Molecular Response to Nilotinib 600 Mg Bid for Imatinib Resistance in a Patient with CML AP with Multiple Mutations Including G250E and E255K.
Authors: Souza Jacqueline Holanda , Quixada Acy , Costa Clara , Araujo Ana Angelica , Magalhàes Silvia M.M. 
Published: October 2019

Abstract 4287

Resistance to imatinib has emerged as a common management problem that has been addressed first by dose escalation and later by the use of second generation tyrosine kinase inhibitors (2TKI). In about half the cases the basis for acquired resistance to imatinib is the emergence of mutant bcr-abl whose “in vitro” sensitivity to 2TKIs has been reported. In theory, mutations with intermediate “in vitro” sensitivity to nilotinib could be overcome by the use of higher doses (600mg bid).Higher doses of nilotinib have been administered safely in phase I and II clinical trials involving patients in CP, AP and BC of CML. Total steady-state drug levels were reported in 18 patients receiving the 600mg bid and a dose-proportional increase in exposure was observed between the 400mg and 600mg bid schedules. The mean serum trough level at the steady-state was 1.7(mu)M at 400mg bid and 2.3(mu)M at 600mg bid.

We present and discuss the successful use of 600mg bid of nilotinib in a patient with Chronic Myeloid Leukemia (CML) resistant to imatinib 800mg qd and to nilotinib 400mg bid in whom G250E and E255K mutations were sequentially detected. Previous publications have suggested that E255K is unresponsive to nilotinib.

A 44 years old male was diagnosed with chronic phase CML with intermediate risk Sokal score and no histocompatible siblings; six months after diagnosis imatinib 600mg qd was started due to progression to AP. The patient achieved hematologic and cytogenetic remissions in 2 and 12 months respectively. Nineteen months later, loss of hematologic response was detected. Trials of imatinib 800mg qd and low dose Ara-C were not effective. Mutational analysis of bcr-abl revealed G250E, a p-loop mutation, with in vitro sensitivity to nilotinib. Within six months the patient had symptomatic transfusion-dependent anemia (Hb < 7 g/dL), bone pain, hepatomegaly and painful lymphadenopathy. Nilotinib 400mg bid was initiated with significant clinical improvement (becoming asymptomatic and transfusion independent in a few weeks). Within 18 months a complete cytogenetic response and a 2 log reduction of the bcr-abl transcripts by quantitative PCR was demonstrated (IS: 1,48%). Loss of hematologic response was observed six months later. There was quick deterioration of clinical status. A second mutation analysis demonstrated G250E and E255K.

Nilotinib was then increased to 600mg bid with rapid clinical improvement, followed by CHR in four weeks. Weekly CBC and chemistry profile as well as monthly EKG's were performed for safety. Due to marrow fibrosis cytogenetics was not available, but a major molecular response could be demonstrated after 3-months with 4 log reduction of bcr-abl transcripts (IS: 0,026%). The depth of molecular response has continued to improve with 5 log reduction after seven months (IS: 0,0026%). No serious side effects was seen on the higher dose schedule. Mild indirect hyperbilirrubinemia has remained stable on serial measurements. There was no significant change in the QTc interval (baseline QTc: 0,33).

Due to a favourable toxicity profile, nilotinib 600mg bid may be an option for refractory patients with mutations of intermediate sensitivity to nilotinib and who have progressed, especially when a suitable bone marrow donor is not identified.

Disclosures:

No relevant conflicts of interest to declare.