Evidence for D276G and L364I Bcr-Abl mutations in Ph plus leukaemic cells obtained from patients resistant to Imatinib

TypeofStudy:This study presented the outcome of Glivec monotherapy in patients with chronic myelogenous leukemia (CML) in blast crisis (BC)/accelerated phase (AP) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and described the development of resistance to Glivec treatment in these patients. Letter to the editor.DosageDuration:Initially, 600-mg and 800-mg daily in 2 patients, respectively. Duration: at least 4 and 5 months in 2 patients, respectively. Dosage and duration in other patients not specified.Results:After a follow-up of 40 months after relapse, only 1 patient survived. This patient, diagnosed with CML-BC, after 4 months of Glivec therapy, achieved a complete hematological response (CHR) of 2 months duration, developed resistance, and underwent an allogeneic-related BM transplantation. The median survival time after the development of resistance is of 6 months, and only 1 patient survived more than 12 months (excluding the patient who was successfully transplanted). FISH analysis showed no evidence of BCR-ABL gene amplification in all 20 patients. 7/14 patient scored positive for BCR-ABL mutations. The presence of mutations did not cause significant differences in survival between the two groups of resistant patients with and without BCR-ABL mutations. Mutation L3641 and D276G were identified in 2 patients (nos. 2 and 15). Patient 2, diagnosed with CML-AP in April 1994, started Glivec therapy in December 1999 and by the end of January 2000 achieved a CHR followed by a major cytogenetic response in June 2000. In November 2000, the patient relapsed, with 70% blasts in BM and died in December 2000. Patient 15, diagnosed with Ph+ ALL in April 2001 obtained a CHR and a complete cytogenetic response following chemotherapy. The patient started Glivec therapy in August 2001 and after 5 month of Glivec treatment, the patient relapsed, with 70% lymphoid blasts in BM and peripheral blood. The patient died 2 months after the diagnosis of relapse. The clonal analysis of BCR-ABL in patient 15 identified a point mutation at position 827 (a → g) in 7/9 evaluable clones, producing a missense D276G mutation. In patient 2, mutation L3641, corresponding to 1090 (c → a) at the nucleotide level, was identified in three clones on a total of 10. Genomic sequencing analysis confirmed the presence of the mutation in two clones out of a total of 28.AdverseEffects:No adverse events were mentioned.AuthorsConclusions:In the present manuscript, we present data obtained in one of the first cohorts of patients treated with Imatinib. The development of resistance represented a poor prognostic sign in this group of advanced, usually heavily pretreated patients, with short survival following the onset of resistance, independent of the length of Imatinib administration or of the underlying disease. Patients carrying mutations in Bcr-Abl have a similarly poor prognosis when compared to patients with different, yet unknown, mechanisms of resistance to Imatinib; however, the small number of patients precludes a firm conclusion on this point. The sensitivity for Imatinib was significantly decreased for mutation D276G, while it was only modestly increased in L3641 mutants. It is likely, however, that both these mutations play a causal role in causing resistance. Finally, it has to be recalled that resistant cells maintained sensitivity to Imatinib concentrations that are substantially lower than those observed in the plasma of patients.FreeText:Other treatment: allogeneic bone marrow (BM) transplantation (n=1). Tests: fluorescence in situ hybridization (FISH, BCR-ABL gene amplification), clonal analysis, and genomic sequence analysis.Indications:20 patients with chronic myelogenous leukemia (blast crisis or accelerated phase) or Philadelphia chromosome-positive acute lymphoblastic leukemia.Patients:20 patients were studied. Patients were followed up for up to 40 months (n=1).