Perspectives and Emotional Experiences of Patients With Chronic Myeloid Leukemia During ENESTPath Clinical Trial and Treatment-Free Remission: Rationale and Protocol of the Italian Substudy

Lidia Borghi, Gianantonio Rosti, Alessandro Maggi, Massimo Breccia, Eros Di Bona, Alessandra Iurlo, Gaetano La Barba, Paolo Sportoletti, Francesco Albano, Sara Galimberti, Flavia Rivellini, Giovanna Rege Cambrin, Isabella Capodanno, Antonio Cuneo, Massimiliano Bonifacio, Simona Sica, Luca Arcaini, Enrico Capochiani, Claudia Minotto, Fabio Ciceri, Monica Crugnola, Luigi Di Caprio, Sharon Supekar, Chiara Elena, Michele Baccarani, Elena Vegni, Lidia Borghi, Gianantonio Rosti, Alessandro Maggi, Massimo Breccia, Eros Di Bona, Alessandra Iurlo, Gaetano La Barba, Paolo Sportoletti, Francesco Albano, Sara Galimberti, Flavia Rivellini, Giovanna Rege Cambrin, Isabella Capodanno, Antonio Cuneo, Massimiliano Bonifacio, Simona Sica, Luca Arcaini, Enrico Capochiani, Claudia Minotto, Fabio Ciceri, Monica Crugnola, Luigi Di Caprio, Sharon Supekar, Chiara Elena, Michele Baccarani, Elena Vegni

Abstract

Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian 'patient's voice CML' substudy was to evaluate patients' psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive BCR-ABL1+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed via patients' emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination. NCT number: NCT01743989, EudraCT number: 2012-005124-15.

Keywords: Chronic myeloid leukemia; ENESTPath; emotional experience; mixed methods; nilotinib; psychological distress; quality of life; study protocol.

Conflict of interest statement

LB received a research fellowship from her institution on the project titled “CML patients’ voice: A pilot study exploring the emotional experience of patients during CAMN107AIC05 study and its discontinuation” funded by Novartis Pharma AG. SSu and LC are employees of Oncology Region Europe, Novartis Farma SpA, Origgio, Italy. EV received grant support, paid to her institution, from Novartis for the research project titled "CML patients’ voice: A pilot study exploring the emotional experience of patients during CAMN107AIC05 study and its discontinuation". MC received honoraria from Novartis, Celgene and Janssen. MBo received honoraria (advisory board) from Novartis, Pfizer, Incyte and Amgen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Novartis Pharma AG. The funder had the following involvement in the study: study design, writing of the article, and decision to submit it for publication.

Copyright © 2021 Borghi, Rosti, Maggi, Breccia, Di Bona, Iurlo, La Barba, Sportoletti, Albano, Galimberti, Rivellini, Cambrin, Capodanno, Cuneo, Bonifacio, Sica, Arcaini, Capochiani, Minotto, Ciceri, Crugnola, Di Caprio, Supekar, Elena, Baccarani and Vegni.

Figures

Figure 1
Figure 1
ENESTpath Italian sub-study design.
Figure 2
Figure 2
Writing instructions for diaries compilation at month 18 and at month 24.

References

    1. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The Biology of Chronic Myeloid Leukemia. New Engl J Med (1999) 341(3):164–72. 10.1056/NEJM199907153410306
    1. Johansson B, Fioretos T, Mitelman F. Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia. Acta Haematol (2002) 107(2):76–94. 10.1159/000046636
    1. Melo JV, Barnes DJ. Chronic Myeloid Leukaemia as a Model of Disease Evolution in Human Cancer. Nat Rev Cancer (2007) 7(6):441–53. 10.1038/nrc2147
    1. Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. . Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Network (2018) 16(9):1108–35. 10.6004/jnccn.2018.0071
    1. Hanfstein B, Müller M, Hehlmann R, Erben P, Lauseker M, Fabarius A, et al. . Early Molecular and Cytogenetic Response is Predictive for Long-Term Progression-Free and Overall Survival in Chronic Myeloid Leukemia (Cml). Leukemia (2012) 26(9):2096–102. 10.1038/leu.2012.85
    1. Hochhaus A, Masszi T, Giles F, Radich J, Ross D, Casares MG, et al. . Treatment-Free Remission Following Frontline Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From the ENESTfreedom Study. Leukemia (2017) 31(7):1525–31. 10.1038/leu.2017.63
    1. Hochhaus A, Baccarani M, Silver R, Schiffer C, Apperley J, Cervantes F, et al. . European LeukemiaNet 2020 Recommendations for Treating Chronic Myeloid Leukemia. Leukemia (2020) 1-19:966–84. 10.1038/s41375-020-0776-2
    1. Hughes TP, Ross DM. Moving Treatment-Free Remission Into Mainstream Clinical Practice in CML. Blood (2016) 128(1):17–23. 10.1182/blood-2016-01-694265
    1. Rea D, Rousselot P, Nicolini FE, Legros L, Tulliez M, Giraudier S, et al. . Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia (CML) Patients (Pts) With Stable Undetectable Bcr-Abl Transcripts: Results From the French Cml Group (Filmc). Blood (2011) 118(21):604. 10.1182/blood.V118.21.604.604
    1. Rea D, Nicolini FE, Tulliez M, Guilhot F, Guilhot J, Guerci-Bresler A, et al. . Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia: Interim Analysis of the STOP 2g-TKI Study. Blood (2017) 129(7):846–54. 10.1182/blood-2016-09-742205
    1. Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K, Takezako N, et al. . Dasatinib Cessation After Deep Molecular Response Exceeding 2 Years and Natural Killer Cell Transition During Dasatinib Consolidation. Cancer Sci (2018) 109(1):182–92. 10.1111/cas.13430
    1. Mahon F-X, Boquimpani C, Kim D-W, Benyamini N, Clementino NCD, Shuvaev V, et al. . Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Internal Med (2018) 168(7):461–70. 10.7326/M17-1094
    1. Okada M, Imagawa J, Tanaka H, Nakamae H, Hino M, Murai K, et al. . Final 3-Year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-Line Treatment. Clin Lymph Myeloma Leukemia (2018) 18(5):353–360. e351. 10.1016/j.clml.2018.03.004
    1. Rea D, Cayuela J-M. Treatment-Free Remission in Patients With Chronic Myeloid Leukemia. Int J Hematol (2018) 108(4):355–64. 10.1007/s12185-017-2295-0
    1. Ross DM, Masszi T, Casares MTG, Hellmann A, Stentoft J, Conneally E, et al. . Durable Treatment-Free Remission in Patients With Chronic Myeloid Leukemia in Chronic Phase Following Frontline Nilotinib: 96-Week Update of the ENESTfreedom Study. J Cancer Res Clin Oncol (2018) 144(5):945–54. 10.1007/s00432-018-2604-x
    1. Takahashi N, Nishiwaki K, Nakaseko C, Aotsuka N, Sano K, Ohwada C, et al. . Treatment-Free Remission After Two-Year Consolidation Therapy With Nilotinib in Patients With Chronic Myeloid Leukemia: Stat2 Trial in Japan. Haematologica (2018) 103(11):1835–42. 10.3324/haematol.2018.194894
    1. Nicolini FE, Dulucq S, Boureau L, Cony-Makhoul P, Charbonnier A, Escoffre-Barbe M, et al. . Evaluation of Residual Disease and TKI Duration are Critical Predictive Factors for Molecular Recurrence After Stopping Imatinib First-Line in Chronic Phase CML Patients. Clin Cancer Res (2019) 25(22):6606–13. 10.1158/1078-0432.CCR-18-3373
    1. Rea D, Rosti G, Cross NC, Hellman A, Niederwieser D, Pungolino E, et al. . Enestpath: A Phase III Study to Assess the Effect of Nilotinib Treatment Duration on Treatment-Free Remission (TFR) in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients (Pts) Previously Treated With Imatinib: Interim Analysis From the First Year of Induction Phase. Blood (2015) 126:4040. American Society of Hematology Washington, DC. 10.1182/blood.V126.23.4040.4040
    1. Ritchie EK, Catchatourian R, Klisovic RB, Deininger MW, Erba HP, Radich JP, et al. . Rapid Achievement of MR4. 5 After Switching From Imatinib (IM) to Nilotinib (NIL) in Patients (Pts) With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Preliminary Results From Enestgoal. Blood (2015) 126:4050. 10.1182/blood.V126.23.4050.4050
    1. Hughes T, Boquimpani C, Takahashi N, Benyamini N, Clementino N, Shuvaev V, et al. . Results From Enestop: Treatment-Free Remission (Tfr) Following Switch to Nilotinib (NIL) in Patients (Pts) With Chronic Myeloid Leukemia in Chronic Phase (Cml-Cp). Ferrata Storti Foundation Via Giuseppe Belli 4, 27100 Pavia, Italy: Haematologica; (2016).
    1. Kadowaki N, Kawaguchi T, Kuroda J, Nakamae H, Matsumura I, Miyamoto T, et al. . Discontinuation of Nilotinib in Patients With Chronic Myeloid Leukemia Who Have Maintained Deep Molecular Responses for At Least 2 Years: A Multicenter Phase 2 Stop Nilotinib Trial. Blood (2016) 128:790. 10.1182/blood.V128.22.790.790
    1. Ritchie EK, Catchatourian R, Klisovic RB, Pinilla-Ibarz J, Deininger MW, Erba HP, et al. . Enestgoal Treatment-Free Remission Study: Updated Preliminary Results and Digital Polymerase Chain Reaction Analysis in Patients With Chronic Myeloid Leukemia in Chronic Phase Who Switched From Imatinib to Nilotinib. Blood (2016) 128:3090. American Society of Hematology Washington, DC. 10.1182/blood.V128.22.3090.3090
    1. Takahashi N, Nakaseko C, Nishiwaki K, Wakita H. Two-Year Consolidation by Nilotinib is Associated With Successful Treatment Free Remission in Chronic Myeloid Leukemia With MR4. 5: Subgroup Analysis From STAT2 Trial in Japan. Blood (2016) 128:1889. American Society of Hematology Washington, DC. 10.1182/blood.V128.22.1889.1889
    1. Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NCD, et al. . Deep Molecular Responses Achieved in Patients With CML-CP Who are Switched to Nilotinib After Long-Term Imatinib. Blood (2014) 124(5):729–36. 10.1182/blood-2013-12-544015
    1. Richter J, Mahon F, Guilhot J, Hjorth-Hansen H, Almeida A, Janssen J, et al. . Stopping Tyrosine Kinase Inhibitors in a Very Large Cohort of European Chronic Myeloid Leukemia Patients: Results of the EURO-SKI Trial. Haematologica (2016) 101:22–3.
    1. National Comprehensive Cancer Network . Nccn Clinical Practice Guidelines in Oncology (NCCN Guidelines) – Chronic Myeloid Leukemia. Available at: (Accessed July 10, 2020).
    1. McKernan M, McMillan D, Anderson J, Angerson W, Stuart R. The Relationship Between Quality of Life (Eortc QLQ-C30) and Survival in Patients With Gastro-Oesophageal Cancer. Br J Cancer (2008) 98(5):888–93. 10.1038/sj.bjc.6604248
    1. Quinten C, Coens C, Mauer M, Comte S, Sprangers MA, Cleeland C, et al. . Baseline Quality of Life as a Prognostic Indicator of Survival: A Meta-Analysis of Individual Patient Data From EORTC Clinical Trials. Lancet Oncol (2009) 10(9):865–71. 10.1016/S1470-2045(09)70200-1
    1. Braun DP, Gupta D, Staren ED. Quality of Life Assessment as a Predictor of Survival in non-Small Cell Lung Cancer. BMC Cancer (2011) 11(1):353. 10.1186/1471-2407-11-353
    1. Osthus A, Aarstad A, Olofsson J, Aarstad H. Health-Related Quality of Life Scores in Long-Term Head and Neck Cancer Survivors Predict Subsequent Survival: A Prospective Cohort Study. Clin Otolaryngol (2011) 36(4):361–8. 10.1111/j.1749-4486.2011.02342.x
    1. Ediebah DE, Quinten C, Coens C, Ringash J, Dancey J, Zikos E, et al. . Quality of Life as a Prognostic Indicator of Survival: A Pooled Analysis of Individual Patient Data From Canadian Cancer Trials Group Clinical Trials. Cancer (2018) 124(16):3409–16. 10.1002/cncr.31556
    1. Sitlinger A, Zafar SY. Health-Related Quality of Life: The Impact on Morbidity and Mortality. Surg Oncol Clinics (2018) 27(4):675–84. 10.1016/j.soc.2018.05.008
    1. Sajid M, Tonsi A, Baig M. Health-Related Quality of Life Measurement. Int J Health Care Qual Assurance (2008) 21(4):365–73. 10.1108/09526860810880162
    1. Lin X-J, Lin I-M, Fan S-Y. Methodological Issues in Measuring Health-Related Quality of Life. Tzu Chi Med J (2013) 25(1):8–12. 10.1016/j.tcmj.2012.09.002
    1. Cox K. Assessing the Quality of Life of Patients in Phase I and II Anti-Cancer Drug Trials: Interviews Versus Questionnaires. Soc Sci Med (2003) 56(5):921–34. 10.1016/S0277-9536(02)00100-4
    1. Bruner DW, Bryan CJ, Aaronson N, Blackmore CC, Brundage M, Cella D, et al. . Issues and Challenges With Integrating Patient-Reported Outcomes in Clinical Trials Supported by the National Cancer Institute–sponsored Clinical Trials Networks. J Clin Oncol: Off J Am Soc Clin Oncol (2007) 25(32):5051. 10.1200/JCO.2007.11.3324
    1. Lipscomb J, Reeve BB, Clauser SB, Abrams JS, Watkins Bruner D, Burke LB, et al. . Patient-Reported Outcomes Assessment in Cancer Trials: Taking Stock, Moving Forward. J Clin Oncol (2007) 25(32):5133–40. 10.1200/JCO.2007.12.4644
    1. O’Mara AM, Denicoff AM. Health Related Quality of Life in NCI-sponsored Cancer Treatment Trials. Semin Oncol Nurs (2010) 26(1):68–78. 10.1016/j.soncn.2009.11.009
    1. Osoba D. Health-Related Quality of Life and Cancer Clinical Trials. Ther Adv Med Oncol (2011) 3(2):57–71. 10.1177/1758834010395342
    1. Jensen R, Moinpour C, Fairclough D. Assessing Health-Related Quality of Life in Cancer Trials. Clin Invest (2012) 2(6):563–77. 10.4155/cli.12.48
    1. Hand C. Measuring Health-Related Quality of Life in Adults With Chronic Conditions in Primary Care Settings: Critical Review of Concepts and 3 Tools. Can Family Phys (2016) 62(7):e375–83.
    1. Borghi L, Galimberti S, Baratè C, Bonifacio M, Capochiani E, Cuneo A, et al. . Chronic Myeloid Leukemia Patient’s Voice About the Experience of Treatment-Free Remission Failure: Results From the Italian Sub-Study of ENESTPath Exploring the Emotional Experience of Patients During Different Phases of a Clinical Trial. Front Psychol (2019) 10:329. 10.3389/fpsyg.2019.00329
    1. Cattell RB, Eber HW, Tatsuoka M. Handbook for the 16 Personality Factor Questionnaire. Champaign, IL: Institute for Personality and Ability Testing; (1970).
    1. Cattell HEP. The Sixteen Personality Factor Questionnaire (16pf). In: Dorfman WI, Hersen M, editors. Understanding Psychological Assessment. Perspectives on Individual Differences. Boston, MA: Springer; (2001). 10.1007/978-1-4615-1185-4_10
    1. Cattell RB, Cattell AKS, Cattell HE. 16 PF-5, Sixteen Personality Factor Questionnaire (Fifth Edition), Institute for Personality and Ability Testing, Inc.: Boston: Springer; (1994).
    1. Sirigatti S, Stefanile C. Adattamento Italiano Del MBI—Maslach Burnout Inventory. Org Speciali Firenze (1993). 10.1080/02678370500297720
    1. Sirigatti S, Stefanile C. Stili Alimentari in Adolescenti: Ricerca-Intervento Di Prevenzione Primaria. In: Morosini P, de Girolamo G, Picardi A, Di Fabio F, editors. Progetto Nazionale Salute Mentale. Roma: Rapporti Istisan; (2001). p. 169–71.
    1. Derogatis LR, Rickels K, Rock AF. The SCL-90 and the MMPI: A Step in the Validation of a New Self-Report Scale. Br J Psych (1976) 128:280–289. 10.1192/bjp.128.3.280
    1. Derogatis L. “Scl-90-R: Administration, Scoring and Procedures Manual. Minneapolis: National Computer Systems.” Inc. (1994).
    1. Sarno I, Preti E, Prunas A, Madeddu F. Scl-90-R Symptom Checklist-90-R Adattamento Italiano. Giunti, Organizzazioni Speciali; (2011).
    1. Carver CS, Scheier MF, Weintraub JK. Assessing Coping Strategies: A Theoretically Based Approach. J Pers Soc Psychol (1989) 56(2):267. 10.1037/0022-3514.56.2.267
    1. Sica C, Magni C, Ghisi M, Altoè G, Sighinolfi C, Chiri LR, et al. . Coping Orientation to Problems Experienced-Nuova Versione Italiana (Cope-Nvi): Uno Strumento Per La Misura Degli Stili Di Coping. Psicoterapia Cognit e Comportamentale (2008) 14(1):27.
    1. Efficace F, Baccarani M, Breccia M, Saussele S, Abel G, Caocci G, et al. . International Development of an EORTC Questionnaire for Assessing Health-Related Quality of Life in Chronic Myeloid Leukemia Patients: The Eortc Qlq-Cml24. Qual Life Res (2014) 23(3):825–36. 10.1007/s11136-013-0523-5
    1. Pennebaker JW. Writing About Emotional Experiences as a Therapeutic Process. psychol Sci (1997) 8(3):162–6. 10.1111/j.1467-9280.1997.tb00403.x
    1. Pennebaker JW, Chung CK. Expressive Writing, Emotional Upheavals, and Health. Brazil: Foundations of Health Psychology; (2007).
    1. Pennebaker JW, Francis ME, Booth RJ. Linguistic Inquiry and Word Count: LIWC 2001. Mahway: Lawrence Erlbaum Assoc (2001) 71(2001):2001. 10.1192/apt.11.5.338
    1. Baikie KA, Wilhelm K. Emotional and Physical Health Benefits of Expressive Writing. Adv Psychiatr Treat (2005) 11(5):338–46. 10.1192/apt.11.5.338
    1. Smith JA. Beyond the Divide Between Cognition and Discourse: Using Interpretative Phenomenological Analysis in Health Psychology. Psychol Health (1996) 11(2):261–71. 10.1080/08870449608400256
    1. Smith JA, Flowers P, Larkin M. “Interpretative Phenomenological Analysis: Theory, Method and Research”. London: SAGE; (2009).
    1. Eatough V, Smith J. Interpretative Phenomenological Analysis. In: The SAGE Handbook of Qualitative Research in Psychology. London: SAGE; (2008). p. 179–94. 10.4135/9781848607927.n11
    1. Smith JA, Shinebourne P. Interpretative Phenomenological Analysis. Washington: American Psychological Association; (2012). 10.1037/13620-005
    1. Conroy SA. A Pathway for Interpretive Phenomenology. Int J Qual Methods (2003) 2(3):36–62. 10.1177/160940690300200304
    1. Richards L, Morse JM. “Readme First for a User’s Guide to Qualitative Methods”. Thousand Oaks: Sage Publications; (2007).
    1. Griffiths M, Schweitzer R, Yates P. Childhood Experiences of Cancer: An Interpretative Phenomenological Analysis Approach. J Pediatr Oncol Nurs (2011) 28(2):83–92. 10.1177/1043454210377902
    1. Hilgart J, Mercer J, Thirlaway K. Individuals’ Experiences of, and Responses to, a Negative Genetic Test Result for Familial Hypercholesterolaemia. J Health Psychol (2013) 18(3):339–49. 10.1177/1359105312443403
    1. Vegni E, Leone D, Biasoli C, Moja EA. Difficult Encounters With a Hemophilic Patient: The Inner Perspective of Physicians. J Health Psychol (2014) 19(12):1499–507. 10.1177/1359105313493813
    1. Smith JA, Osborn M. Pain as an Assault on the Self: An Interpretative Phenomenological Analysis of the Psychological Impact of Chronic Back Pain. Psychol Health (2007) 22:517–34. 10.1080/14768320600941756
    1. Lou J, Huang J, Wang Z, Wen B, Tu C, Huang W, et al. . Chronic Myeloid Leukemia Patients and Treatment-Free Remission Attitudes: A Multicenter Survey. Patient Preference Adherence (2018) 12:1025. 10.2147/PPA.S163393
    1. Villemagne Sanchez LA, O’Callaghan C, Gough K, Hall K, Kashima Y, Seymour JF, et al. . Patient Perceptions of Treatment-Free Remission in Chronic Myeloid Leukemia. Leukemia Lymph (2018) 59(2):406–15. 10.1080/10428194.2017.1337114
    1. Cella D, Jensen SE, Webster K, Hongyan D, Lai J-S, Rosen S, et al. . Measuring Health-Related Quality of Life in Leukemia: The Functional Assessment of Cancer Therapy–Leukemia (Fact-Leu) Questionnaire. Value Health (2012) 15(8):1051–8. 10.1016/j.jval.2012.08.2210
    1. Ware JE, Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (Sf-36): I. Conceptual Framework and Item Selection. Med Care (1992) 30(6):473–83. 10.1097/00005650-199206000-00002

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