Retro-prospective Observational Study on Risk of Progression in CP-CML Patients Eligible for TKI Discontinuation

Retro-prospective Observational Study on Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR - PRO)

The purpose of this study is to investigate the safety profile of TKI discontinuation in clinical practice, with particular regard on the risk of progression after treatment discontinuation.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia

Detailed Description

This study will enroll approximately 3000 CP-CML patients that must have a history of at least 4 years of TKI treatment and at least 18 months of DMR. Events developing in patients after the end of discontinuation and TKI resumption will be considered as linked to the discontinuation if they will develop within 36 months from the end of discontinuation. This rule will apply also to subsequent TD attempts. In case of a second or subsequent discontinuation attempt after the failure of a previous one (for molecular relapse), patients must have re-achieved a DMR with TKI therapy resumption and must keep DMR for at least 18 months before another TD.

Collection of data will be retrospective and prospective, as each center will collect the data for 24 months. Patients who discontinued before the opening of this study will contribute to the retrospective cohort, while those who will discontinue after it will contribute to the prospective cohort. Patients who discontinued before the opening of this study but will continue their discontinuation after it, will contribute to both cohorts. For patients prospectively recruited, monitoring of disease status will be performed to assess the maintenance of the molecular remission during the study period.

Patients with an atypical BCR-ABL1 fusion gene, which does not allow the use of Q-RT-PCR, will be monitored by qualitative PCR and will be analyzed separately. For these patients, negativity of nested qualitative RT-PCR will be considered a surrogate of DMR of patients monitored by Q-RT-PCR, while loss of negativity of first-round qualitative PCR will be considered a surrogate of loss of MMR (i.e. molecular relapse). Accordingly, for patients monitored by qualitative PCR, TKI resumption after TD will be provided in case of a new positivity of first-round PCR.

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• Study Type: Observational
• Enrollment (Actual): 260

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • McGill University - Jewish General Hospital Division of Hematology and Department of Oncology
• Germany
  • Berlin, Germany, 13353
    • Charité University of Berlin - Clinic of Medicine - Hematology and Oncology
  • Mannheim, Germany
    • University of Mannheim, Mannheim, Germania
• Italy
  • Bologna, Italy
    • Istituto di Ematologia "Lorenzo e A. Seragnoli" Policlinico S. Orsola Malpighi,
  • Cagliari, Italy
    • CTMO Ematologia Ospedale "Businco"
  • Catania, Italy
    • Università di Catania Cattedra di Ematologia Ospedale "Ferrarotto"
  • Catanzaro, Italy
    • SOC Ematologia Az. Ospedaliera Pugliese Ciaccio (AOPC)
  • Cuneo, Italy
    • Ematologia Ospedale Cuneo
  • Miano, Italy
    • UO Ematologia O spedale Milano S. Raffaele
  • Napoli, Italy
    • Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria Università degli Studi di Napoli "Federico II" Facoltà di Medicina e Chirurgia
  • Palermo, Italy
    • U.O. di Ematologia con trapianto A.U. Policlinico "Paolo Giaccone"
  • Parma, Italy
    • Unità operativa Ematologia e CTMO Az Ospedaliera Universitaria
  • Pavia, Italy
    • Fondazione IRCCS Policlinico San Matteo
  • Pisa, Italy
    • Università di Pisa Azienda Ospedaliera Pisana Divisione di Ematologia
  • Reggio Emilia, Italy
    • Azienda Unita Sanitaria Locale Irccs
  • Torino, Italy
    • Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino S. G.Battista
  • Torino, Italy
    • Struttura Complessa a Dir. Universitaria Ematologia e Terapie Cellulari A.S.O. Ordine Mauriziano, P.O. U mberto I
  • Varese, Italy
    • S.C. Ematologia, Ospedale di Circolo e Fondazione Macchi Varese, ASST dei Sette Laghi,
  • Venezia, Italy
    • U.O. di Ematologia Ospedale dell'Angelo Mestre
  • Verona, Italy
    • Istituti Ospitalieri di Verona Div. di Ematologia Policlinico G.B. Rossi
  • Vicenza, Italy
    • U.O. Complessa di Ematologia Azienda ULSS 8 "Berica" Ospedale San Bortolo
  • Italy/MB
    • Monza, Italy/MB, Italy, 20900
      • ASST-Monza
  • Italy/Milano
    • Milano, Italy/Milano, Italy, 20162
      • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC di Ematologia
  • Italy/Rome
    • Rome, Italy/Rome, Italy, 00142
      • Universita di Tor Vergata Ospedale S. Eugenio
• Spain
  • Barcelona, Spain
    • University Hospital Clínic de Barcelona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The target population will include all CML patients presently eligible for treatment discontinuation independently of whether they discontinued or not. For the time they did not discontinue they will contribute to the reference cohort, while after TD they will contribute data to the discontinuation cohort. In case of treatment resumption, the patient will still contribute to the discontinuation cohort for 36 months after treatment resumption, while he/she will contribute to the reference cohort thereafter, assuming a new TD did not occur.

Description

Inclusion Criteria:

1. Signed and dated IRB/IEC-approved informed consent for the prospective cohort patients.
2. Age >= 18 years.
3. Male or female patients with CML diagnosed in chronic phase (CP).
4. At least 4 years of TKI treatment.
5. At least 18 months of DMR.

Exclusion Criteria:

• Allogeneic hematopoietic stem cell transplantation.
• CML diagnosed in AP or BC

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Retrospective cohort; Patients who discontinued before the opening of this study will contribute to the retrospective cohort.
Prospective cohort; Patients who will discontinue after it will contribute to the prospective cohort.
Retrospective/Prospective cohort; Patients who discontinued before the opening of this study but will continue their discontinuation after it, will contribute to both cohorts.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The quantification of the risk of progression	To quantify the risk of progression to accelerated phase (AP) or blast phase (BP), expressed as time adjusted rate (TAR), after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt	36 Month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the time adjusted rate (TAR) of progression from Chronic phase-Chronic Myeloid Leukemia to Accelerated phase (AP) or Blastic phase (BP) by using the percentage of blasts, promyelocytes, basophils or platelet in blood or bone marrow	To compare the TAR (time adjusted rate) of progression to AP or BP that is obtained in the target population to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment	36 Month
Progression free survival (PFS) after TKI discontinuation.	PFS will be defined as time between discontinuation and progression to AP or BP.	36 Month
Rate of molecular relapse (loss of MR3 or MMR)	Rate of molecular relapse (loss of MR3 or MMR) at 12 and 24 months after TKI discontinuation.	36 Month
Relapse free survival (RFS) after TKI discontinuation.	Relapse free survival (RFS) after TKI discontinuation. RFS will be defined as time between discontinuation and loss of MMR (i.e. molecular relapse).	36 Month
Percentage of relapsed patients who obtain a new deep molecular response (DMR) within 6-12 months of treatment resumption among all patients who restart TKI treatment because of a molecular relapse after TKI discontinuation.	The following criteria will be used to define DMR (43): MR4 = either (i) detectable disease with <0.01% BCR-ABL1IS or (ii) undetectable disease in cDNA with >10 000 ABL1 transcripts.; MR4.5 = either (i) detectable disease with <0.0032% BCR-ABL1IS or (ii) undetectable disease in cDNA with >32 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1.; MR5 = either (i) detectable disease with <0.001% BCR-ABL1IS or (ii) undetectable disease in cDNA with >100 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1.	36 Month

Collaborators and Investigators

• Sponsor: University of Milano Bicocca
• Investigators: Principal Investigator: Elisabetta Abruzzese, MD, Ospedale S. Eugenio Roma; Principal Investigator: Vincenzo Accurso, MD, A.U. Policlinico "Paolo Giaccone" Palermo; Principal Investigator: Mario Annunziata, MD, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" Napoli; Principal Investigator: Francesco Passamonti, MD, Ospedale di Circolo e Fondazione Macchi Varese, ASST dei Sette Laghi Varese; Principal Investigator: Massimo Bonifacio, MD, Istituti Ospitalieri di Verona- Policlinico G.B. Rossi Verona; Principal Investigator: Giovanni Caocci, MD, CTMO - Ospedale "Businco" Cagliari; Principal Investigator: Francesca Lunghi, MD, Ospedale Milano S. Raffaele Milano; Principal Investigator: Chiara Elena, MD, Fondazione IRCCS Policlinico San Matteo di Pavia; Principal Investigator: Monica Crugnola, MD, Az Ospedaliera Universitaria Parma; Principal Investigator: Sara Galimberti, MD, Azienda Ospedaliera Pisana Pisa; Principal Investigator: Alessandra Iurlo, MD, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Milano; Principal Investigator: Luciano Levato, MD, Az. Ospedaliera Pugliese - Ciaccio (AOPC) Catanzaro; Principal Investigator: Maria Cristina Miggiano, MD, Azienda ULSS 8 "Berica" Ospedale San Bortolo Vicenza; Principal Investigator: Patrizia Pregno, MD, A.O. Città della Salute e della Scienza di Torino S. G.Battista Torino; Principal Investigator: Davide Rapezzi, MD, Ospedale Cuneo; Principal Investigator: Rosaria Sancetta, MD, Ospedale dell'Angelo Mestre Venezia; Principal Investigator: Fabio Stagno, MD, P.O. Gaspare Rodolico, Catania; Principal Investigator: Luigia Luciano, MD, Azienda Ospedaliera Universitaria-Università degli Studi di Napoli "Federico II"; Principal Investigator: Carmen Fava, MD, A.S.O. Ordine Mauriziano, P.O. Umberto I Torino; Principal Investigator: Philipp leCoutre, MD, Charité University of Berlin · Medical Department, Division of Oncology and Hematology; Principal Investigator: Susanne Saussele, MD, University of Mannheim; Principal Investigator: Alberto Álvarez-Larrán, MD, University Hospital Clínic de Barcelona; Principal Investigator: Sarit Assouline, MD, Jewish General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2020
• Primary Completion (Actual): September 30, 2021
• Study Completion (Actual): August 14, 2023

Study Registration Dates

• First Submitted: September 14, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: TFR-PRO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No