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Leukemia Research 37 (2013) 487– 495

Contents lists available at SciVerse ScienceDirect

Leukemia Research

jo ur nal homep age: www.elsev ier .com/ locate / leukres

nvited review

onsiderations for early switch to nilotinib or dasatinib in patients with chronicyeloid leukemia with inadequate response to first-line imatinib

lfonso Quintás-Cardama ∗, Elias J. Jabbourniversity of Texas, M.D. Anderson Cancer Center, Houston, TX, United States

r t i c l e i n f o

rticle history:eceived 13 July 2012eceived in revised form 10 January 2013ccepted 12 January 2013vailable online 4 February 2013

a b s t r a c t

Clinical evidence in chronic myeloid leukemia demonstrates a significant link between optimal responseto tyrosine kinase inhibitor (TKI) therapy and favorable clinical outcome. For patients with suboptimalresponse to first-line TKI, clinical data show that a considerable proportion can be rescued by second-lineTKI. Practice guidelines now recommend that clinicians consider a switch in TKI for patients with sub-optimal response as early as 3 months after first-line TKI initiation, thus allowing clinicians to intervenein a timely manner and consider the potential benefit of a switch in TKI therapy.

eywords:hronic myeloid leukemia

matinibilotinibasatinibrug resistance

© 2013 Elsevier Ltd. All rights reserved.

dverse drug event

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4872. Early response to TKI treatment predicts favorable long-term outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4903. Second-line nilotinib, dasatinib, and bosutinib after first-line imatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4914. Second-line nilotinib, dasatinib, and bosutinib in patients intolerant of first-line imatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4925. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

. Introduction

Imatinib was the first tyrosine kinase inhibitor (TKI) approvedor treatment of chronic myeloid leukemia (CML). In the Inter-ational Randomized Study of Interferon versus STI571 (IRIS),

matinib significantly improved the rate of complete cytogeneticesponse (CCyR) and lowered the rate of progression to acceler-

durable in a high proportion of patients [2–4]. Landmark anal-ysis of IRIS showed correlations between the achievement ofCCyR at 12 months and progression-free survival (PFS) at 5 years[3].

Acknowledging the IRIS landmark analysis, the EuropeanLeukemiaNet (ELN) and the National Comprehensive CancerNetwork® (NCCN®) both outline expected responses to imatinib

ted phase (AP) or blast crisis (BC), compared with interferon-�lus cytarabine [1]. Long-term follow-ups of the IRIS study showhat imatinib-induced cytogenetic and molecular responses are

∗ Corresponding author at: University of Texas, M.D. Anderson Cancer Center,515 Holcombe Blvd # 428, Houston, TX 77030, United States.el.: +1 713 792 0077; fax: +1 713 792 5640.

E-mail address: aquintas@mdanderson.org (A. Quintás-Cardama).

145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.leukres.2013.01.006

treatment (i.e., milestones) at specified intervals during the first 18months of therapy [5,6] (Table 1 ). The ELN defines criteria for opti-mal response, suboptimal response, and treatment failure, as wellas warning signs that may indicate poorer treatment response andnecessitate more frequent monitoring [5]. Because the ELN consid-

ers that patients with suboptimal response may still benefit fromcontinuing imatinib, albeit with reduced chances of optimal out-come, it recommends continuing with the same imatinib dose, or“testing” either imatinib at a higher dose, nilotinib, or dasatinib

488 A. Quintás-Cardama, E.J. Jabbour / Leukemia Research 37 (2013) 487– 495

Table 1Definitions of imatinib treatment response and evaluation of overall responses to first-line imatinib by the European LeukemiaNet (ELN) and the National ComprehensiveCancer Network (NCCN) [5,6,47].

ELN: response criteria and treatment milestones

Complete hematologicresponse (CHR)

Cytogenetic response(% Ph+ metaphases)

Molecular response

• White bloodcells <10 × 109/L

• Complete (CCyR): 0% • Complete (CMR): undetectable BCR-ABL1 mRNA transcripts byreal-time quantitative and/or nested PCR in two consecutive bloodsamples of adequate quality (sensitivity > 104)

• Basophils < 5% • Partial (PCyR): 1–35% • Major (MMR): ratio of BCR-ABL1 to ABL1 (or other housekeeping genes)≤0.1% (IS)

• No myelocytes,promyelocytes, ormyeloblasts in thedifferential

• Major (MCyR): 0–35%

•Platelets < 450 × 109/L

• Minor (mCyR): 36–65%

• Spleen nonpalpable • Minimal (minCyR): 66–95%• None (noCyR): >95%

Optimal response Suboptimal response Failure Warnings

Baseline – – – High-risk Sokal or HasfordscoreCCA in Ph+ cells

3 months CHR and at least mCyR No CyR No CHR –6 months At least PCyR Less than PCyR No CyR –12 months CCyR PCyR Less than PCyR Less than MMR18 months MMR Less than MMR Less than CCyR –Any time Stable or improving MMR Loss of MMR

Imatinib-sensitivemutations

Loss of CHRLoss of CCyRImatinib-resistantmutationsCCA in Ph+ cells

Rise in BCR-ABL1 transcriptlevelsCCA in Ph− cells

NCCN: response criteria and summary of treatment milestones

CHR Cytogeneticresponse (%Ph+metaphases)

Molecular response

• Complete normalization of peripheral blood counts • CCyR: 0% • CMR: BCR-ABL1 mRNA undetectable by QPCR (IS) using anassay with sensitivity ≥4.5 log below the standardized baseline

• Leukocyte count < 10 × 109/L • PCyR: 1–35% • MMR: ≥3-log reduction in IS of BCR-ABL1 mRNA• No immature cells, such as myelocytes, promyelocytes,or blasts in peripheral blood

• MCyR: 0–35%

• Platelet count < 450 × 109/L • mCyR: >35%• No sign or symptoms of disease with disappearance ofpalpable splenomegaly

Response for which no change in therapy is recommended Response for which a change in therapy may be recommended

3 months BCR-ABL1 transcript level ≤10% or PCyR on bone marrow cytogenetics BCR-ABL1 transcript level >10% or less than PCyR on bone marrow cytogenetics12 months CCyR PCyR or worse, or cytogenetic relapse18 months CCyR PCyR or worse, or cytogenetic relapse

CCA, clonal chromosomal abnormality; CML-CP, chronic myeloid leukemia in chronic phase; IS, international scale; Ph−, Philadelphia chromosome–negative; Ph+, Philadel-phia chromosome–positive; RT-PCR, reverse transcriptase polymerase chain reaction.Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia V.3.2013. © 2013 National Com-prehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the expressw of theN rks ow

[Gntinacp[p

m

ritten permission of the NCCN. To view the most recent and complete version

ETWORK® , NCCN® , NCCN GUIDELINES® , and all other NCCN Content are tradema

5]. The NCCN in its Clinical Practice Guidelines in Oncology (NCCNuidelines®) defines optimal response and treatment failure, butot suboptimal response [7]. For patients without optimal responseo standard-dose imatinib, the NCCN may recommend, depend-ng on the time at which suboptimal response occurs, a switch toilotinib, dasatinib, or bosutinib, an imatinib dose increase (if not

candidate for an alternative TKI), evaluation for allogeneic stemell transplantation, or enrollment in a clinical trial [6]. Another TKI,onatinib, was recently approved for third-line treatment of CML

8], but the NCCN Guidelines do not yet address treatment withonatinib.

It is clear that by either ELN or NCCN criteria, patients with treat-ent failure should be considered for a change in therapy. What

NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCERned by the National Comprehensive Cancer Network, Inc.

remains less clear is whether patients with suboptimal response totreatment rather than failure should also be considered for a treat-ment change, because each set of guidelines takes a distinct viewon this point.

This review discusses the cumulative evidence that achieve-ment of cytogenetic or molecular response to imatinib—particularly early in treatment—predicts favorable long-term out-comes, and clinical data regarding the use of the newer TKIs(nilotinib, dasatinib, and bosutinib) in patients who are intolerant

of imatinib or have imatinib-resistant disease. Available evidenceindicates that early identification of patients with inadequateresponse to imatinib facilitates a switch in therapy that may resultin improved long-term outcomes.

A. Quintás-Cardama, E.J. Jabbour / Leukemia Research 37 (2013) 487– 495 489

Table 2Correlations between imatinib (400 mg) response and long-term outcomes, by time on therapy.

Study Outcome 3 months P value

Marin 2008 [12] ≥HR (n = 216) No HR (n = 8)5-year OS 93.2% 60.2% .00035-year PFS 84.6% 56.2% .0025-year CCyR 80.1% 0.0% .0003

Ohm 2012 [48] ≤10% FISH+ (n = 37) >10% FISH+ (n = 8)CCyR at 12 months 95% 67% .04EFS at 48 months 100% 65% .006

Latagliata 2011 [49] CCyR (n = 118) No CCyR (n = 32)5-year EFS 83.3% 35.2% <.0001

Hochhaus 2011 [50] ≤10% BCR-ABL1 (IS) (n = 154) >10% BCR-ABL1 (IS) (n = 85)CCyR by 12 months 90% 45% –MMR by 24 months 66% 19% –AP/BC at any time 3% 9% –PFS at 24 months 96% 85% –

Jabbour 2011 [23] CCyR (n = 125) No CCyR (n = 74)3-year EFSa 98% 84% .005

Marin 2012 [18] ≤9.84% BCR-ABL1 (IS) (n = 211) >9.84% BCR-ABL1 (IS) (n = 68)8-year OS 93.3% 56.9% <.001

Study Outcome 6 months P value

Marin 2008 [12] ≥CHR (n = 182) <CHR (n = 37)5-year OS 95.5% 81.8% .025-year PFS 87.1% 73.4% .0095-year CCyR 91.2% 18.9% <.00015-year loss of CCyR 12.9% 65.7% .009

≥PCyR (n = 154) <PCyR (n = 28)5-year PFS 91.4% 61.5% .055-year CCyR 97.2% 64.0% <.0001

Alvarado 2009 [19] ≥PCyR (n = 242) <CHR (n = 9)CCyR by 24 months 92% 0% <.001MMR by 24 months 60% 0% <.001CCyR by 48 months 89% 13% <.001MMR by 48 months 64% 0% <.001Transformationb 6% 22% .003Eventsb 11% 67% <.001

Jabbour 2011 [23] CCyR (n = 37) No CCyR (n = 33)3-year EFS 97% 74% .001

CCyR (n = 164) No CCyR (n = 30)3-year EFSa 97% 68% <.0013-year OSa 99% 92% .001

Marin 2012 [18] ≤1.67% BCR-ABL1 (IS) (n = 187) >1.67% BCR-ABL1 (IS) (n = 87)8-year OS 93.7% 74.7% <.001

Study Outcome 12 months P value

Druker 2006 [3] CCyR (n = 350) <PCyR (n = 73)AP/BC by 60 months 3% 19% <.001

Marin 2008 [12] ≥PCyR (n = 165) <PCyR (n = 50)5-year OS 95.1% 87.1% .025-year PFS 90.0% 76.0% .0025-year CCyR 94.1% 26.7% <.00015-year loss of CCyR 10.3% 51.0% <.0001

≥CCyR (n = 120) <CCyR (n = 45)5-year OS 98.4% 85.4% .025-year PFS 96.1% 73.4% .0155-year CCyR 100.0% 77.8% <.0001

Alvarado 2009 [19] ≥PCyR, <CCyR (n = 19) <PCyR (n = 14)CCyR by 24 months 56% 0% .003CCyR by 48 months 69% 18% .02

≥CCyR (n = 214) <PCyR (n = 14)MMR by 24 months 63% 0% <.001MMR by 48 months 68% 0% <.001Transformationb 5% 21% .05Eventsb 8% 57% <.001

Jabbour 2011 [23] CCyR (n = 45) No CCyR (n = 23)3-year EFS 98% 72% <.0013-year OS 100% 88% .046

CCyR (n = 169) No CCyR (n = 18)3-year EFSa 98% 58% <.0013-year OSa 99% 100% .03

Marin 2012 [18] ≤0.53% BCR-ABL1 (IS) (n = 164) >0.53% BCR-ABL1 (IS) (n = 93)8-year OS 95.4% 74.7% <.001

490 A. Quintás-Cardama, E.J. Jabbour / Leukemia Research 37 (2013) 487– 495

Table 2 (Continued )

Study Outcome 18 months P value

Druker 2006 [3] CCyR + MMR (n = 139) No CCyR (n = 88)AP/BC by 60 months 0% 13% .0001

Marin 2008 [12] ≥CCyR (n = 131) <CCyR (n = 66)5-year OS 98.5% 87.8% .035-year PFS 97.1% 76.4% .0015-year CCyR 100.0% 31.8% <.00015-year loss of CCyR 9.6% 27.2% .001

≥MMR (n = 40) <MMR (n = 91)5-year loss of CCyR 0% 24.6% .008

Alvarado 2009 [19] CCyR, <MMR (n = 91) <CCyR (n = 21)MMR by 24 months 38% 0% <.001MMR by 48 months 54% 6% <.001

≥MMR (n = 113) <CCyR (n = 21)Transformationb 5% 24% .002Eventsb 10% 52% <.001

–, not reported; AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CHR, complete hematologic response; EFS, event-free survival; FISH, fluorescencein situ hybridization; HR, hematologic response; IS, international scale; MMR, major molecular response; OS, overall survival; PCyR, partial cytogenetic response; PFS,progression-free survival.

a

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ocioaImwwo1htwa

ioteisomoeb

s≤irwpilAw[a

Patients received imatinib 800 mg/day dose.b Median follow-up (range): 52 months (2–90 months).

. Early response to TKI treatment predicts favorableong-term outcomes

Numerous studies have evaluated the prognostic significancef imatinib treatment response (Table 2), and several notable con-epts have emerged. First, at any time point, better responses tomatinib predict better long-term outcome. This holds regardlessf the level of response being compared (e.g., CCyR vs. no CCyRt 3, 6, or 12 months, or BCR-ABL1 ≤10% vs. >10% at 3 months).n patients receiving imatinib after interferon-� failure, achieving

ajor molecular response (MMR) or MCyR at 12 months correlatedith significantly better 10-year overall survival (OS), comparedith achieving minor CyR or complete hematologic response (CHR)

nly [9]. Similarly, patients in the IRIS study who achieved MMR at8 months of imatinib treatment (optimal response by ELN criteria)ad a significantly better event-free survival (EFS) rate at 7 yearshan patients without MMR at 18 months, suggesting that patientsith a lesser response to imatinib are at higher risk of experiencing

n event over time [10].Second, patients who achieve deep levels of response earlier

n the treatment course have higher odds of favorable long-termutcome than patients with deep levels of response later in thereatment course. Study findings indicate that the probability ofver achieving CCyR and MMR decreases steadily over time if CCyRs not achieved by 3, 6, or 12 months of imatinib [11]. Two separatetudies found that patients considered “responders” (achievers ofptimal response, by ELN criteria) at 6 or 12 months—but not 18onths—had significantly better 5-year OS, PFS, and probability

f CCyR [12] or 7-year OS, PFS, and EFS [13] than patients consid-red “nonresponders” (those with suboptimal response or failure,y ELN criteria).

Third, landmark analyses at 3 months of imatinib treatmenthow that achieving reduction in BCR-ABL1 transcript levels to10% is a significant predictor of long-term outcome. First noted

n a subset analysis of the IRIS trial [14] and subsequently corrobo-ated by M.D. Anderson Cancer Center investigators [11], patientsith BCR-ABL1 levels >10% at 3 months had significantly lowerrobability of ever achieving CCyR or MMR and higher probabil-

ties of disease progression, compared with those with BCR-ABL1evels ≤10%. More recent studies show that achievement of BCR-

BL1 levels ≤10% at 3 months of imatinib significantly correlatedith achievement of MMR at 12 months [15], CMR at 12 months

16], CCyR at 12 months and MMR at 24 months, PFS at 24 months,nd transformation to AP/BC at any time [14], OS and PFS at 5 years

[17], and OS, PFS, EFS, and current CCyR survival at 8 years [18].Based on these observations, the NCCN now recognizes the pro-gnostic significance of achieving the milestone of BCR-ABL1 levels≤10% at 3 months [6].

Fourth, evidence suggests that outcomes are similar for patientswith suboptimal response or treatment failure. One study foundthat 4-year EFS and transformation-free survival (TFS) for patientswith suboptimal response to imatinib at 6 months were similar tothose for patients with treatment failure and significantly lowerthan those for patients with optimal response [19]. Two separatestudies found that the criteria used to define suboptimal response at3 months [12], 6 months [12,20], and 12 months [12,20] were suffi-cient to significantly discriminate between patients with favorableand unfavorable outcomes.

There are limited data for analogous landmark analyses withnilotinib and dasatinib, but the available data support the cor-relation of early responses with favorable long-term outcome[14,21–25]. Because this is an area of intense interest, furtherreports and updates of landmark analyses with nilotinib and dasa-tinib are eagerly awaited.

These findings reinforce the importance of identifying patientswith suboptimal response early in TKI treatment. Although theNCCN Guidelines have been updated recently to recommend aswitch in therapy for patients with BCR-ABL1 transcript levels >10%at 3 months [6], clinicians should be aware of the possibility thatbasing treatment decisions on a single assessment may lead toan unnecessary change in treatment. There is evidence to sug-gest that factors other than BCR-ABL1 level at 3 months may havelong-term prognostic value in CML [26]. In the ELN and NCCNGuidelines, appropriate monitoring requires the use of quantitativereverse transcription polymerase chain reaction (qRT-PCR) assayswith >104 sensitivity corresponding to the international scale (IS)to assess treatment response and detect minimal residual disease.The use of other, less sensitive or non-standardized monitoringmethods, such as non-IS–standardized qRT-PCR assays, may lead toinappropriate treatment decisions. Furthermore, the NCCN Guide-lines recommend against using fluorescence in situ hybridization(FISH) for monitoring response to treatment, on the basis that FISHdetection of Philadelphia chromosome positivity less than 5–10%becomes problematic [6]. Therefore, patients who are identified

as suboptimal responders at 3 months should undergo additionalevaluation for adherence to therapy and/or BCR-ABL1 mutationalstatus. Studies have shown that lower rates of adherence to imati-nib correlate significantly with failure to achieve optimal response

A. Quintás-Cardama, E.J. Jabbour / Leukemia Research 37 (2013) 487– 495 491

Table 3Summary of clinical studies of second-line nilotinib, dasatinib, and bosutinib.

Study Study description/cohorts CCyR MMR Survival

2101 [51,52] 48-month follow-up: Nilotinib400 mg BID in patients withimatinib resistance or intolerance(N = 321)

24-month: 44% 24-month: 56% 24-month OS: 87%48-month OS: 78%48-month PFS: 57%

ENABL [53] 17-month follow-up: Nilotinib300 mg BID in patients withsuboptimal molecular responsewith imatinib (N = 18)

100% 83% –

ENESTnd extension[54]

15- to 18-month follow-up:Nilotinib 400 mg BID in patientswith suboptimal response orfailure with:

Nilotinib 300 mg BID(n = 19)

33% 39%a 18-month OS: 94%18-month PFS: 95%

Imatinib (n = 35) 58% 32%a 18-month OS: 87%18-month PFS: 85%

ENESTcmr [55] ≥12-month follow-up: Suboptimalmolecular response to imatinib400 or 600 mg QD randomized to:

Nilotinib 400 mg BID(n = 104)

– MR4: 48.6%(P = .006)MR4.5: 33.0%(P = .008)CMR: 20.8%(P = .03)

–

Imatinib same dose(n = 103)

– MR4: 25.6%MR4.5: 16.5%CMR: 10.0%

–

TIDEL-II [36] Suboptimal response to imatinib600 mg QD treated with:

Nilotinib (n = 105);24-month follow-up

– 12-/24-monthMMR: 63%/69%CMR: 22%/25%

–

Imatinib 800 mgQD → nilotinib(n = 105); 42-monthfollow-up

– 12-/24-monthMMR: 65%/77%CMR: 13%/31%

–

RE-NICE [33] 11-month follow-up: Suboptimalmolecular response to imatinibtreated with:

Nilotinib 400 mg BID(n = 13)

– 20-month MMR:59.0%P = .047

–

Imatinib 400 mg BID(n = 17)

– 20-month MMR:27.4%

–

START-C [56] 8-month follow-up: Dasatinib70 mg BID in patients with imatinibresistance or intolerance (N = 186)

MCyR: 52% – PFS: 92.4%

CA180-034 [57,58] 5-year follow-up: Dasatinib100 mg QD in patients withimatinib resistance or intolerance(N = 167)

24-monthMCyR: 63%CCyR: 50%

5-year: 44% 5-year PFS: 57%5-year OS: 78%

START-R [34,35] ≥2-year follow-up: Patients withimatinib resistance treated with:

Dasatinib 70 mg BID(n = 101)

MCyR: 53%(P = .017)CCyR: 44%(P = .0025)

29% (P = .028) 2-year PFS: 86%

Imatinib 400 mg BID(n = 49)

MCyR: 33%CCyR: 18%

12% 2-year PFS: 65%

Quintás-Cardama 2009 [37] Dasatinib after MCyR loss onimatinib (n = 151)

72% 60%b 24-month EFS: 89%24-month OS: 98%

Dasatinib after both MCyR and CHRloss on imatinib (n = 33)

42% 29%b 24-month EFS: 29%24-month OS: 93%

Dasatinib after CHR loss onimatinib (n = 109)

26% 26%b 24-month EFS: 64%24-month OS: 86%

Garcia-Gutierrez 2011[32]

32-month follow-up: Nilotinib ordasatinib (n = 38)

86% (P = NS) 71% (P = .009) PFS: 94%

39-month follow-up: High-doseimatinib, chemotherapy, orallogeneic SCT (n = 60)

73% 42% PFS: 88%

Cortes [42] ≥2-year follow-up: Bosutinib500 mg QD in patients withimatinib resistance or intolerance(N = 288)

41% MMR: 64%CMR: 53%

1-year/2-year PFS:91%/79%1-year/2-year OS:97%/92%

–, not reported; BID, twice daily; CCyR, complete cytogenetic response; CHR, complete hematologic response; CMR, complete molecular response; EFS, event-free survival;MMR, major molecular response; OS, overall survival; PFS, progression-free survival; QD, once daily; MCyR, major cytogenetic response; MR4, molecular response with≥4-log reduction in BCR-ABL1 transcripts; MR4.5, ≥4.5-log reduction in BCR-ABL1 transcripts; NS, not significant; SCT, stem cell transplantation.

ot in M

[mpqba

a Includes patients previously not in MMR and patients previously in CCyR but nb In assessed patients only, enrolled in the START-C study.

27,28]. If poor adherence is suspected as the reason for subopti-al response, then enhanced patient education and more frequent

atient follow-up may improve treatment adherence and, conse-uently, treatment response. Furthermore, these patients shoulde reassessed at 6 months. If there is no improvement at 6 months,

change of treatment strategy is warranted.

MR.

3. Second-line nilotinib, dasatinib, and bosutinib afterfirst-line imatinib

Before their approval to treat first-line CML in chronic phase(CML-CP), both nilotinib and dasatinib were approved for use insecond-line CML-CP following therapy including imatinib [29,30].

492 A. Quintás-Cardama, E.J. Jabbour / Leukemia Research 37 (2013) 487– 495

Table 4Nilotinib [40] and dasatinib [41] cross-intolerance in patients with imatinib intolerance.a

Total N = 95 Grade 3/4 AE or persistentgrade 2 AE with imatinib,b

n (%)

Grade 3/4 AE withnilotinib,c n (%)

Persistent grade 2 AE withnilotinib,d n (%)

AE leading to dosereduction/discontinuationof nilotinib, n (%)

Nonhematologic AEs 60 (63) 1 (1) 3 (3) –Rash/skin 28 (29) – – –Fluid retention 18 (19) – – –Diarrhea 12 (13) 1 (1) 2 (2) –Myalgia/arthralgia 10 (11) – – –ALT elevation 3 (3) – 1 (1) –AST elevation 4 (4) – – –Hematologic AEs 31 (33) 17 (18) 2 (2) 12/7 (13/7)Thrombocytopenia 25 (26) 14 (15) 2 (2) 10/7 (11/7)Neutropenia 9 (9) 5 (5) – 2/0 (2/0)Anemia 3 (3) 1 (1) – –

Total N = 271e ≥Grade 3 AE with imatinib, n (%) ≥Grade 3 AE with dasatinib, n (%) AE leading to discontinuation of dasatinib, n (%)

Nonhematologic AEs 210 (77) 9 (3) 2 (<1)Rash 87 (32) 3 (1) 1 (<1)Hepatotoxicity 48 (18) – –Myalgia/arthralgia 22 (8) 1 (<1) 1 (<1)GI toxicities 15 (6) 2 (<1) –Fluid retention 10 (4) – –Pulmonary toxicities 10 (4) – –Bone pain 5 (2) – –Others 13 (5) 3f(1) –

Persistentg grade 4 AE with imatinib, n (%) ≥Grade 3 AE with dasatinib, n (%) AE leading to discontinuation of dasatinib, n (%)

Hematologic AEs 43 (16) 37 (14) 6 (2)

–, none; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal.a Detailed information regarding bosutinib cross-intolerance is not yet available.b Patients with multiple reasons for imatinib intolerance were counted in each category.c Number of imatinib-intolerant patients who experienced the same grade 3/4 AEs that caused imatinib intolerance during nilotinib therapy.d Number of imatinib-intolerant patients who experienced the same grade 2 AEs persisting for >30 days that caused imatinib intolerance during nilotinib therapy.e Cause of imatinib intolerance was not determined for 15 patients with nonhematologic AEs and 3 patients with hematologic AEs.

ACscdMdwts[s[owaTtB>ttslopfrtv

f One case each of fatigue, headache, and cardiac toxicity.g Grade 4 AE persisting for >7 days.

t present, bosutinib is approved for second-line use only [31].linical studies of second-line TKIs following first-line imatinib areummarized in Table 3. Based on these studies, several noteworthyoncepts have emerged. First, second-line treatment with nilotinib,asatinib, or bosutinib can yield high rates of response, includingMR, in patients with inadequate response to imatinib. Second,

ose escalation of imatinib can improve response rates in patientsith inadequate response to standard-dose imatinib, but switching

o second-line nilotinib or dasatinib can be more effective. Severaltudies that evaluated second-line nilotinib [32,33] or dasatinib32,34,35] and high-dose imatinib (400 mg BID) have demonstratedignificantly higher rates of CHR [34,35], CCyR [32,34,35], and MMR32–35] with the newer TKIs than with high-dose imatinib. More-ver, PFS in these studies was better with the newer TKIs thanith high-dose imatinib [32,34,35]. In addition, earlier switch to

second-line TKI may be more effective than later switch. In theIDEL-II study, the cohort of patients that was switched directlyo nilotinib following suboptimal response to imatinib (defined asCR-ABL1 transcript levels >10% at 3 months, >1% at 6 months, or0.1% at 12 months) had a higher rate of CMR at 12 months thanhe cohort that had dose escalation of imatinib before switchingo nilotinib [15]. At 24 months, however, the rates of CMR wereimilar between the two cohorts [36]. Whether or not the ear-ier achievement of CMR might affect long-term clinical outcomef the early-switch cohort is not yet known. In a retrospectiveooled analysis of three clinical studies of second-line dasatinib

or patients who were intolerant of imatinib or have imatinib-esistant disease, patients who were switched to dasatinib afterhe loss of major CyR (MCyR, defined as PCyR + CCyR; early inter-ention group) had higher rates of CHR, CCyR, and MMR, as well as

24-month EFS, TFS, and OS, than patients who were switched afterthe loss of both MCyR and CHR (late intervention group) [37].Although this analysis included studies with differing study designsand dosing schedules of dasatinib, the core finding that earlierswitch to dasatinib was associated with better outcomes than laterswitch was reasonably consistent.

At present, only the ELN guidelines include provisional crite-ria for suboptimal response to and treatment failure of second-lineTKI therapy with nilotinib or dasatinib [5]. These criteria were basedon findings that patients with CML-CP who had BCR-ABL1 transcriptlevels >10% at 3 months after starting second-line nilotinib or dasa-tinib had significantly lower rates of MMR and MCyR at 24 months[38]. Thus, the BCR-ABL1 10% threshold carries prognostic value inboth the first- and second-line settings.

4. Second-line nilotinib, dasatinib, and bosutinib inpatients intolerant of first-line imatinib

The safety profiles of the TKIs overlap to a large degree.Nonhematologic adverse events common to all approved TKIs doc-umented in clinical studies of first-line and second-line treatmentinclude nausea, rash, headache, fatigue, and diarrhea [29,30,39].Imatinib, nilotinib, dasatinib, and bosutinib are also associatedwith grade 3 or 4 hematologic adverse events: neutropenia (16.7%,31%, 36%, 11%, respectively), thrombocytopenia (8.9%, 30%, 23%,26%, respectively), and anemia (4.4%, 11%, 13%, 9%, respectively)

[29–31,39].

Although TKIs are generally well tolerated in the second-linesetting, when patients intolerant of first-line imatinib are switchedto nilotinib, dasatinib, or bosutinib, concerns may arise about

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ross-intolerance—that the adverse event(s) that indicated imat-nib intolerance may reemerge with second-line TKI treatmentTable 4). Clinical data show that cross-intolerance with nonhema-ologic adverse events between second-line TKIs and imatinib wasncommon and rarely led to second-line treatment discontinua-ion. Cross-intolerance with hematologic adverse events, however,as more common but still only led to discontinuation of nilot-

nib in 7 of 31 patients [40], dasatinib in 6 of 43 patients [41],nd bosutinib in 12 of 88 patients [42] with imatinib intoler-nce. Overall, patients who experienced nonhematologic adversevents with imatinib are unlikely to have similar reactions withecond-line TKIs. Patients who experienced hematologic adversevents with imatinib, however, might benefit from closer mon-toring after switching, particularly during the first 2–3 monthsf second-line TKI therapy, when myelosuppression typicallyccurs [40].

. Conclusions

Studies of imatinib—and more recently, nilotinib andasatinib—strongly indicate that both depth and time of responseo TKI therapy are predictive of long-term response and survivalutcome. As early as 3 months after the start of TKI therapy,reatment responses have been shown to correlate significantlyith likelihood of cytogenetic and molecular responses and longerS, PFS, and EFS. Thus, patients who meet or exceed treatment

esponse milestones at 3–6 months are considered to be respon-ing well to treatment; patients who do not achieve milestoneesponses should be monitored more closely. At present, lackingrospective data, whether patients with inadequate response at

months would fare better with a switch in therapy remains annteresting proposition that needs further exploration.

For patients with imatinib-resistant disease, switching to aecond-line TKI aligns with current ELN and NCCN practice guide-ines. Clinical data show that treatment with second-line TKIsesults in high rates of cytogenetic and molecular response thatre more durable than those obtained with imatinib dose escala-ion. Moreover, switching to second-line treatment sooner (e.g.,efore the loss of CHR) is associated with overall more favor-ble outcomes than switching later (e.g., after the loss of CHR).here are several practical implications of these observations forlinicians. First, clinicians should be aware of treatment responseilestones in the ELN and NCCN Guidelines. In particular, clinicians

hould implement regular cytogenetic and molecular monitoring ofCR-ABL1 transcript levels per established guidelines. Several sur-eys of practice patterns suggest that a considerable proportion oflinicians do not [43–45]. Quarterly molecular monitoring, usingRT-PCR assays that conform to the IS, can allow clinicians to accu-ately track disease burden over time and help identify patientshowing consistent inadequate response to treatment, who mayenefit from more frequent follow-up or, possibly, a change inreatment plan.

For patients intolerant of first-line imatinib therapy, the treat-ent approach may depend in part on how soon after treatment

nitiation the adverse event occurs. If symptoms arise soon afterhe start of treatment, for instance within the first 3 months, a doseeduction of imatinib might alleviate some symptoms [46]. If symp-oms persist and a switch to second-line TKI therapy is warranted,linicians should be aware that cross-intolerance, particularly ofonhematologic adverse events, is uncommon and does not leadften to second-line treatment discontinuation.

In summary, clinicians proactively implementing disease mon-toring and patient follow-up have the opportunity to identifyotential problems early in the course of TKI treatment andeadjust treatment plans—as well as patient expectations—in

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mia Research 37 (2013) 487– 495 493

a timely manner, before adverse event occurrence or diseaseprogression.

Role of the funding source

Financial support for medical editorial assistance was providedby Novartis Pharmaceuticals. No additional funding sources wereused.

Authors’ contributions

AQC participated in the drafting of the manuscript, and AQCand EJ reviewed and revised this manuscript, and provided finalapproval for submission.

Conflict of interest

AQC: Consultancy, Novartis Pharmaceuticals, Bristol-MyersSquibb; EJ: Honoraria, Bristol-Myers Squibb, Pfizer Corporation,Novartis Pharmaceuticals.

Acknowledgements

We thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percola-tion Communications LLC for their medical editorial assistance.

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