Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Authors


Abstract

Identification of BCR-ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR-ABL inhibitor, is the standard of care for the first-line treatment of patients with chronic-phase CML because of its high long-term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard-dose imatinib (400 mg daily), imatinib dose escalation (600-800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR-ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second-generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib-resistant or imatinib-intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

Chronic myelogenous leukemia (CML), which accounts for 15% of adult leukemias in Western countries, can occur at any age, although the incidence of the disease increases with age.1 CML is characterized by a translocation that involves fusion of the Abelson oncogene (ABL) located on chromosome 9q34 with the breakpoint cluster region (BCR) on chromosome 22q11.2. The reciprocal translocation t(9;22)(q34;q11.2) results in a shortened chromosome 22 called the Philadelphia (Ph) chromosome, 22q-, which encodes the cytoplasmic fusion protein BCR-ABL. This protein has constitutive tyrosine kinase activity, which stimulates hematopoietic transformation.2-7 Various translocation breakpoints and differential messenger RNA splicing result in different isoforms of BCR-ABL associated with specific leukemia types (Fig. 1).3, 8 The predominant isoform of BCR-ABL is a 210-kDa protein that is present in >90% of patients with CML.8

Figure 1.

The t(9;22) translocation and its products, the breakpoint cluster region-Abelson (BCR-ABL) oncogene on the Philadelphia chromosome (Ph), and the reciprocal ABL-BCR on chromosome 9q+ are shown. The most common isoform, p210, contains functional domains from the amino terminus of BCR (dimerization domain [DD], sarcoma (Src) homology 2 [SH2]-binding [bind.] domain [P-S/T], and the Rho GTP-GDP exchange factor [rho-GEF] domain) and the carboxy terminus of ABL (Src homology regions SH1, SH2, and SH3 and the DNA-binding [bind.] and actin-binding domains). Reprinted with permission from Melo JV, Deininger MW. Biology of chronic myelogenous leukemia—signaling pathways of initiation and transformation. Hematol Oncol Clin North Am. 2004;18:545-568, with permission from Elsevier.3

Use of Tyrosine-Kinase Inhibitors for the Treatment of CML

Imatinib, dasatinib, and nilotinib all are approved BCR-ABL inhibitors for use in the treatment of patients with CML. However, all 3 inhibit tyrosine kinases other than BCR-ABL. Imatinib targets BCR-ABL, ABL, ABL-related gene (ARG) product, C-kit receptor (KIT), the platelet-derived growth factor receptors alpha (PDGFRα) and PDGFRβ, and colony-stimulating factor 1 receptor (c-FMS).9-13 Dasatinib targets several kinases, including BCR-ABL, ABL, ephrin type-A receptor 2 (EPHA2), KIT, PDGFR, and sarcoma (Src) family members14; whereas nilotinib inhibits BCR-ABL, ABL, ARG, KIT, and PDGFR (Table 1).15, 16

Table 1. Targets of Imatinib, Nilotinib, and Dasatinib
ImatinibNilotinibDasatinib
  1. Adapted from Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma. 2008;49:615-619.16

ABLABLABLBMXILK
ARGARGARGTXKLIMK1
BCR-ABLBCR-ABLBCR-ABLDDR1LIMK2
KITKITKITDDR2MYT1
PDGFRPDGFRPDGFRACKNLK
DDR1DDR1SRCACTR2BPTK6/Brk
NQO2NQO2YESACVR2QIK
  FYNBRAFQSK
  LYNEGFR/ERBB1RAF1
  HCKEPHA2RET
  LCKEPHA3RIPK2
  FGREPHA4SLK
  BLKEPHA5STK36/ULK
  FRKFAKSYK
  CSKGAKTAO3
  BTKGCKTESK2
  TECHH498/TNNI3KTYK2
    ZAK

Imatinib

Imatinib is the standard of care for first-line treatment of chronic-phase CML (CML-CP) because of its high long-term response rates and favorable tolerability profile compared with previous standard therapies. Imatinib, as an effective inhibitor of BCR-ABL, targets a key initiation event in the development of CML (Fig. 2).17-19

Figure 2.

This is a molecular model of imatinib binding within the ABL kinase domain of the BCR-ABL tyrosine kinase.

After phase 1 studies,18, 19 a phase 2 study of imatinib was initiated in 532 interferon alpha (IFN)-resistant/refractory patients who had late-phase CML-CP.20 Imatinib was associated with high response rates: A major cytogenetic response (MCyR) was observed in 67% of patients, a complete cytogenetic response (CCyR) was in observed in 57% of patients, and a complete hematologic response (CHR) was observed in 96% of patients. Imatinib also conferred survival benefits, with 6-year progression-free survival (PFS) and overall survival (OS) rates of 61% and 76%, respectively. Imatinib also was well tolerated, as serious grade 3/4 adverse events (AEs) were uncommon, occurring in <5% of patients. At the 6-year cutoff, 255 patients (56%) discontinued the study: Eight percent discontinued treatment because of AEs.

The superiority of imatinib over IFN was established in the phase 3 International Randomized Study of Interferon and STI571 (IRIS) trial.21, 22 In that study, 1106 treatment-naive patients with CML-CP were randomized to receive either imatinib 400 mg daily or IFN plus cytarabine (n = 553 patients each).22 At 18 months, an MCyR was achieved in 87% of patients who received imatinib compared with 35% of patients who received IFN (P < .001). Most imatinib-treated patients experienced a CCyR (76.2% vs 14.5% with IFN; P < .001). A major molecular responses (MMR), defined as a decrease ≥3-log in BCR-ABL transcripts compared with a standardized baseline value, occurred in 39% of imatinib-treated patients versus 2% of IFN-treated patients (P < .001) (Fig. 3).21 The MMR rate was higher in patients who achieved a CCyR (57% for imatinib vs 24% for IFN; P = .003). After 6 years of imatinib therapy, long-term response rates remained high.23, 24 Of the 456 patients who achieved a CCyR on imatinib therapy, 325 patients (71%) were still on study treatment and maintained a CCyR at 6 years. From Year 1 to Year 6, the annual event rate (loss of CHR, loss of MCyR, progression to accelerated phase/blast crisis [AP/BC], or death) on imatinib decreased over time (3.3%, 7.5%, 4.8%, 1.7%, 0.8%, and 0.4% for Years 1-6, respectively).23

Figure 3.

A reduction from baseline in transcript levels of BCR-ABL is illustrated compared with baseline levels in patients on both arms of the International Randomized Study of Interferon and STI571 trial after 12 months on therapy.13 Approximately 39% of the patients who received imatinib had a reduction of at least 3 log at 12 months, compared with 2% of patients who received interferon plus cytarabine (P < .001). Reprinted with permission from Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432. Copyright © 2003 Massachusetts Medical Society. All rights reserved.21

There was a downward trend in the risk of disease progression on imatinib, with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC between Years 5 and 6. Approximately 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib treatment. The estimated 6-year survival rate for all patients who received imatinib as initial therapy was 88%, and the rate was 95% for CML-related deaths only. The 6-year PFS (without progression to AP/BC) occurred in 97% of patients who achieved a CCyR within 6 months compared with 80% of patients without a CCyR at this early time point (P < .001) (Fig. 4). The IRIS study demonstrated that, in addition to its efficacy advantages, imatinib was tolerated better than high-dose IFN.22 Grade 3/4 AEs, including fatigue, depression, myalgias, arthralgias, neutropenia, and thrombocytopenia, were more common in the IFN arm. AEs in the imatinib arm were mostly grade 1 or 2. The most common grade 3/4 AEs among the patients who received imatinib were neutropenia (14%), thrombocytopenia (8%), anemia (3%), and elevated liver enzymes (5%). These AEs were not cumulative and decreased over time, occurring mostly in Years 1 and 2, and the rates decreased to <2% after Year 4.25 Typically, severe cytopenias can be managed effectively in patients who receive imatinib 400 mg daily by temporary withdrawal of imatinib. After resolution of the cytopenia, imatinib may be restarted at a lower dose of 300 mg daily and, if tolerated, imatinib 400 mg daily can be resumed. However, if cytopenia persists and has an adverse impact on the course of imatinib therapy, then nilotinib or dasatinib may be used as alternative treatment options for these patients.

Figure 4.

The rate of progression to accelerated phase (AP) or blast crisis (BC) is illustrated in patients with chronic myelogenous leukemia according to the response after 6 months of imatinib therapy.45 CCyR indicates complete cytogenetic response; Ph+, Philadelphia chromosome positive; PCyR, partial cytogenetic response; CyR, cytogenetic response. Reprinted by permission from Macmillan Publishers, Ltd. Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054-1061.23

Follow-up at 6 years revealed that imatinib has a favorable long-term safety profile.23 No new serious AEs were identified between Years 5 and Year 6. Furthermore, first-line treatment with imatinib did not affect later success on salvage therapies (IFN, allogeneic hematopoietic stem cell transplantation [HSCT]).26, 27 The survival benefits of imatinib could not be determined in the IRIS study because of the high rate of patient crossover, but they were confirmed by historic comparison studies.28, 29 A retrospective comparison of newly diagnosed patients with CML who received imatinib (n = 279) or IFN (n = 650) at The University of Texas M. D. Anderson Cancer Center (MDACC) demonstrated improved response and survival for imatinib-treated patients.28 CCyR rates were 87% for imatinib-treated patients versus 28% for IFN-treated patients (P < .001). Survival was correlated with cytogenetic response for both imatinib and IFN, suggesting that the survival benefits of imatinib were a result of the high cytogenetic response rates induced by this drug. The estimated 5-year survival rate was significantly higher (88%) for imatinib-treated patients compared with IFN-treated patients (63% P = .001). The benefits of imatinib were observed in all prognostic risk groups. Another retrospective study that examined outcomes from the imatinib arm of the IRIS trial and the IFN/cytarabine arm of the CML91 trial was in complete concordance with the MDACC study.29 The safety, response, and survival advantages of imatinib over IFN has led to broad acceptance of imatinib as the drug of choice for initial therapy of CML.21-23

Assessing imatinib response and resistance

The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) recommend similar monitoring schedules for patients who are treated with imatinib.1, 30, 31 When a patient initiates treatment with a tyrosine kinase inhibitor (TKI), bone marrow cytogenetics should be measured every 6 months until a CCyR is achieved and then every 1 to 3 years as long as MMR is stable. BCR-ABL transcript levels should be monitored at least every 3 months and every 3 to 6 months once a CCyR is reached.31 To assess MMR, major guidelines recommend determining BCR-ABL transcript levels every 3 months to 6 months using real-time, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and should be expressed according to an international scale.31 In patients with rising BCR-ABL levels, transcript testing may be performed more frequently, and BCR-ABL mutation analysis may be considered. Definitions of imatinib response are provided in Table 2.30 Updated ELN recommendations have been elaborated. Updated NCCN guidelines are available now, and physicians should use either the updated ELN or NCCN documents as resources for the management of their patients moving forward.

Table 2. Definitions of Poor Response to Imatinib
 Response
Time on Imatinib, moFailureSuboptimal
  1. CHR indicates complete hematologic response; CyR, cytogenetic response; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome positive; CCyR, complete cytogenetic response; MMR, major molecular response; T315I mutation, threonine-to-isoleucine mutation of Bcr-Abl at codon 315.

  2. Adapted from Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–6051.

3Less than CHRNo CyR (Ph+ >95%)
6No CyR (Ph+ >95%)Less than PCyR (Ph+ >35%)
12Less than PCyR (Ph+ >35%)PCyR (Ph+ 1% to 35%)
18Less than CCyRLess than MMR
AnyLoss of CHR; loss of CCyR; T315I and imatinib insensitive mutations; clonal evolutionLoss of MMR; other mutations

There is debate over the definition of “rising” transcript levels and the threshold at which such a rise should constitute a change in therapy. A 2-fold increase in BCR-ABL transcript levels has been associated with detectable BCR-ABL mutations.31 Some investigators advocate mutational analysis for patients who experience a 2-fold to 10-fold rise in BCR-ABL transcript levels by quantitative PCR.32 In a prospective study of 90 patients who had CML in CCyR on imatinib, an increase in BCR-ABL RNA levels >3.2-fold was a significant predictor of disease recurrence and may be an appropriate threshold for considering a change in therapy.33 Conversely, in a more recent study, Kantarjian et al observed that, for most patients in CCyR during imatinib therapy, a rising transcript level did not generally increase the risk of progression.32 Only those patients who lost an MMR or who never achieved an MMR were at increased risk for disease progression when transcript levels increased more than 1-log as determined by PCR.

In all instances of rising transcript levels, it is important to determine whether the patient was fully compliant with their imatinib therapy. Imatinib trough blood level concentrations at 4 weeks into therapy have been associated with outcome.34 Imatinib blood level testing also may be useful when a patient does not achieve or has lost an optimal response, exhibits signs of potential drug-drug interactions, or is experiencing unusually severe side effects. However, the results of individual imatinib blood level tests should be considered with caution, because they may not be a true reflection of long-term imatinib blood levels and, thus, may not necessarily have an impact on the course of therapy.

Resistance to imatinib developed in 2% to 4% of patients annually. In the IRIS trial, the estimated annual event rate after the start of imatinib therapy was 3.3% in the first year, 7.5% in the second year, 4.8% in the third year, 1.5% in the fourth year, 0.8% in the fifth year, and 0.4% in the sixth year.23 The most common cause of secondary imatinib resistance is point mutations in BCR-ABL that prevent effective binding of imatinib but may retain kinase activity.35-39 These mutations are clustered primarily within the kinase domain of BCR-ABL (ABL exons 4-10).40 They exhibit differential relative resistance to imatinib in vitro.36 Representatives of high-level resistance mutations are Y253F/H or E255K/V.36 Mutation T315I has no residual sensitivity to imatinib and also confers resistance to second-generation TKIs.15, 41 Mutations associated with intermediate resistance include M244V, M351T, H396P/R, and F359V.42 High-dose imatinib may prevent the development of mutations that confer imatinib resistance.43

The prognostic impact of BCR-ABL mutations is difficult to determine, and routine mutational analysis is not recommended currently in the absence of treatment failure or suboptimal response.40, 44, 45 Suboptimal imatinib response, for instance, may be caused by BCR-ABL–independent factors, such as lack of compliance with long-term therapy. The NCCN and the ELN recommend continuation of standard-dose imatinib or dose escalation to 600 mg or 800 mg daily in patients who have a suboptimal response.1, 30 Treatment options for patients without an adequate response to imatinib include high-dose imatinib, a second-generation TKI (such as nilotinib or dasatinib), a clinical trial, or allogeneic HSCT.1, 30

High-dose imatinib

On the basis of the IRIS results, the recommended starting dose of imatinib is 400 mg once daily. However, higher doses currently are being investigated in previously treated, slowly responding patients; patients with loss of response; and populations with treatment-naive CML. In a study of patients with recurrent/refractory CML-CP, a dose increase of imatinib to 800 mg daily led to a CHR in 65% of patients, and 56% of patients who previously were unresponsive to 400 mg daily achieved a CCyR or a partial cytogenetic response.46 Several other studies have confirmed the efficacy of high-dose imatinib (600 mg or 800 mg daily) in patients who had suboptimal responses to standard-dose imatinib. Investigators at MDACC evaluated long-term efficacy in 84 patients with CML-CP who had dose escalation on imatinib.47

At a median follow-up of 61 months, 69% of patients remained alive. A CCyR was achieved in 34 patients (40%), including 33 of 63 patients (52%) with cytogenetic failure and 1 of 21 patients (5%) with hematologic failure. Responses were long lasting: An MCyR lasted a median of 5 years. The 3-year event-free and OS rates were 47% and 76%, respectively. Another evaluation of 23 patients with CML-CP who received imatinib dose escalations for cytogenetic or molecular suboptimal responses to standard doses of imatinib supported these findings.48 All 10 patients who had a cytogenetic suboptimal response obtained a CCyR after a median of 4 months on high-dose imatinib, and 5 of 13 patients (38%) who had a suboptimal molecular response achieved an MMR after a median follow-up of 11 months. A retrospective analysis of dose escalation among patients who were randomized to receive first-line imatinib in the IRIS trial demonstrated that many patients can achieve improved, durable responses with an increased dose of imatinib.49 Among the 33 patients who met IRIS criteria for dose escalation, 17 patients (52%) achieved the clinical hematologic or cytogenetic response that they failed to achieve or previously lost. Nine of those patients (27%) achieved an MCyR. Thus, imatinib dose escalation can restore sustained molecular and cytogenetic responses in patients with failure or suboptimal response to standard-dose imatinib.

High-dose imatinib also has demonstrated high cytogenetic and molecular response rates in patients with newly diagnosed CML-CP. In a cohort of 114 newly diagnosed patients who received 800 mg daily imatinib, high-dose imatinib was associated with improved rates of CCyR (P = .0005), MMR (P = .00001), and complete molecular response (P = .001) compared with a historic control group that received standard-dose imatinib.43 A phase 2 dose-escalation study in imatinib-naive patients who were started on 600 mg daily and increased to 800 mg daily if response criteria were not met further demonstrated CCyR and MMR rates that exceeded those of the IRIS trial.50

These promising results prompted the initiation of several prospective randomized trials evaluating high-dose imatinib in newly diagnosed patients. The randomized phase 3 Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study evaluated 400 mg (standard-dose imatinib [SD-IM]) versus 800 mg (high-dose imatinib [HD-IM]) in patients with newly diagnosed, previously untreated CML-CP. The primary endpoint of the trial was the MMR rate at 12 months. Preliminary results from the study indicated that the CCyR was significantly better at 6 months with HD-IM (45% SD-IM vs 57% HD-IM; P = .0146), but there was no statistical difference in CCyR at 12 months (66% SD-IM vs 70% HD-IM).51 MMR rates were higher with HD-IM at 3 months and 6 months compared with SD-IM (12% vs 3% at 3 months, P = .0011; 34% vs 17% at 6 months, P = .0002) although no difference in the MMR rate at 12 months was observed (46% vs 40%; P = .20). However, there was a trend toward improved MMR at 12 months in patients who had high Sokal risk scores (26% SD-IM vs 41% HD-IM; P = .16).51 The ELN also performed a randomized study of standard-dose imatinib (400 mg daily) versus high-dose imatinib (800 mg daily) as front-line therapy for patients with high Sokal risk CML-CP in which the CCyR rate at 12 months was the primary endpoint.52 There was no difference in the CCyR rate at 12 months in the intention-to-treat analysis. CCyR was correlated with mean daily dose, where the rate of CCyR was 86% among patients who received a median daily imatinib dose of 600 mg to 800 mg compared with 66% for patients who received a median daily dose <600 mg (P = .013).

Other potential dosing strategies for imatinib currently are being explored. An ongoing phase 3 study is comparing SD-IM (400 mg daily) versus induction with HD-IM (800 mg daily) for 6 months, followed by a dose reduction to SD-IM in pretreated patients.53 Early results indicate that significantly more patients who received HD-IM induction followed by maintenance achieved an MCyR than patients who received SD-IM at 12 weeks and 24 weeks (P = .01 and P = .009, respectively). Furthermore, more patients on HD-IM achieved a CCyR at 12 weeks, 24 weeks, and 48 weeks (12 weeks: 6.2% vs 24.5%; P < .001; 24 weeks: 20% vs 44%; P < .001; 48 weeks: 37% vs 48%, nonsignificant). High-dose imatinib was associated with higher rates of AEs, including grade 3/4 anemia, neutropenia, and thrombocytopenia,53, 54 along with rash, diarrhea, myalgia, superficial edema, and dyspnea.54

For nontrial patients who have CML-CP, the recommended starting dose of imatinib should be 400 mg daily based on long-term data from the IRIS trial and on confirmatory data from the TOPS study.24, 51 It has been demonstrated that imatinib 800 mg daily is an effective strategy for overcoming resistance to imatinib 400 mg daily and can be tolerated long-term, as demonstrated in the studies of imatinib dose escalation from the IRIS and MDACC studies and from the TOPS study.47, 49, 51

Second-Generation TKIs

Nilotinib

Nilotinib is a derivative of imatinib that is highly selective against ABL. It is 30-fold more potent than imatinib at inhibiting BCR-ABL in vitro.15, 55 Nilotinib also inhibits ARG, KIT, PDGFR-α, and PDGFR-β15 but does not affect Src, fms-like tyrosine kinase 3 (FLT-3), vascular endothelial growth factor receptor, or epidermal growth factor receptor kinases. Nilotinib is active against most imatinib-resistant mutants except T315I in both cell culture and murine models.15, 55, 56

In a dose-ranging (50 mg once daily to 600 mg twice daily) phase 1 study in 119 patients with imatinib-resistant CML, nilotinib demonstrated activity in all phases of CML.57 Eleven of 12 patients who had CML-CP (92%) had a CHR. Thirty-three of 46 patients (72%) who had CML-AP had a hematologic response, and 22 patients (48%) had a cytogenetic response; 13 of 33 patients (39%) with CML-BC had a hematologic response, and 9 patients (27%) had a cytogenetic response. Responses were comparable among patients with or without BCR-ABL mutations. Results from that phase 1 study led to the recommended dose of 400 mg twice daily.

Approval of nilotinib was based on a phase 2 trial of patients with imatinib-resistant or imatinib-intolerant CML in all phases. Among patients with CML-CP (N = 321; 71% imatinib resistant and 29% imatinib intolerant),58, 59 158 of 206 patients (77%) who did not have a CHR at baseline achieved a CHR during nilotinib therapy. An MCyR was noted in 186 patients (59%), and 44% achieved a CCyR. Most of those patients (84%) maintained an MCyR for >18 months, and the response was rapid (median time to MCyR, 2.8 months). The 18-month survival rate was 91%.

Nilotinib also has demonstrated activity in patients who failed both prior imatinib and prior dasatinib.60 Among 37 evaluable patients with CML-CP, 81% achieved a CHR with nilotinib therapy, 38% achieved an MCyR, and 18% achieved a CCyR.

Nilotinib has a favorable overall tolerability profile.57 Nilotinib was associated with very low rates of pleural or pericardial effusions (approximately 1; none have been grade 3/4).58 The most common grade 3/4 AEs associated with nilotinib therapy were thrombocytopenia (20%-33%), neutropenia (13%-31%), elevated bilirubin (7%), and elevated serum lipase (5%-15%).57, 58, 61 Food increases the bioavailability of nilotinib,62 and no food should be taken at least 2 hours before and at least 1 hour after nilotinib is taken. Grapefruit products and other foods that are known to inhibit hepatic metabolic pathways like CYP3A4 should be avoided. Patients with baseline corrected QT (QTc) prolongation should not receive nilotinib, and medications that prolong the QTc interval should be avoided on nilotinib therapy.

Low rates of cross intolerance with imatinib have been reported in nilotinib-treated patients.63 Only 1% of patients with imatinib intolerance caused by nonhematologic AEs experienced a recurrence of similar grade 3/4 AEs during nilotinib therapy and did not lead to dose reductions or discontinuations. Of 39 patients who had imatinib intolerance because of hematologic AEs, only 7 (18%) discontinued nilotinib therapy because of a recurrence of similar grade 3/4 AEs; all occurred in patients with CML-CP who experienced intolerable thrombocytopenia.

In a recent subanalysis of a phase 2 study of nilotinib treatment in patients with CML-CP that compared those with and without a baseline mutation, the response to nilotinib did not differ statistically between the 2 groups.64 Only patients who harbored BCR-ABL mutations with lower sensitivity to nilotinib in vitro (50% inhibitory concentration [IC50] >150 nM) had less favorable responses, and 13%, 43%, and 9% of patients who harbored the Y253H, E255V/K, and F359V/C mutations achieved an MCyR, respectively. No patients who had these baseline mutations achieved a CCyR. Thus, imatinib-resistant patients with BCR-ABL mutations benefit from nilotinib therapy except perhaps patients with Y253H, E255V/K, F359V/C, and T315I mutations. Approximately 20% of patients had newly detectable BCR-ABL mutations during nilotinib therapy, and this appeared to be more frequent in patients who had baseline mutations (30%) compared with those who had no baseline mutation (11%).

Dasatinib

Dasatinib is an ABL kinase inhibitor that binds the active conformation of the ABL kinase domain and also targets similarly structured Src family kinases. There has been debate and there is conflicting evidence regarding its ability to also bind the inactive confirmation.65, 66 Dasatinib is approximately 300 times more active than imatinib in vitro toward unmutated BCR-ABL.41 Dasatinib inhibits all imatinib-resistant BCR-ABL mutants except T315I41 and possibly F317L.67, 68 It inhibits PDGFRs and KIT more potently than imatinib or nilotinib and also inhibits the ephrin receptor tyrosine kinases68 and the Src family kinases.69

Results from phase 2 trials led to the approval of dasatinib in the United States, the European Union, and other regions for use in imatinib-resistant CML.70-73 In SRC/ABL Tyrosine Kinase Inhibition Activity Research Trial C (or the START-C trial), dasatinib was administered at 70 mg twice daily to 387 patients who had CML-CP and resistance (n = 288) or intolerance (n = 99) to imatinib.70 After a median follow-up of 15.2 months, 91% of patients achieved a CHR, 59% achieved an MCyR, and 49% achieved a CCyR. Responses to dasatinib were durable, and 97% of patients who achieved an MCyR maintained this response at 18 months. Survival rates were noteworthy, with PFS and OS rates of 90% and 96%, respectively.

Grade 3/4 hematologic toxicities in the phase 2 study of patients with imatinib-resistant or imatinib-intolerant CML-CP were thrombocytopenia (48%), anemia (22%), neutropenia (49%), and leukopenia (27%).70 Dasatinib also was associated with grade 3/4 nonhematologic AEs, including pleural effusion in 6% of patients.70 To minimize dasatinib-related toxicity while maintaining efficacy, a dose-optimization study was initiated.74 In that phase 3 trial, 670 patients with imatinib-resistant or imatinib-intolerant CML-CP were randomized to receive 1 of 4 doses of dasatinib: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Patients who received dasatinib once daily (100 mg once daily) achieved an MCyR rate comparable to that achieved by patients who received dasatinib twice daily (70 mg twice daily). It is noteworthy that the rates of grade 3/4 hematologic and nonhematologic toxicities, including pleural effusions, were decreased with 100 mg once-daily dasatinib dosing.74 Currently, a once-daily dose of 100 mg is approved for patients with CML-CP based on these findings. Dasatinib at 70 mg twice daily and 140 mg once daily currently are dosing options for patients with CML-AP and CML-BC. The once-daily dosing of dasatinib in patients with CML-AP and CML-BC produced comparable rates of hematologic and cytogenetic response.75, 76 Patients with baseline QTc prolongation should be treated with caution on dasatinib therapy.

The efficacy of dasatinib in patients with CML-CP who failed prior imatinib does not appear to be compromised in patients who have BCR-ABL mutations after imatinib therapy.77 After 2 years of follow-up, response rates were similar in patients with a mutation compared with those without a mutation. Only patients who harbored mutations that had low sensitivity to dasatinib in vitro (IC50 >3 nM; including Q252H, E255K/V, V299L, and F317L) had lower response rates (MCyR, 34%; CCyR, 25%) compared with patients who harbored mutations that had greater sensitivity to dasatinib (IC50 ≤3 nM; MCyR, 58%; CCyR, 47%). Thus, imatinib-resistant patients with BCR-ABL mutations may benefit from dasatinib therapy, except perhaps patients with Q252H, V299L, F317L, and T315I mutations.

Currently, physicians must choose between nilotinib and dasatinib for patients with resistance to imatinib in the absence of head-to-head trials comparing these 2 agents. Thus, decisions on which agent to choose must be based on the individual patient. Overall, the efficacy of these agents is comparable for patients with CML-CP who are resistant to imatinib. A minority of patients with imatinib resistance may harbor BCR-ABL mutations that are less sensitive to either nilotinib or dasatinib.64, 77 For patients with T315I mutations, a clinical trial or allogeneic stem cell transplantation should be considered. However, the majority of patients, regardless of mutation status, will be candidates for effective therapy with either agent. The other critical factor to consider when choosing therapy is the overall safety profile of the agent as well as the patient's preexisting conditions. For example, patients with a history of pulmonary disease might be suited better for nilotinib therapy, whereas patients with a history of severe pancreatitis may be suited better for dasatinib therapy. Overall, the final choice of therapy should be tailored to the individual patient.

The Future of CML Therapy

Possibly the most promising future developments in CML therapy will be the use of second-generation TKIs, such as nilotinib or dasatinib, in the front-line setting. Nilotinib treatment (800 mg daily) is being assessed in patients with newly diagnosed CML-CP in several ongoing studies. In a study that is being conducted at MDACC, a CCyR was achieved in 97% of patients within 6 months of therapy and 50% of patients achieved an MMR by 6 months of therapy. Both CCyRs and MMRs were maintained for 12 months.78 In another study, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML Working Party reported a 97% CCyR rate on nilotinib by 6 months and an MMR rate of 75%.79 Dasatinib also has been evaluated as front-line therapy in a phase 2 study that is being conducted at MDACC. At 6 months, the rate of CCyR was 94%, and the MMR rate was 36%.80 Although these data are promising, the use of second-generation TKIs in patients with newly diagnosed CML-CP cannot be recommended until the results of ongoing phase 3 studies of nilotinib versus imatinib and dasatinib versus imatinib have been reported.

Other TKIs are currently in development for CML. Bosutinib is a dual inhibitor of both the ABL and Src kinases.81-83 Bosutinib is more active than imatinib in vitro and has minimal activity against PDGFR or c-kit.84, 85 In preliminary data from the phase 2 portion of a phase 1/2 study investigating bosutinib in patients with CML-CP and resistance or intolerance to imatinib, 75 of 96 evaluable patients (78%) achieved a CHR, 47 of 106 (44%) achieved an MCyR, and 35 (33%) achieved a CCyR.86 An MMR was achieved in 27 of 85 patients (32%), of which 15 (18%) were complete molecular response (CMR). The most common AEs were gastrointestinal and usually were grade 1/2, manageable, and improved spontaneously after 3 or 4 weeks. Bosutinib also has demonstrated activity in patients with CML in AP and BC with a similar safety profile.87 Imatinib-based combinations are being studied and may increase the efficacy of imatinib and decrease the risk of resistance.88-92 The efficacy and tolerability of IFN maintenance therapy after experimental imatinib/IFN induction has been explored in an attempt to avoid the need for lifelong imatinib therapy.93

Although imatinib has revolutionized therapy for patients with CML-CP, responding patients must continue imatinib therapy indefinitely. Recently, there have been attempts to investigate the feasibility of discontinuing imatinib therapy in patients who achieve a long-term (>2 years) CMR. The Stop Imatinib (STIM) trial has been initiated with the goal of evaluating molecular remissions after imatinib discontinuation.94 Molecular relapse occurred in 41% of patients, and 96% of recurrences occurred within the first 6 months after discontinuation. Although all patients who developed disease recurrence after imatinib discontinuation remained sensitive to imatinib treatment, it is unclear what the long-term consequences of allowing relapse might be for treatment outcomes. Currently, routine discontinuation of imatinib in responding patients cannot be recommended outside of a clinical trial.

Conclusions

Many outstanding issues remain in the field of CML therapy. These include the role of molecular testing in routine patient monitoring, the preferred second-line treatment regimen for patients with imatinib failure, the role of nilotinib and dasatinib as first-line CML therapy, and the future use of novel treatment approaches and combination therapies in both newly diagnosed and treated patients. Results from ongoing studies that have been initiated to address these issues are eagerly anticipated.

Acknowledgements

We thank Erinn Goldman, PhD, and Michael Mandola, PhD (Articulate Science), for medical editorial assistance.

CONFLICT OF INTEREST DISCLOSURES

Financial support was provided by Novartis Pharmaceuticals. Drs. Kantarjian, Cortes, and Hochhaus received research grant funding from Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, and Wyeth Pharmaceuticals. Dr. Hochhaus was supported by the German José Carreras Leukemia Foundation (DJCLS H03/01). Dr. La Rosee received travel expenses from Bristol-Myers Squibb and was a member of the Speakers Bureau for Novartis Pharmaceuticals Corporation.

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