Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment

Abstract

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged [= or >, slanted]65 years in optimal and stable response with [= or >, slanted]2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.

OPEN

Citation: Blood Cancer Journal (2015) 5, e347; doi:http://dx.doi.org/10.1038/bcj.2015.75

Web End =10.1038/bcj.2015.75

http://www.nature.com/bcj

Web End =www.nature.com/bcj

ORIGINAL ARTICLE

Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment

D Russo1, M Malagola1, C Skert1, V Cancelli1, D Turri2, P Pregno3, M Bergamaschi4, M Fogli5, N Testoni5, A De Vivo5, F Castagnetti5, E Pungolino6, F Stagno7, M Breccia8, B Martino9, T Intermesoli10, GR Cambrin11, G Nicolini12, E Abruzzese13, M Tiribelli14, C Bigazzi15, E Usala16, S Russo17, A Russo-Rossi18, M Lunghi19, M Bocchia20, A DEmilio21, V Santini22, M Girasoli23, R Di Lorenzo24, S Bernardi1,A Di Palma1, BM Cesana25, S Soverini5, G Martinelli5, G Rosti5 and M Baccarani26

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged 65 years in optimal and stable response with 2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% condence interval 3559%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to

Blood Cancer Journal (2015) 5, e347; doi:http://dx.doi.org/10.1038/bcj.2015.75

Web End =10.1038/bcj.2015.75 ; published online 18 September 2015

INTRODUCTION

More than 80% of patients with Philadelphia-positive (Ph+), BCR

ABL1+, chronic phase chronic myeloid leukaemia (CML) are alive after 45 years and are projected to have a life expectancy very close or even identical to that of a non-leukaemic matched control population.15 These results were obtained using the tyrosine kinase inhibitor (TKI) imatinib (Gleevec or Glivec, Novartis Pharmaceutics), frontline.19 Some of these patients, in a proportion estimated to range between 20% and 40%, achieve a deep molecular response (DMR), that is to say a BCR-ABL1 transcripts level 0.01% on the International Scale.912 About 50% of them were reported to maintain that remission status after discontinuation of imatinib and to achieve a stable treatment-free remission (TFR).1316 The introduction of the so-called second-generation TKIs, both in rst and second line, is expected to fare even better, with up to 50% or more of the patients achieving a DMR,1720 and

up to 50% of them entering into a TFR status. If these expectations will be fullled, the proportion of patients who will

be in TFR will range between 25% and 50%. However, about 50% of all patients will not be able to discontinue, and for them, the current policy is to continue the treatment with the same TKI, at the same dose and schedule, indenitely and lifelong.3,5 Until

today, the case of the chronic treatment of these patients has not received the same attention as the case of TFR policies. But the issue is important for obvious reasons of quality of life,21

treatment-related side effects and complications2229 and also

because of drug and management costs.3,5,30

For these reasons, we designed and initiated a pilot study testing the effect of a non-standard, dose-reduced, policy of imatinib treatment.31 We report here on the long-term results of that trial.

PATIENTS AND METHODS

The study (EUDRACT protocol number 2007-005102-42, approved by the

Ethic Committee of the Spedali Civili of Brescia, Italy and registered at

1Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy; 2Ematologia 1-TMO, AOR Villa Soa-Cervello, Palermo, Italy; 3S.C. Ematologia, Dipartimento di Oncologia ed Ematologia, A.O.U. Citt della Salute e della Scienza di Torino, Torino, Italy; 4Dipartimento di Terapie Oncologiche Integrate, IRCCS AOU S. Martino-IST, Genova, Italy; 5Institute of Hematology 'L. & A. Sergnoli', DIMES, University of Bologna, Bologna, Italy; 6Division of Hematology, Department of Oncology and Hematology, Niguarda Ca' Granda Hospital, Milan, Italy; 7Divisione Clinicizzata di Ematologia AOU Policlinico-V. Emanuele, University of Catania, Catania, Italy; 8Azienda Policlinico Umberto I, Sapienza Universit, Roma, Italy; 9Hematology Unit, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy; 10Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; 11University of Turin, San Luigi Gonzaga Hospital, Turin, Italy; 12Hematology and Hematopoietic Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy; 13Hematology, S Eugenio Hospital Tor Vergata University, Rome, Italy; 14Division of Hematology and BMT, Azienda OspedalieroUniversitaria di Udine, Udine, Italy; 15Hematology, Mazzoni Hospital, Ascoli Piceno, Italy; 16U O Ematologia e CTMO Ospedale A., Businco-Cagliari, Italy; 17UOC Ematologia AOU 'G Martino' Policlinico Universitario di Messina, Messina, Italy; 18Division of Hematology, University of Bari, Bari, Italy; 19Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 20Hematology and Transplants, University of Siena and AOUS, Siena, Italy; 21Department of Cellular Therapies and Haematology, San Bortolo Hospital, Vicenza, Italy; 22Unit di Ematologia, AOU Careggi, University of Florence, Florence, Italy; 23Hematology Department, 'A. Perrino' Hospital, Brindisi, Italy; 24Division of Haematology, Spirito Santo Hospital, Pescara, Italy; 25DMMT, Unit of Medical Statistics, University of Brescia, Brescia, Italy and 26Department of Haematology-Oncology 'L. and A. Sergnoli' S. Orsola Malpighi Hospital, University of Bologna, Bologna, Italy. Correspondence: Professor D Russo, Department of Clinical and Experimental Sciences, Unit of Blood Disease and Stem Cell Transplantation, University of Brescia, AO Spedali Civili di Brescia, Italy P.le Spedali Civili 1, Brescia 25123, Italy. E-mail: mailto:[email protected]

Web End [email protected] Received 14 July 2015; accepted 21 July 2015

optimal response.

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BASELINE

76 pts on INTERIM

16 pts lost CCgR and MR3.0

16 pts resumed IM daily

1 pt regained CCgR13 pts regained CCgR and MR3.0

1 pt regained CCgR and MR4.0

1 pt lost at f up

16 pts lost MR3.0 alone

16 pts resumed IM daily

1 pt maintained CCgR 12 pts regained MR3.0

2 pts regained MR4.0

1 pt regained MR4.5

@ 15th mo discontinued INTERIM atrial fibrillation CCgR and MR3.0 @ 24th mo discontinued INTERIM informed consent withdrawn CCgR and MR3.0 @ 59th mo discontinued INTERIM informed consent withdrawn CCgR@ 60th mo discontinued INTERIM informed consent withdrawn Unknown@ 70th mo discontinued INTERIM informed consent withdrawn CCgR and MR4.0

@ 24th mo myocardial infarction CCgR and MR3.0 OFF NTERIM @ 36th mo intracranial hemorrahage CCgr and MR3.0 ON NTERIM @ 37th mo carcinosis CCgR and MR3.0 ON NTERIM @ 37th mo COPD CCgR and MR3.0 ON NTERIM @ 40th mo pancreas neoplasia CCgR and MR3.0 ON NTERIM @ 40th mo COPD CCgR and MR3.0 OFF NTERIM @ 60th mo kidney neoplasia CCgR and MR3.0 ON NTERIM @ 63rd mo lung neoplasia CCgR and MR3.0 ON NTERIM @ 65th mo lung neoplasia CCgR and MR3.0 OFF NTERIM

9 pts died

@ 72 MONTHS

30 pts on INTERIM

Figure 1. Flow diagram of INTERIM studyupdate at 72 months.

ClinicalTrials.Gov with the number: NCT00858806) was limited to patients aged 65 years who had been treated rst line with imatinib once daily (OD) for chronic phase CML, for a minimum of 2 years, and were in complete cytogenetic response (CCyR). One hundred and fourteen patients were screened in 24 GIMEMA (Gruppo Italiano Malattie Ematologiche dellAdulto) centres. Nineteen patients (17%) did not t the inclusion criteria, 19 (17%) did not consent and 76 were enrolled. The median age at enrolment was 72 years (range 6583 years). The median duration of imatinib treatment was 5.75 years (range 2.06.6 years). Sokal risk32 distribution at diagnosis was 33% low risk, 55% intermediate risk and 12% high risk. At enrolment, all patients were in CCyR, and all but one were in major molecular response (MMR or MR3.0, BCR-ABL1 transcripts level 0.1% on the International Scale).

The daily dose of imatinib was not modied (400 mg OD in 81% of patients, 200300 mg OD in 17% of patients and 600 mg in one patient), but imatinib was given 1 week on/1 week off for 1 month, 2 weeks on/2 weeks off for another 2 months and then on a 1 month on/1 month off schedule. The protocol originally mandated to proceed with the intermittent schedule as long as the CCyR was maintained so that the return to continuous daily treatment was mandatory only in case of CCyR

loss. After 2 years, an amendment allowed a return to the continuous daily schedule also in case of MMR loss.

The cytogenetic response was assessed by chromosome banding analysis of marrow cell metaphases or by interphase uorescence in situ hybridization analysis of peripheral blood cell nuclei, as described elsewhere.33 The cytogenetic test was performed every 6 months for the rst 2 years, and then only in case of loss of MR3.0. A CCyR was dened

either by the absence of Ph+ metaphases out of at least 20 metaphases or by o1% BCR-ABL1+ nuclei out of 4200 nuclei. The molecular response was evaluated every 3 months and was reported according to the International Scale by reverse transcriptase-PCR of peripheral blood leukocytes.3436 The tests were performed at one GIMEMA reference laboratory for 4 years, then also at other laboratories that had received their conversion factor through the EUTOS project36 and were certied by the Labnet GIMEMA network. A mutational analysis, by Sanger sequencing technique,37 was performed in the Bologna reference laboratory in all cases of loss of CCyR or MR3.0. The denition of the phases of the disease and of response was those recommended by EuropeanLeukemiaNet 2013.3

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StatisticsThe KaplanMeier method38 was used to estimate overall survival. Death by any cause was the event of interest for overall survival. CCgR loss (CBA-positivity), MMR (MR3.0) loss and the probability of continuing INTERIM were calculated using the cumulative incidence procedure.39 Death was considered competing risk for CCgR and MMR loss, whereas death and refusal were the competing risks for the probability of continuing INTERIM.

RESULTSThe results of intermittent imatinib treatment, with a median follow-up of 5.75 years (range 2.06.6 years) are shown in the ow diagram (Figure 1). Sixteen patients (21%) lost CCyR and MR3.0, 11

of them during the rst 2 years and 5 later on. One of these patients was lost to follow-up. All the remaining 15 patients recovered a CCyR, with MR3.0 in 13 patients and MR4.0 in one. Sixteen patients (21%) lost MR3.0 after the second year. All these patients recovered an MR3.0, and two of them achieved a DMR

(MR4.0 in one case and MR4.5 in one case). One patient went off the study because of an atrial brillation. He was back on standard imatinib, then was switched to nilotinib and is in MMR. Four patients withdrew their consent after 2470 months. They went back to standard daily imatinib; 3 are in MR3.0, the fourth achieved

a MR4.0 and is currently in TFR. Nine patients (12%) died after 2460 months, being in MR3.0, of the causes that are listed in the ow diagram, namely another cancer (ve patients), chronic pulmonary obstructive disease (two patients) and cardiovascular events (two patients). The median age at death was 75 years (range 7280). No patients progressed to accelerated phase or blastic phase. No BCR-ABL1 kinase domain point mutations were detected at the time of CCyR or MR3.0 loss.

The distribution over time of the loss of CCyR and of MR3.0 is

shown in Figures 2a and b, respectively. The probability of maintaining the intermittent treatment schedule is shown in Figure 3a, where events were the return to the continuous, daily treatment, whatever the reason for that. At 6 years, 48% of patients were still on the intermittent schedule. Overall survival is shown in Figure 3b, where it should be noticed that all deaths occurred in remission. There were no progressions.

With a median follow-up of about 6 years, 30 patients are still on intermittent treatment taking the same imatinib dose as at baseline, 1 month on/1 month off. Four of them are in CCyR, 4 are in MR3.0, 20 are in MR4.0 and 2 are in MR4.5.

DISCUSSIONThe current policies of TKI treatment of chronic phase CML mandate using TKIs at their respective approved or maximum tolerated doses lifelong, with the possibility of opening a window for treatment discontinuation when a DMR has been achieved and maintained for an as yet unspecied period of time.3,5,12,16,40 The

window for treatment discontinuation can be enlarged in some of the patients who received imatinib rst line, by switching early or late to a second-generation TKI,4043 as well as using second-

generation TKIs rst line.1720,44,45 Other policies have not been tested prospectively, particularly for treatments alternative to discontinuation, when discontinuation is not possible. The importance of the compliance to the treatment dose is highlighted by studies reporting that poor compliance is associated with a poorer molecular response.46,47 However, it is time to open a debate not on compliance but on which dose should be used for chronic treatment, once a stable, optimal response has been achieved.

The concept of dose adaptation for chronic treatment can be tested in many different ways. Different schedules, such as a continuous daily treatment with a reduced dose or 1 day on/1 day off or 1 week on/1 week off, could be tested. In this exploratory study, it was decided to maintain the standard daily dose on a

1 month on/1 month off schedule. No pharmacokinetic studies were performed, but it is conceivable that the plasma concentration of imatinib fell to zero during the month off.

This study shows that a policy of imatinib reduction to 50% of the initial standard dose was associated with a substantial loss of response in 42% of patients but had no negative effects on outcome, particularly on progression and leukaemia-related deaths. It should be noted that at baseline all patients were in MMR, while after 6 years of intermittent treatment 22 of the original 76 patients (29%) were in DMR and could be eligible for a trial of treatment discontinuation. Therefore, even an intermittent schedule can improve the response, with time. A systematic, prospective study of the quality of life was not designed and performed. All these patients were tolerating imatinib well. Only 20 of them were complaining of minor side effects. In all, 50% of them reported the disappearance of the side effects, particularly of muscle pain and cramps, and of uid retention. No evidence of a discontinuation syndrome was found, as it was reported in patients discontinuing imatinib in the EUROSKI study.48,49 In this

exploratory study, only elderly patients (65 years) were selected and enrolled, because elderly patients tolerate TKIs less well, have

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Figure 2. (a) Probability of maintaining the CCyR. In all, 16/76 patients (21%) lost CCyR, of whom 11 during the rst 2 years and 5 later on. The probability of remaining in CCyR was 84% (95% CI 7390) at 2 years, 81% (95% CI 6988) at 4 years and 76% (95% CI 6484) at 6 years. All 16 patients but 1 who was lost to follow-up were back to continuous imatinib treatment, same daily dose, and recovered the CCyR. (b) Probability of maintaining the MMR. In all, 32/76 patients (42%) lost MMR, including the 16 patients who had lost also the CCyR (Figure 1). The probability of remaining in MMR was 67% (95% CI 5476) at 2 years and 60% (95% CI 4770) at 4 and 6 years. All 32 patients but 1 who was lost to follow-up were back to continuous imatinib treatment, same daily dose, and recovered the MMR.

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ACKNOWLEDGEMENTS

This work was supported in part by EuropeanLeukemiaNet (ELN)European Treatment and Outcome Study (EUTOS) and by Con 2009. Special thanks to the following authors for their participation in the development of the manuscript: Francesco Fabbiano (Palermo), Umberto Vitolo (Torino), Marco Gobbi and Ivana Pierri (Genova), Roberto Cairoli (Milano), Francesco Di Raimondo (Catania), Giuliana Alimena (Roma La Sapienza), Alessandro Rambaldi (Bergamo), Giuseppe Saglio (Orbassano), Giuseppe Visani (Pesaro), Paolo De Fabritiis (Roma Tor Vergata), Renato Fanin (Udine), Piero Galieni (Ascoli Piceno), Emanuele Angelucci (Cagliari), Caterina Musolino (Messina), Giorgina Specchia (Bari), Gianluca Gaidano (Novara), Francesco Rodeghiero (Vicenza), Alberto Bosi (Firenze), Angela Malpignano (Brindisi), and Giuseppe Fioritoni (Pescara). Special thanks to Multilingue Group for English revision (http://www.multilingue.it

Web End =http://www.multilingue.it).

0

12 24 36 48 60 72Months

Figure 3. (a) Probability of remaining in the intermittent imatinib schedule (INTERIM). In all, 46/76 patients (61%) discontinued the intermittent schedule, of whom 24 during the rst 2 years and 22 later on. The probability of maintaining the intermittent treatment schedule was 74% (95% CI 6282) at 2 years, 59% (95% CI 4669) at 4 years and 48% (95% CI 3559) at 6 years. (b) Overall survival. No patients progressed and died of leukaemia. Nine patients (median age at death, 75 years) died in MMR for an overall survival of 87% (95% CI 7895%) at 6 years.

more comorbidities, take more medications and have a shorter life expectancy. Moreover, the median age at diagnosis is already close to 60 years,50 and the proportion of elderly patients is destined to grow with time. However, also the younger patients who will not achieve a TFR will deserve attention. Although there is only another study (DESTINY studyClinicalTrials.gov NCT01804985) looking for the minimum effective dose of any TKI, there is no doubt that the so called standard or approved dose is critical for achieving an optimal response as fast as possible and to prevent progression to blastic phase.3,5 However, the issue is not to challenge the choice of the initial dose but to understand if the same dose is required indenitely, and if so, for which purpose. This challenge has biological, clinical and nancial implications. Biologically, almost all studies suggest that once an optimal response is achieved, the residual Ph+ cells may not be completely BCR-ABL1 addicted, and are resistant to TKI inhibition,51,52 so that it may be necessary to consider other

approaches testing other drugs in trials where toxicity and safety may prevail.53 In any case, those residual Ph+ cells can hardly give rise to new resistant Ph+ clones, because late relapses are exceptional.9 Therefore, the probability of dying of leukaemia becomes so small that one must worry more of other diseases and of the risk of treatment-related complications, a risk that will never be equal to zero, and that is difcult to predict over a very long period of time.3,5,2224 From a nancial perspective, the indenite

continuation of the standard, approved dose will expand the cost of the treatment exponentially.30 These considerations are also a valid argument in favour of a policy of treatment discontinuation

and TFR, a policy that is more radical and more appealing.11,12,16

However, the point is not only which policy is better. The point is to acknowledge that a policy of TFR cannot be always successful, because at least 50% of patients are estimated to never reach a TFR, even with the largest use of second-generation TKIs. For the patients who do not achieve a TFR, it is necessary to reconsider some current concepts of treatment and to begin to look for a minimum effective therapy.

On these bases, we continue to work on the intermittent schedule with a standard daily dose, and we are now testing a progressive increase of the off-treatment period, up to 1 month on/3 months off.

CONFLICT OF INTEREST

Domenico Russo, Patrizia Pregno and Simona Soverini receives compensation as a consultant for Novartis, Bristol-Myers Squibb and Ariad. Elisabetta Abruzzese receives compensation as a consultant for Ariad, Bristol-Myers Squibb, Novartis, Takeda and Pzer. Giovanni Martinelli receives compensation as a consultant for Novartis, Bristol-Myers Squibb and Pzer. Gianantonio Rosti, Fausto Castagnetti and Michele Baccarani receives compensation as a consultant for Novartis, Ariad, Bristol-Myers Squibb and Pzer. Mario Tiribelli receives compensation as a consultant for Novartis, BMS and Ariad. The remaining authors declare no conict of interest.

AUTHOR CONTRIBUTIONSDomenico Russo and Michele Baccarani designed the study; all the authors collected the data; Domenico Russo, Michele Baccarani, Giannatonio Rosti, Michele Malagola, Crisitna Skert, Antonio De Vivo and Bruno Mario Cesana analysed the data; all the authors wrote the manuscript and gave nal approval of the manuscript.

REFERENCES

1 Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet 2005;

370: 342350.2 Kantarjian HM, OBrien S, Jabbour E, Garcia-Manero G, Quintas-Cardama A, Shan J et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood 2012; 119: 19811987.3 Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872884.4 Hoglund M, Sandin F, Hellstrom K, Bjreman M, Bjrkholm M, Brune M et al. Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based swedish CML registry. Blood 2013; 122: 12841292.5 National Comprehensive Cancer Network: NCCN. Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, version 1, 2015. http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf

Web End =www.nccn.org/profes http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf

Web End =sionals/physician_gls/pdf/cml.pdf .6 Hochhaus A, OBrien S, Guilhot F, Druker BJ, Branford S, Foroni L et al. Six-year follow-up of patients receiving imatinib for the rst-line treatment of chronic myeloid leukemia. Leukemia 2009; 23: 10541061.7 Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C et al. Multicenter independent assessment of outcome in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011; 103: 553561.

Blood Cancer Journal

Intermittent imatinib treatment of CML D Russo et al

5

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

9 Hehlmann R, Muller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-Study 4. J Clin Oncol 2013; 32: 415423.

10 Etienne G, Dulucq S, Nicolini FE, Morisset F, Fort MP, Schmitt A et al. Achieving deeper molecular response is associated with a better clinical outcome in chronic myeloid leukemia patients on imatinib front-line therapy. Haematol 2014; 99: 458464.

11 Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res 2014; 20: 310322.

12 Apperley J. Chronic myeloid leukemia. Semin Hematol 2014; 5: 113.13 Mahon FX, Ra D, Guilhot J, Guilhot F, Huguet F, Nicolini F et al. Discontinuation of imatinib in patients with chronic mye loid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010; 11: 10291035.14 Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT et al. Safety and efcacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013; 122: 515522.15 Thielen N, van der Holt B, Cornelissen JJ, Verhof GE, Gussinklo T, Biedmond BJ et al. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013; 49: 32423246.16 Mahon FX. Discontinuation of tyrosine kinase therapy in CML. Ann Hematol 2015; 94: 187193.17 Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. New Engl J Med 2010; 362: 22512259.18 Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 11231129.19 Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqu C et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123: 494500.20 Larson R, Kim D, Issaragrisil S, le Coutre P, Llacer Dorlhiac PE, Etienne G et al. Efcacy and safety of Nilotinib (NIL) vs Imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up (f/u) of ENESTnd. Blood 2014, 124: 4541.21 Efcace F, Baccarani M, Breccia M, Alimena G, Rosti G, Cottone F et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 2011; 118: 45544560.22 Valent P. Severe adverse events associated with the use of second-line BCR/ABL tyrosine kinase inhibitors: preferential occurrence in patients with comorbidities. Haematol 2011; 96: 13951397.23 Steegmann JL, Cervantes F, le Coutre P, Porkka K, Saglio G. Off-target effects of BCR-ABL1 inibitors and their potential long-term implications in patients with chronic myeloid leukemia. Leuk Lymphoma 2012; 53: 23512361.24 Breccia M, Tiribelli M, Alimena G. Tyrosine kinase inhibitors for elderly chronic myeloid leukemia: a systematic review of efcacy and safety data. Crit Rev Oncol Hematol 2012; 84: 93100.25 Giles FJ, Mauro MJ, Hong F, Ortmann CE, McNeill C, Woodman RC et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013; 27: 13101315.26 Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinibor imatinib. Leukemia 2013; 27: 13161321.27 Irvine E, Williams C. Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Pharmacotherapy 2013; 33: 868881.28 Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre Pl. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 2015; 125: 901906.29 Cortes J, Mauro M, Steegmann JL, Saglio G, Malhotra R, Ukropec JA et al. Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL

inhibitors: data from the FDA adverse event reporting system. Am J Hematol 2015; 90: E66E72.30 Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013; 121: 44394442.31 Russo D, Martinelli G, Malagola M, Skert C, Soverini S, Iacobucci I et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013; 121: 51385144.32 Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson GE et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984; 63: 789799.33 Testoni N, Marzocchi G, Luatti S, Amabile M, Baldazzi S, Stacchini M et al. Chronic myeloid leukemia: a prospective comparison of interphase uorescence in situ hybridization and chromosome banding analysis for the denition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood 2009; 114: 49394943.34 Hughes T, Deininger M, Hochhaus A, Brandford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCRABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 2837.35 Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized denitions of molecular response in chronic myeloid leukemia. Leukemia 2012; 26: 21722175.36 Cross NC, Hochhaus A, Mller MC. Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization. Ann Hematol 2015; 94: 219225.37 Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118: 12081215.38 Kaplan PM, Meier HT. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.39 Gooley TA, Leisenring W, Crowley J, Storer B. Estimation of failure probabilities in the presence of competing risk: new representations of old estimators. Stat Med 1999; 18: 695706.40 Ross DM, Hughes TP. How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia. B J Haematol 2014; 166: 311.41 Quints-Cardama A, Jabbour EJ. Considerations for early switch to nilotinib or dasatinib in patients with chronic myeloid leukemia with inadequate response to rst-line imatinib. Leuk Res 2013; 37: 487495.42 Hughes T, White D. Which TKI? An embarrassment of riches for chronic myeloid leukemia patients. Hematology Am Soc Hematol Educ Program 2013; 2013: 168175. Presented at the 55th American Society of Hematology Meeting; 710 December; New Orleans, Louisiana, USA.43 Yeung DT, Osborn MP, White DL, Brandford S, Braley J, Herschtal A et al. TIDEL-II: rst-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015; 125: 915923.44 Jabbour E, Kantarjian HM, OBrien S, Shan J, Quintas-Cardama A, Garcia-Manero G et al. Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response? J Clin Oncol 2011; 29: 42604265.45 Shami PJ, Deininger M. Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as rst-line therapy. Leukemia 2012; 26: 214224.46 Noens L, van Lierde MA, De Bock R, Verhoef G, Zache P, Berneman Z et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009; 113: 54015411.47 Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukaemia who achieve complete cytogenetic response on imatinib. J Clin Oncol 2010; 28: 23812388.48 Mahon FX, Richter J, Guilhot J, Muller MC, Dietz C, Porkka K et al. Interim analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia: the EURO-SKI study. Blood 2014, 124 (Abs 151).49 Richter J, Sderlund S, Lbking A, Dreimane A, Lot K, Markevarn B et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol 2014; 32: 28212823.50 Hoffmann V, Baccarani M, Hasford J, Lindoerfer D, Burgstaller S, Sertic D et al. The EUTOS population-based registry incidence and clinical characteristics of 2094 CML patients in 20 European countries. Leukemia 2015; 29: 13361343.

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Intermittent imatinib treatment of CML D Russo et al

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51 Chomel JC, Bonnet ML, Sorel N, Bertrand A, Meunier MC, Fichelson S et al. Leukemia stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 2011; 118: 36573660.

52 Chu S, McDonald T, Lin A, Chakraborty S, Huang Q, Snyder DS et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood 2011; 118: 55655572.

53 Ahmed W, Van Etten RA. Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond. Hematology Am Soc Hematol Educ Program 2013; 2013:

189200. Presented at the 55th American Society of Hematology Meeting; 710 December, New Orleans, Louisiana, USA.

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