second-line TKI therapy. Based on the available data, patients receiving dasatinib or nilotinib with no cytogenetic response at 3, 6, or 12 months should be considered for alternative therapies or allogeneic HSCT, if a suitable donor is available.
Discontinuation of TKI Therapy
Imatinib has become a standard front-line treatment for patients with CML. CCyR can be achieved in most patients with CP-CML. Results of the IRIS study suggest that the annual mortality rate among patients with CML receiving imatinib is less than 5% in the first 5 to 6 years of treatment compared with 10% to 20% in the pre-imatinib era, and patients experiencing response to imatinib are likely to maintain their responses on long-term therapy.14,187 However, the disease usually relapses if imatinib therapy is stopped, even in patients who experienced complete response.188 In a pilot study (n = 12), Rousselot et al.189 suggested that discontinuation of imatinib is feasible in a subset of patients achieving sustained CMR.189 Most of the patients in this study (10 of 12) had received prior interferon therapy. Ross et al.190 also concluded that imatinib withdrawal in patients with a stable CMR is safe with close molecular monitoring. However, the sample size was small (n = 18) and follow-up was short.
A multicenter Stop Imatinib study evaluated the persistence of complete molecular remission after discontinuation of imatinib in 50 patients (25 of whom had no prior interferon treatment).191 In this study, more than half of the patients who were not pretreated with interferon had not experienced relapse, confirming that treatment can be stopped in patients with sustained CMR, even in those treated with imatinib alone, and particularly in male patients, those with a low Sokal score, and those with cytotoxic NK cells in the peripheral blood before discontinuation. Thus, investigators recommend that imatinib should be withdrawn only in the setting of a clinical trial.
In the absence of data from studies evaluating the probability of discontinuing dasatinib and nilotinib in patients experiencing response, the findings from the studies involving patients treated with imatinib could be extrapolated to these drugs. Additional prospective studies are needed to determine the optimal duration of TKI therapy in patients who are experiencing complete molecular remission. Currently, discontinuation of TKI therapy is not recommended outside of a clinical trial for patients whose disease is responding to TKI therapy.
Patient Adherence to TKI Therapy
Treatment interruptions and nonadherence to TKI therapy may lead to undesirable clinical outcomes.192-194 The ADAGIO (Adherence Assessment with Glivec: Indicators and Outcomes) study showed that nonadherence to imatinib therapy in patients with CML was associated with poorer response. Patients with suboptimal response had significantly higher mean percentages of imatinib not taken (23%) than those who had an optimal response (7%).194 Marin et al.193 recently identified adherence as the only independent predictor for achieving CMR on standard-dose imatinib. Patients whose imatinib doses were increased had poor adherence (86%), and adherence was the only independent predictor for inability to achieve an MMR in these patients. Poor adherence to imatinib therapy has also been identified as the most important factor contributing to cytogenetic relapse and imatinib failure.195 Patients with an adherence rate of 85% or less had a higher probability of losing their CCyR at 2 years than those with an adherence rate greater than 85% (27% and 1.5%, respectively). Although the effects of nonadherence to dasatinib and nilotinib have not been reported yet, Marin et al.193 suggest that the findings from the imatinib studies may apply equally to these drugs.
Patient education regarding adherence to TKI therapy and close monitoring of adherence is critical to achieve optimal responses.196,197 In a significant proportion of patients with TKI-induced toxicities, responses have been observed with doses well below their determined maximal tolerated doses.198 Short interruptions or dose reductions, when medically necessary, may not have a negative impact on the control of disease or other outcomes. Adequate and appropriate management of side effects and scheduling appropriate follow-ups to review side effects could be helpful to improve patient adherence to therapy.
Advanced Phase CML
AP-CML
Varying definitions have been used for AP-CML199-202 (see Definitions of Accelerated Phase on page 77). The most commonly used definition is the WHO criteria, which defines accelerated phase as the presence of any of the following features: 10% to 19% of blasts in the peripheral blood or bone marrow; 20% or more of basophils in the peripheral blood; persistent thrombocytopenia (< 100 × 109/L) unrelated to therapy or persistent thrombocytosis (> 1000 × 109/L) unresponsive to therapy; increasing spleen size; and increasing WBC count unresponsive to therapy.202 Cortes et al.203 suggested a modification to the WHO criteria (≥ 15% of peripheral blood blasts; ≥ 30% of peripheral blood blasts and promyelocytes; ≥ 20% of basophils; platelet count ≤ 100 × 109/L; and clonal evolution). Notably, clinical trials of TKIs have largely reported efficacy data using the modified MD Anderson Cancer Center accelerated phase criteria.203
BP-CML
Approximately 50% of all the blast phase cases are of the myeloid subtype, 25% are of the lymphoid subtype, and the rest are undifferentiated. According to the Center for International Bone Marrow Transplant Registry (CIBMTR), blast crisis is defined as 30% or greater blasts in the blood, bone marrow, or both, or as the presence of extramedullary disease.204 In the WHO criteria, blast crisis is defined as 20% or greater blast cells in the peripheral blood or bone marrow, the presence of extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy202 (see Definitions of Blast Crisis on page 77).
Workup and Treatment Options
The panel recommends bone marrow cytogenetics and mutational analysis before initiation of treatment for patients with advanced phase CML. Participation in a clinical trial is recommended for all patients with accelerated or blast phase.
High-dose combination chemotherapy is associated with 30% to 60% response rates in patients with AP-CML.205 Imatinib,206-210 dasatinib,38,40,50 and nilotinib59,61 also induce favorable response rates in patients with accelerated or blast phase CML. A significant portion of patients treated with dasatinib or nilotinib achieve a MCyR but not a concomitant CHR because of persistent cytopenias. Fava et al.211 reported that failure to achieve a CHR at the time of MCyR was associated with an inferior outcome. The 2-year survival rate was 37% compared with 77% for patients with MCyR and concomitant CHR. These results suggest that patients with a MCyR but no CHR should be considered for alternate therapies. The addition of TKI to chemotherapy has been shown to improve outcome in patients with de novo or minimally treated or newly diagnosed Ph-positive ALL.212-216
Chemotherapy in combination with imatinib or dasatinib should be considered for patients presenting with de novo Ph-positive BP-CML. For patients with disease progression (defined as loss of hematologic or cytogenetic response or progression to accelerated or blast phase), the selection of TKI therapy is based on prior therapy and/or mutational testing.
Dasatinib (140 mg once daily) or nilotinib (400 mg twice daily) are appropriate options for patients with disease progression to accelerated phase after TKI therapy. Allogeneic HSCT can be considered based on response to TKI therapy. TKI therapy alone or in combination with chemotherapy (ALL-type induction therapy for those with a lymphoid blast crisis and AML-type induction therapy for those with a myeloid blast crisis) followed by allogeneic HSCT (if feasible) is recommended for patients in myeloid or lymphoid blast phase.
Allogeneic HSCT
Although allogeneic HSCT is a potentially curative treatment for patients with CML, the excellent results with imatinib have challenged its role as a first-line therapy.217,218 The widespread application of allogeneic HSCT is limited by donor availability and the high toxicity of the procedure in older patients, which limits the age of eligibility at many centers to younger than 65 years. Ongoing advances in alternative donor sources (such as unrelated donors and cord blood), more-accurate human leukocyte antigen (HLA) typing of unrelated donors, and less-toxic regimens are broadening the use of HSCT. Transplants from unrelated matched donors can now be used for many patients with CML. The advent of molecular DNA assessment of HLA typing has enabled a rigorous and stringent selection of unrelated matched donors, and this improvement in typing has translated into greatly improved transplant outcomes, so that results with unrelated, fully matched donors are comparable to those of matched-related donors.219-221
The potential use of transplantation must be tied to faithful monitoring of disease, because the major potential pitfall in delaying transplantation is “missing” the chronic-phase interval. Outcome is clearly better for patients in chronic phase when they receive a transplant than for those with advanced disease; 5-year survival rates after matched-related transplants are approximately 75%, 40%, and 10% for patients in chronic, accelerated, and blast crisis phases, respectively.221 Survival has improved across all European Group for Blood and Marrow Transplantation risk groups because of significant reduction in treatment-related mortality and incidences of relapse.222 However, survival is still poor for patients transplanted in accelerated or blast phase (40%-47% and 16%, respectively) compared with 70% for those transplanted in chronic phase.
Results from the German CML IV study also confirmed these findings.223 In a subgroup analysis among 84 patients who underwent allogeneic HSCT because of either a high-disease risk score at diagnosis, imatinib failure, or disease progression, the 3-year survival rates were 91% for patients in chronic phase and 59% for those in advanced phase, with a treatment-related mortality of 8%.223 Complete molecular remissions were observed in 88% of patients who received a transplant. A more recent CIBMTR report showed that patients who receive allogeneic HSCT for CML in first chronic phase and remain in remission for at least 5 years have favorable subsequent long-term survival.224
A recent report from MD Anderson Cancer Center indicated that allogeneic HSCT is an effective strategy for patients with CML who have the T315I mutation, particularly in earlier stages.225 In a more recent analysis of patients with imatinib-resistant CML (chronic phase, n = 34; accelerated phase, n = 9; and blast phase, n = 4) who underwent HSCT at MD Anderson Cancer Center, the overall response rate was 89%, and 68% of patients had an MMR.226 The 2-year event-free survival rate was 36% for patients with BCR-ABL mutations and 58% for those with no mutations, respectively. The corresponding 2-year overall survival rates were 44% and 76%, respectively. These findings indicate that allogeneic HSCT is an appropriate treatment option in patients for whom TKI therapy failed and those with T315I and other BCR-ABL mutations.
Investigational approaches using nonmyeloablative “mini transplants” have been pioneered to engender a graft-versus-leukemia effect without exposing the patient to the toxicity associated with the myeloablative preparative regimen.227-232 These studies are still investigational but promising, and show that molecular remissions may be achieved in patients with CML.
A concern exists that previous treatment with imatinib might have a deleterious effect on subsequent transplant outcomes, as previously implicated with busulfan and interferon.233-235 However, several large studies examining the use of imatinib before transplant found no significant increase in death, relapse rate, and nonrelapse mortality in these patients over those who did not receive pretransplant imatinib.236-238 These data suggest that pretransplant imatinib does not compromise the outcome of a subsequent allogeneic transplant. In fact, CIBMTR data showed prior use of imatinib to be associated with improved survival for patients undergoing transplant in chronic phase.237
Some studies have also shown that using a second-generation TKI before allogeneic HSCT does not affect the outcome of transplant nor does it increase transplant-related toxicity.239-243
NCCN Recommendations
CP-CML: Given the successful induction of durable responses with imatinib in most patients and the recent results showing superior early efficacy of nilotinib and dasatinib in those with newly diagnosed CML, allogeneic HSCT is no longer recommended as a first-line treatment option for patients with CP-CML. In a randomized study, primary HSCT and drug treatment were compared in 621 patients with newly diagnosed CML.244 Among the 354 patients who were eligible for HSCT based on the availability of a related donor, 123 received a HSCT and 219 received the best possible drug treatment (interferon until imatinib became available later in the trial; imatinib was offered to patients for whom interferon failed). Survival with drug therapy was clearly superior for the first 5 years. Survival differences were significant in low-risk patients, and no survival difference was observed in intermediate-risk or high-risk patients.244
The role of HSCT in the treatment of CML should be discussed with the patient. Allogeneic HSCT is recommended for patients with the T315I mutation whose disease does not respond to imatinib, dasatinib, or nilotinib. Nonmyeloablative transplant is investigational and should be performed only in a clinical trial.
Evaluation for allogeneic HSCT based on response to second-line TKI therapy is recommended for all patients whose disease fails to respond firstline TKI therapy, as indicated by the following:
-
Less than CHR at 3 months
-
No cytogenetic response at 6 months
-
Minor or no cytogenetic response at 12 months
-
Partial cytogenetic response at 18 months
-
Cytogenetic relapse at 12 or 18 months
Disease Progression: Allogeneic HSCT can be considered for patients experiencing disease progression after first-line TKI therapy. In patients with disease progression on TKI therapy, treatment with a course of an alternate TKI (not received before) will be beneficial as a “bridge” to transplantation.
Disease Monitoring and Follow-up Therapy after Allogeneic HSCT
The BCR-ABL transcripts persist after many years in most patients after allogeneic HSCT. Several studies examined the clinical significance of monitoring BCR-ABL transcript levels using QPCR after HSCT.245-250 Radich et al.247 reported that PCR positivity 6 or 12 months after HSCT is associated with a higher risk of disease relapse (42%) than negative PCR results (only 3%). This study also showed that early PCR positivity is associated with more aggressive disease and a high risk of relapse. Olavarria et al.249 reported similar findings. QPCR was performed at 3 to 5 months after allogeneic HSCT. At 3 years after allogeneic HSCT, the cumulative relapse rate was 17% for patients with no evidence of BCR-ABL transcripts, 43% for those who had fewer than 100 BCR-ABL transcripts, and 86% for those with more than 100 BCR-ABL transcripts.249 PCR positivity at 6 months or less was also highly predictive of relapse in patients who received a T-cell-depleted transplant.248 The prognostic significance of BCR-ABL positivity is less evident after a longer period after transplantation. Costello et al.251 reported that the relapse rate was only 8% in patients who were BCR-ABL-positive at more than 36 months after HSCT.
Other investigators have reported that BCR-ABL transcripts persist even in patients who experience complete remission for more than 10 years after HSCT.252 More recently, Radich et al.250 analyzed 379 consecutive patients with CML alive at 18 months or more after HSCT to assess the relapse risk associated with BCR-ABL detection in “late” CML survivors. Of 379 patients, 90 (24%) had at least one positive BCR-ABL test 18 months after transplantation or later; 13 of 90 BCR-ABL-positive patients (14%) and 3 of 289 BCR-ABL-negative patients (1.0%) experienced relapse.
Thus, the prognostic significance of BCR-ABL positivity is influenced by the time of testing after transplantation. Although a QPCR assay positive for BCR-ABL at 6 to 12 months after transplant is associated with a high risk of relapse, a positive QPCR assay at a much later time point after transplant is associated with a lower risk of relapse. Early detection of BCR-ABL transcripts after transplant may be useful for identifying patients who may be in need of alternative therapies before the onset of complete relapse.
Donor lymphocyte infusion (DLI) is effective in inducing remissions in patients with relapsed CML after allogeneic HSCT, although it is more effective in chronic phase than advanced phase.253 DLI induces complete remissions in most patients with CML experiencing early-stage relapse.254 DLI is also associated with complications, such as graft-vs-host disease (GVHD), susceptibility to infections, and immunosuppression. Improvements in the methods of detecting BCR-ABL transcripts to predict relapse; modified delivery of lymphocytes with the deletion of CD8+ cells and escalating the dose of donor T cells; and the development of reduced-intensity conditioning regimens have reduced the incidence of GVHD.255,256
Recently, imatinib has been shown to be very effective in inducing remissions, particularly in patients with relapsed CP-CML after allogeneic HSCT.238,257-261 In a prospective evaluation of patients with Ph-positive ALL or CML beyond first chronic phase treated with myeloablative conditioning, Carpenter et al.261 showed that imatinib can be safely administered during the first 90 days after myeloablative allogeneic HCT at a dose-intensity comparable to that used in primary therapy.261 However, in a recent retrospective analysis, disease-free survival was significantly higher among patients receiving DLI than among those in the imatinib group.262 A trend was also seen toward higher rates of complete molecular remissions in the DLI group. These observations are yet to be confirmed in randomized trials. In patients whose disease previously failed to respond to imatinib, no data support the use of posttransplant imatinib. Other TKIs, such as dasatinib or nilotinib, may be more appropriate. Dasatinib has been shown to eradicate central nervous system leukemia.263
NCCN Recommendations
Patients who continue to be in complete cytogenetic remission (QPCR-negative) should undergo regular QPCR monitoring (every 3 months for 2 years, then 6 months for 3 years). Imatinib, dasatinib, DLI, or interferon or pegylated-interferon can be considered options for patients experiencing cytogenetic relapse or those with an increasing level of molecular relapse. Discussion of treatment options with a transplant team is recommended. Participation in a clinical trial should be considered.
Given the high risk for hematologic relapse in patients with prior accelerated or blast phase, posttransplant TKI therapy should be considered for at least 1 year in this cohort of patients who are experiencing remission after allogeneic HSCT.261 For patients who are not experiencing remission or cytogenetic relapse after allogeneic HSCT, monitored withdrawal of immune suppression is recommended before the initiation of follow-up therapy with imatinib, dasatinib, DLI, or interferon or pegylated-interferon.
Summary
CML is a hematopoietic stem cell disease characterized by the presence of the Philadelphia chromosome resulting from the translocation between chromosomes 9 and 22 [t(9;22].
The development of imatinib mesylate, a potent and specific inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the treatment of CML. The results of the IRIS trial established the safety, efficacy, and excellent survival benefit of imatinib in patients with newly diagnosed CML. Imatinib mesylate is the standard first-line treatment for newly diagnosed CP-CML, given at an initial standard dose of 400 mg daily. In recent randomized studies, dasatinib and nilotinib were associated with significantly higher response rates and a reduction in the 12-month incidence of accelerated or blast phase in patients with newly diagnosed CML. These guidelines now include dasatinib and nilotinib as alternative treatment options for patients with newly diagnosed CML.
Monitoring treatment response to TKI therapy is crucial in the management of patients with CML to assess response and detect resistance. These guidelines recommend monitoring response at 3, 6, 12, and 18 months. Patients with suboptimal response (minor cytogenetic response at 6 months and partial cytogenetic response at 12 months) represent a subgroup who require careful monitoring and may benefit from alternate treatment options. Continuation of TKI therapy with dasatinib or nilotinib at the same dose; imatinib dose escalation to 800 mg as tolerated; or a change of therapy to an alternate second-generation TKI are included as options for this group of patients. Determining mutational status at the time of loss of response to a first-generation TKI would be helpful for selecting subsequent TKI therapy. These guidelines recommend mutational analysis in the presence of an inadequate initial response, any sign of loss of response, or disease progression.
Primary hematologic resistance to imatinib is rare in patients with newly diagnosed CP-CML, whereas primary cytogenetic resistance is observed in 15% to 25% of patients. Additionally, some patients will eventually develop secondary resistance to imatinib related to the presence of BCR-ABL mutations, resulting in disease progression. Dose escalation of imatinib has been shown to overcome resistance in some patients experiencing cytogenetic failure while on standard-dose imatinib, particularly those with prior cytogenetic response. Dasatinib and nilotinib are effective in patients with imatinib-resistant or imatinib-intolerant CP-CML. Patients not experiencing response to a second-generation TKI in the first-line setting should be switched to the other second-generation TKI (that they have not received before) for second-line therapy.
Dasatinib or nilotinib are recommended for patients whose disease progresses to accelerated phase. Allogeneic HSCT can be considered based on response to therapy. TKI therapy either alone or in combination with chemotherapy, followed by allogeneic HSCT, is recommended for patients experiencing progression to blast phase.
Allogeneic HSCT remains a potentially curative treatment for patients with CML and is recommended for patients with the T315I mutation and those who experience progression to accelerated or blast phase. For most patients, a trial of alternate TKI (not received before) is reasonable before proceeding to allogeneic HSCT. Posttransplant TKI therapy should be considered for at least 1 year in patients with prior accelerated or blast phase who are experiencing remission after allogeneic HSCT.
Availability of more-potent TKIs has widened the treatment options, and the outlook for patients with CML continues to look promising. Selection of appropriate TKI therapy will depend on the stage of the disease, the agent's side-effect profile, and its relative effectiveness against BCR-ABL mutations.
Individual Disclosures for the NCCN Guidelines Panel for Chronic Myelogenous Leukemia
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