Multicenter Single-arm Pilot Study Evaluating Efficacy of Nilotinib in CML Patients With Molecular Relapse After Glivec Discontinuation Within the Context of the STIM Trials (STIM and STIM2)

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the reciprocal translocation t(9;22). The resulting oncoprotein, bcr-abl is an essential trigger for growth and survival of leukemic cells. In the past decade, the bcr-abl tyrosine kinase inhibitor (TKI) imatinib (IM or Glivec©) has been the standard of care for patients with CML, inducing durable responses. However, requiring continuing IM indefinitely and the ability of IM to eradicate the CML clone was uncertain. In a small proportion of patients, IM can induce complete molecular response (CMR) defined by the disappearance of the bcr-abl transcript in conventional quantitative RT-PCR. The question whether or not these patients are cured and can discontinue drug therapy has been assessed by Mahon and coll, in the STIM study. He demonstrates that IM can be safely discontinued in patient with a CMR of at least 2 year duration and all patients who relapsed after IM discontinuation mainly did it in the first 6 months and responded to reintroduction of imatinib. Nilotinib is a rationally designed second generation tyrosine kinase inhibitor with improved target specificity over imatinib. Its efficacy and safety in the treatment of patients who are resistant or intolerant to imatinib as well as patients with newly diagnosed CML-CP led to the registration in second and first line treatment of CML-CP patients. Nilotinib produces even faster and deeper responses with more occurrence of CMR than does Imatinib. Consequently, one can assume that a more potent drug such nilotinib could induce deeper and sustained CMR allowing longer period off treatment than IM. The objective of this pilot trial is to assess if Nilotinib can rescue STIM patients in molecular relapse after IM discontinuation and to provide an estimation about duration of CMR after nilotinib discontinuation in 2nd line therapy among patients experiencing 2 years of stable CMR with nilotinib.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Male and female patients
* Patient participating to the STIM trials (including STIM, STIM2 et EURO-SKI) and with confirmed molecular relapse on two consecutive RQ PCR, after imatinib discontinuation
* Still in chronic phase
* Not yet treated for this relapse
* At least 18 years old (no upper age limit)
* SGOT and SGPT \< 2.5 UNL
* Serum creatinin \< 2 UNL
* No planned allogeneic stem cell transplantation
* Signed informed consent
* ECOG score 0 to 2

Exclusion Criteria:

* Pregnancy, lactation
* Prior or concurrent malignancy other than CML (exceptions to be mentioned)
* Serious uncontrolled cardiovascular disease
* Severe psychiatric/neurological disease (previous or ongoing)
* Ongoing treatment at risk for inducing "torsades de pointe"
* QTcF \> 450ms despite correction of predisposing factors (i.e electrolytes…)
* Congenital long QTcF
* No health insurance coverage

• RESULTDulucq S, Rigal-Huguet F, Nicolini FE, Cony-Makhoul P, Escoffre-Barbe M, Gardembas M, Legros L, Rousselot P, Liu J, Rea D, De Mas V, Hayette S, Raynaud S, Lacoste-Roussillon C, Robbesyn F, Klein E, Morisset S, Mahon FX, Etienne G. Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study. Br J Haematol. 2023 Jun;201(6):1116-1124. doi: 10.1111/bjh.18796. Epub 2023 Apr 2. PMID 37004981