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3604 Treatment Free Survival (TFS) in Patients (pts) with Chronic Myeloid Leukemia (CML) Carrying Atypical BCR-ABL1 Fusion Transcripts: The French CML Group (Fi-LMC) ExperienceClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Research, Diseases, Myeloid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Hyacinthe Johnson-Ansah, MD1,2*, Aude Charbonnier, MD, PhD1,3*, Delphine Rea, MD, PhD4,5, Gabriel Etienne, MD, PhD6,7*, Lydia Roy, MD6,8*, Laurence Legros, MD, PhD1,9*, Agnes Guerci Bresler, MD10*, Anne Bouvier, MD PhD11*, Emilie Cayssials, MD12,13*, Valerie Coiteux, MD14*, Philippe Rousselot6,15*, Stephanie Dulucq, PharmD, PhD6,16*, Sandrine Hayette, PhD6,17*, Francois-Xavier Mahon, MD, PhD6,18 and Franck E. Nicolini, MD, PhD6,19,20

1Institut Bergonié, French Group of CML, Bordeaux, France
2Institut d'Hématologie de Basse-Normandie, CHU de Caen Normandie, Caen, France
3Hematology department, Institut Paoli Calmettes, Marseille, FRA
4Université de Paris, Hematology department, Saint-Louis hospital, APHP, Paris, France
5Fi-LMC group, Paris, France
6Fi-LMC group, Pessac, France
7Institute Bergonie; Institut National de la Sante et de la Recherche Medicale; Groupe France Intergroupe des Leucemies Myeloides Chroniques, Hopital Haut-Leveque, Pessac, France
8Hematology department, Hopital Henri Mondor, Creteil, France
9Hematology department, Hôpital Paul Brousse, Villejuif, France
10Service d'Hématologie Clinique, Centre Hospitalier Universitaire Brabois, Nancy, France
11Angers University Hospital, Angers, France
12French group of CML (Fi-LMC), Pessac, France
13Poitiers University Hospital, Poitiers, France
14Hematology Department, CHRU Lille, Lille, FRA
15Hematology Department, Centre Hospitalier de Versailles, LE CHESNAY CEDEX, France
16Laboratory of Hematology, University Hospital of Bordeaux, Hôpital Haut Lévêque, Pessac, France
17Centre Hospitalier Lyon Sud, Pierre Benite, FRA
18Cancer Center of Bordeaux, Institut Bergonié, INSERM U1218, University of Bordeaux, Bordeaux, France
1933 Hematology Departments, Centre Léon Bérard, Centre Hospitalier Lyon Sud, Pierre Bénite ; CRCL, Lyon, France
20INSERM U590, CRCL, Lyon, France

Aims

Life expectancy of CML pts optimally responding to tyrosine kinase inhibitors (TKI) is close to that of the general population and recently, TFR has been acknowledged as a new goal of CML management. TKI discontinuation in the view of TFR requires the achievement of deep and long-lasting molecular responses (MR). The gold standard BCR-ABL mRNA quantification technology and MR definitions rely on internationally standardized (IS) RT-qPCR but atypical transcripts located outside the Major-BCR region, harbored by 1-2% of pts, cannot be expressed on the IS scale. Thus, most trials and clinical practice recommendations prevent such pts from attempting TFR. The Fi-LMC group retrospectively collected real-life observations to assess TFR likelihood in this rare population.

Methods

Data from CML pts with precise characterization of atypical transcripts in whom any line TKI was stopped for any reason but after at least 2 years of undetectable molecular residual disease (UMRD) by individualized non-standardized RT-qPCR were collected. RT-qPCR sensitivity varied depending on transcript type and local molecular biology laboratory. TFS was estimated by the Kaplan-Meier method. Relapse was analyzed using the cumulative incidence function, relapse being as UMRD loss at any time and any level during follow-up (FU).

Results

Our series comprised 16 adult CP CML pts with atypical BCR-ABL fusions including 12 males (75%). Median age at CML diagnosis was 56 years (range: 21-75) and that at TKI discontinuation was 67 years [range: 29-82]. Sokal score was low, intermediate and high in 7, 8 and 1 pts, respectively. ELTS score was low and intermediate in 10 and 4 pts, respectively and unknown in 2. Most pts expressed e19a2 (n=6) followed by e6a2 (n=4), b3a3 (n=3), b2a3 (n=2) and e8a2 (n=1). Seven pts discontinued imatinib, 4 stopped dasatinib, 4 nilotinib and 1 bosutinib. Number of lines of therapy was 2 in 8 pts, 1 in 5 pts and 3 in 3 pts. Median TKI treatment duration before discontinuation was 64 months (range: 31-218) and median duration of UMRD was 41 months (range: 21-168). The median FU after TKI discontinuation was 68 months (range: 3-149). Five pts experienced relapse leading to TKI resumption. Four relapses occurred within 3-6 months and included 2 loss of hematologic response in CP, 1 loss of hematologic response in accelerated phase CML and 1 molecular recurrence with BCR-ABL transcripts up to 1.5%. One relapse occurred at 49 months and consisted in loss of a complete cytogenetic response. These 5 pts resumed TKI and regained UMRD within 6 months, including 1 pt who died in UMRD from non-CML-related cause at the age of 82 years and 1 pt who rapidly failed a 2nd TKI discontinuation attempt.

In 1 additional pt, BCR-ABL transcripts became detectable intermittently with maximum transcript level of 0.15% and TKI was not resumed. The median FU of pts who remained treatment-free was 68 months (range: 8-149).

Overall, the 5-year cumulative incidence of relapse regardless of whether TKI was resumed was 41.6% (95% confidence interval: 21.9%-78.7%) (Figure 1). The 5-year TFS rate was 65.2% (95% confidence interval: 40.3%-90.2%) (Figure 2).

Conclusions

Our observational study of TKI discontinuation in CML pts with atypical BCR-ABL transcripts is the largest reported so far. While effort must be made for proper assessment of deep MR, preliminary results suggest that TFS pattern might favorably compare with that obtained in pts with Major-type BCR-ABL transcripts. However, relapses may be more aggressive and caution is required in order to avoid loss of hematologic responses and progression. Whether the type of atypical fusion gene influences TKI discontinuation outcome, as well as other potential prognostic factors, need to be determined in a larger series.

Disclosures: Charbonnier: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne: Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

*signifies non-member of ASH