Response to Imatinib in e13a2 Versus e14a2 BCR-ABL Fusion Transcripts in Chronic Myeloid Leukemia Saudi Patients

Background: Chronic myeloid leukemia (CML) is one of the predominant hematological malignancies in Saudi Arabia (SA). Different BCR-ABL fusion mRNAs occur immediately downstream of exon 2 or 3 of the M-bcr region and result in e13a2 or e14a2 fusion transcripts and the P210 BCR-ABL1 protein. To our knowledge, there is no published data addressing the frequency of BCR-ABL1 fusion transcripts among Saudi CML patients, and whether clinical outcome and gender have any correlation with BCR-ABL transcript type.

Aims: First, to determine whether BCR-ABL transcript type, gender, and response to therapy have any correlation in Saudi CML patients presented at King Abdullah Medical City (KAMC) in Makkah, western region of SA. Second, to determine the frequency of BCR-ABL transcript variants, and compare it with the occurrence reported in other neighboring populations.

Methods: Peripheral blood and bone marrow samples were analyzed by nested and multiplex RT-PCR to detect and quantify BCR-ABL transcripts from 72 evaluable Saudi CML patients seen at KAMC from January 2011 to present. Clinical and laboratory data were obtained from the medical charts of the patients.

Results: From January 2011 to July 2016, 179 patients with newly or previously diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. However, results discussed herein were obtained from 72 evaluable patients for whom complete clinical charts and laboratory data were available.

At diagnosis, the median age was 45 years (range 16-76), and there was nearly an equal number of males (N=35; 49%) versus females (N=37; 51%). These patients had high white blood cells (87.5%), high platelet counts (86%), and splenomegaly (61%). The follow up period ranged from 2 months to 66 months with a mean/median follow up of 1.83/1.7 year, respectively. At three months, 31 evaluable patients (54.4%) achieved early molecular response (EMR; 1 log reduction) of which 51.6% (N=16) were male, and 48.4% (N=15) were female. A major molecular response (MMR; 3-4 log reduction) in one year of treatment was obtained by 26 evaluable patients (36.1%) of which 53.8% (N=14) were male, and 46.2% (N=12) were female. Ten patients (18%) discontinued treatment with imatinib in the first year and were put on second line tyrosine kinase therapy (four for resistance and six for adverse events). Notably, six patients experienced disease progression and had tyrosine kinase domain mutation. We observed two deaths (2.8%), of which one involved E255K mutation.

Out of 72 patients in the study, 48.6% (N=35) patients showed e13a2 fusion transcript, while 51.4% (N=37) patients showed e14a2 transcript. There was no significant differential transcript expression associated with gender as e13a2 expression was found in 42.9% (N=15) of females and 57.1% males (N=20). Similarly, expression of e14a2 was found in 59.5% females (N=22) and 40.5% males (N=15). Of the patients who achieved MMR in e13a2 expressing group, 33.3% (N=4) were female and 66.7% (N=8) were male. In e14a2 expressing patient group who achieved MMR, 57.1% (N=8) were female and 42.9% (N=6) were male.

Conclusions: Our results compare favorably with those reported from the West and some Asian countries. There was no significant correlation between sex, type of BCR-ABL transcript and clinical outcome although we acknowledge that more data is needed in the future. These results further confirm lack of any predominance of the BCR-ABL isoforms e13a2 or e14a2 in Saudi CML patients under investigation, which is discordant with similar studies conducted in other groups of neighboring countries such as Sudan, Pakistan, and Iran.