Thanks to cousinreg for posting this in one of the discussions; didn't want it to get lost.
CESSATION OF DASATINIB OR NILOTINIB THERAPY IN CHRONIC-PHASE CHRONIC MYELOID LEUKAEMIA PATIENTS WITH SUSTAINED COMPLETE MOLECULAR RESPONSES
MD, PhD Rea, Delphine, Hopital Saint-Louis, APHP, Paris, France (Presenting author)
Rousselot, Philippe, CH de Versailles, Le Chesnay, France
Nicolini, Franck, Hopital Edouard Herriot, Lyon, France
Legros, Laurence, GH l'Archet, Nice, France
Tulliez, Michel, Hopital Henri Mondor, Creteil, France
Guilhot, Francois, CHRU de Poitiers, La Miletrie, France
Mahon, Francois-Xavier, Hopital Haut Leveque, Bordeaux, France
8. Chronic myeloid leukemia - Clinical
Chronic myeloid leukemia, Tyrosine kinase inhibitor
Background: Despite the outstanding efficacy of tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia (CML), the curative potential of these drugs remains uncertain. Recent results from the STop IMatinib trial suggest that imatinib may be safely discontinued in patients with long-lasting complete molecular responses (CMR) (Mahon et al. Lancet Oncol. 2010).
Aims: We asked whether second generation (2G)-TKI could ever be stopped in CML patients intolerant or resistant to imatinib who had achieved durable CMR. The primary objective was to evaluate the risk of losing major molecular responses (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ? 0.1%) and the key secondary objective to measure treatment-free survival.
Methods: Patients aged at least 18 years with chronic phase (CP)-CML with prior imatinib treatment were proposed dasatinib or nilotinib discontinuation provided that (1) no prior progression to accelerated phase or blast crisis occurred (2) CMR was achieved and sustained on continuing therapy. CMR was defined by RQ-PCR, using a detection threshold of BCR-ABL of at least 4.5 Log (CMR4.5). After 2G-TKI discontinuation, BCR-ABL transcripts were quantified monthly during the first year and every 2 to 3 months thereafter. Dasatinib or nilotinib re-introduction was triggered by the loss of MMR which defined relapse.
Results: As of February, 2011, 17 patients entered the study after informed consent. The results presented here focus on a subgroup of 12 patients with a minimum follow-up 6 months (median 12, range, 7-18). These were 7 females and 5 males, with a median age of 59 years (range, 34-81). The Sokal risk group was low in 8/12 (68%), intermediate in 1/12 (8%), high in 1/12 (8%) and unknown in 2/12 (16%). Imatinib was discontinued owing to intolerance (n=11) or resistance (n=1) and replaced by dasatinib (n=8) or nilotinib (n=4) after a median duration of therapy of 50 months (range, 3-92). At start of 2G-TKI, 1 patient had a complete hematologic response only, 2 had a partial cytogenetic response, 1 had a complete cytogenetic response but lacked MMR, 3 had a MMR without CMR and 5 had a CMR. The median time on 2G-TKI therapy prior to discontinuation was 33 months (range, 21-56). The median duration of sustained CMR was 29 months (range, 21-39).
Subsequently, 30% (4/12) of patients lost MMR by 6 months. MMR was rapidly regained upon early 2G-TKI re-introduction. Treatment was also re-started in 1 patient without MMR loss but showing CMR loss on 2 consecutive assessments. Seven patients remained off therapy at the last follow-up after a median of 11 months (range, 7-18), with either a stable CMR or weakly detectable BCR-ABL transcripts on one or more occasions. Treatment-free survival rate by 6 months was estimated to 58.3 % (95%CI: 21.7-31.3).
Conclusion: 2G-TKI may be safely discontinued in CML patients with stable CMR4.5. Importantly, a very low level of detectable residual disease after 2G-TKI withdrawal may be compatible with treatment-free survival. A longer follow-up is required to ascertain whether CML will recur. Our study provides a reasonable basis for subsequent prospective clinical trials. Updated results will be presented.