Response to Imatinib mesylate in chronic myeloid leukemia patients with variant BCR-ABL fusion transcripts

Abstract

Chronic myeloid leukemia patients with different BCR-ABL transcripts might respond differently to Imatinib mesylate. This prompted us to study BCR-ABL transcripts in chronic myeloid leukemia (CML) patients and their correlation with response to Imatinib. Eighty-seven chronic phase CML patients (median age, 35 years; range, 13-62 years; M/F, 59:28) were included in this study; 57 patients had received interferon-alpha and/or hydroxyurea, and 30 were previously untreated. All patients received Imatinib mesylate (Gleevec) 400 mg daily. Complete hematological remission rate and major cytogenetic response (CGR) rates were 99% and 72%, respectively. B3a2 transcript was present in 53% of patients, b2a2 in 39%, and both transcripts in 8% of patients. Twenty of 34(59%) patients with b2a2 type achieved complete CGR compared to 15 of 53 (28%) patients with b3a2, p = 0.04. Among 24 patients with minor or no CGR, six (25%) had b2a2 compared to 18 (75%) b3a2 type, p = 0.04. Expression of BCR-ABL/ABL% was higher in b3a2 patients compared to b2a2, p = 0.120. Pre-treatment characteristics-mean spleen size (6.6 vs. 6.4 cm, p = 0.868), mean hemoglobin (G/dl; 12.0 vs. 11.8, p = 0.690), mean WBC count (83 x 10(9) vs. 77 x 10(9)/L, p = 0.923), and mean platelets counts (360x10(9) vs. 340 x 10(9)/L, p = 0.712)-were not significantly different in the b3a2 vs. b2a2 transcripts groups. Our preliminary findings suggest that CML patients with b2a2 BCR-ABL transcript might have higher CGRs to Imatinib mesylate (Gleevec).

Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML)

“…They also found that pre-treatment characteristics like mean spleen size, mean hemoglobin, mean, and mean platelets counts were not significantly different in the b3a2 vs. b2a2 transcripts groups [26], which supports our findings. These observations highlight the need for more extensive studies in different ethnic groups on the role of different BCR-ABL splice variants in biology [27] and treatment response of the BCR-ABL positive leukemia patients, as acquired BCR-ABL point mutations and other factors associated with imatinib resistance do not explain the reason of imatinib resistance in all BCR-ABL positive patients [28][29][30].…”

“…Verma et al [25] reported that rare variants like e1a2 have an inferior response to imatinib. Sharma et al [26] found that 59% patients with b2a2 type achieved complete cytogenetic response (CGR) as compared to 28% patients with b3a2 (p = 0.04) while in 24 patients with minor or no CGR, 25% had b2a2 compared to 75% b3a2 type (p = 0.04). Moreover, expression of BCR-ABL/ABL% was higher in b3a2 patients compared to b2a2 (p = 0.120).…”

BCR-ABL1 transcript types showed distinct laboratory characteristics in patients with chronic myeloid leukemia

“…Some authors have found a better molecular response with the e14a2 transcript (Hanfstein et al, 2014;Lin et al, 2016;Jain et al, 2016) or e13a2 (de Lemos et al, 2005Sharma et al, 2010). Lin et al (2016) showed that males with e13a2 were a less favorable group in their response to imatinib treatment.…”

“…In this regard, some authors found no significant association but others suggested a possible prognostic value of the transcript types in relation to better response to treatment with Imatinib (de Lemos et al, 2005;Lucas et al, 2009;Sharma et al, 2010).…”

Chronic myeloid leukemia: Relevance of cytogenetic and molecular assays

“…Several reports have suggested that the type of the chimeric mRNA (e13a2 or e14a2) is associated with differences in the clinical and hematological characteristics of CML patients, despite that others failed to confirm any significant correlation (Kurzrock et al, 1988;Faderl et al, 1999b;De Lemos et al, 2005;Lucas et al, 2009;Sharma et al, 2010;Mondal et al, 2006a;Adler et al, 2009).…”