Incidence and outcome of BCR‐ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors

Gabriel Etienne (1, 2) , Stéphanie Dulucq (3) , Françoise Huguet (4, 4) , Anna Schmitt (1) , Axelle Lascaux (5) , Sandrine Hayette (6) , Marie-Pierre Fort (1) , Pierre Sujobert (7) , Fontanet Bijou (1) , Stéphane Morisset (8) , Suzanne Tavitian (9) , Audrey Bidet (10) , Béatrice Turcq (11, 12) , Fanny Robbesyn (13) , Claudine Chollet (13) , Francis Belloc (2) , Françoise Durrieu (1) , François-Xavier Mahon (1, 13, 1, 2) , Franck Nicolini (14)

1 Institut Bergonié [Bordeaux]
2 Laboratory of Mammary and Leukaemic Oncogenesis, INSERM U1218, Université de Bordeaux
3 Laboratoire d'Hématologie, Hôpital Haut Lévêque CHU de Bordeaux, Pessac
4 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
5 Service des maladies du sang, Hôpital Haut Lévêque CHU de Bordeaux, Pessac
6 Service d'hématologie [Hôpital Edouard Herriot - HCL]
7 Laboratoire d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite
8 Hôpital Edouard Herriot [CHU - HCL]
9 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
10 Laboratoire d'Hématologie, Hôpital Haut Lévêque CHU de Bordeaux, Pessac
11 Laboratory of Mammary and Leukaemic Oncogenesis, INSERM U1218, Université de Bordeaux
12 CNRS - Centre National de la Recherche Scientifique
13 Laboratoire d'Hématologie, Hôpital Haut Lévêque CHU de Bordeaux, Pessac
14 Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL]

Purpose To assess the incidence of BCR‐ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP‐CML) patients treated with tyrosine kinase inhibitors (TKIs). Patients and Methods We analyzed characteristics and outcome of 253 CP‐CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first‐line TKI. Results Overall, 80 (32%) patients harbored BCR‐ABL KD mutations. A BCR‐ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP‐BP), and 47%, 29%, 35%, 16% and 26% in patients in CP‐CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively. Overall survival and cumulative incidence of CML‐related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P‐loop vs non‐T315I non‐P‐loop) (P<.001). Considering patients who were in CP at the time of mutation analysis, LCP mutated patients had a significantly worse outcome than ECP‐mutated patients despite a lower incidence of T315I and P‐loop mutations (P<.001). With a median follow‐up from mutation analysis to last follow‐up of 5 years, T315I and P‐loop mutations were not associated with a worse outcome in ECP patients (P = .817). Conclusion Our results suggest that early mutation detection together with accessibility to 2nd and 3rd generation TKIs have reversed the worst outcome associated with BCR‐ABL KD mutations whatever the mutation subgroup in CP‐CML patients.

Mots clés: BCR-ABL kinase domain mutation; chronic myeloid leukemia; tyrosine kinase inhibitors

Domaines: Sciences du Vivant [q-bio]; Cancer; Biochimie, Biologie Moléculaire

Gabriel Etienne, Stéphanie Dulucq, Françoise Huguet, Anna Schmitt, Axelle Lascaux, et al.. Incidence and outcome of BCR‐ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Medicine, 2019, 8 (11), pp.5173-5182. ⟨10.1002/cam4.2410⟩. ⟨hal-02395152⟩