Response to |[lsquo]|D276G mutation is associated with a poor prognosis in imatinib mesylate-resistant chronic myeloid leukemia patients|[rsquo]| by Leguay et al

TO THE EDITOR In their letter to the editor, Leguay et al1 present the clinical and molecular characteristics of two patients affected by chronic myeloid leukemia (CML) and treated with imatinib. These two patients showed an aggressive clinical course: they developed resistance to the drug and died soon after the evolution to blast crisis (BC: one lymphoid, one myeloid). Sequencing analysis of the Abl catalytic domain of samples taken during relapse showed the presence of mutation D276G in both cases. Thus, the authors conclude that mutation D276G could be linked to an aggressive disease course and a rapid transformation to acute phase, associated with a particularly poor prognosis. We recently published2 a case report on a patient affected by Bcr/Abl p190 acute lymphoblastic leukemia (ALL) treated with imatinib who developed resistance to the drug and in whom mutation analysis revealed mutation D276G. This patient was diagnosed with ALL on April 2001, started standard chemotherapy regimen and obtained a complete cytogenetic remission (CCR), remaining positive for p190 at the molecular level. On August 2001, he started on imatinib 800 mg daily and remained in cytogenetic remission until January 2002 when bone marrow aspirate showed 70% blasts. He died on November 2002, despite receiving chemotherapy followed by autografting. A second case of D276G mutation identified in our laboratory is a chronic phase (CP) CML patient who was diagnosed on March 1995. The patient started on imatinib, 400 mg daily, in January 2000. After 12 months of treatment, he showed only a minor cytogenetic response; thus, his dose was increased to 800 mg. He obtained a CCR after 6 months, but remained positive on PCR. Clonal mutational screening on a bone marrow sample, taken 3 months after the achievement of CCR (October 2001), revealed the presence of mutation F359V on 6/10 clones analyzed. In a successive analysis (May 2003), mutation F359V was found to be present in 10/10 clones and mutation D276G in 2/10 clones. The patient subsequently lost the CCR but has not progressed to the accelerated phase (AP)/BC, although he developed additional cytological abnormalities. Also, in the original description of D276G mutation,3 the patient first developed a F359V mutation while in remission from a Ph+ ALL, and showed the D276G at the time of clinical relapse. A further review of the literature available also identified a fifth case of Ph+ leukemia resistant to imatinib carrying mutation D276G4; in this case also, the clinical course of the disease was aggressive, with D276G observed at the time of BC development. Clinical data from these patients carrying mutation D276G show, in general, an aggressive course, according to what is suggested by Leguay and co-workers, with the D276G mutation detected at the time of disease progression in four out of five cases. However, in the analysis of these data, prudence is required. Two patients were affected by ALL; thus, their clinical course is not easily comparable with the CML patients; our second patient carried mutation D276G only in a fraction (20%) of the resistant clones; thus, the clinical characteristics of this patient could be linked to the most represented mutation (F359V). Moreover, mutation D276G was present as a double mutant with F359V, and it is known that these two mutations act via different molecular mechanisms;5 thus, an additive effect cannot be ruled out. Finally, it is important to underline that at the moment, to our knowledge, there is no convincing molecular mechanism supporting the aggressive course of mutation D276G other than its increased kinetic activity.