Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 transcript as a result of reciprocal translocation between chromosome 9 and 22. The most common transcripts subtypes are e13a2 (b2a2) and e14a2 (b3a2). The prognostic impact of the type of BCR-ABL1 transcript has been the subject of controversies over time. In the imatinib era, several studies have suggested a deeper and faster response in patients expressing e14a2. However, the impact on response after first line therapy with a second-generation tyrosine kinase inhibitor, nilotinib, is unknown.We retrospectively evaluated 118 patients newly diagnosed with chronic phase CML and treated frontline with nilotinib inside or outside clinical trial in five French centers. Only patients expressing e14a2 or e13a2 transcripts alone were analyzed.At baseline, 55.3% expressed e14a2, 44.7% expressed e13a2. The median age was 51 years and median follow-up was 49 months. Relative risks of CML at diagnosis were similar according to the ELTS score (p = .87). Complete hematological response and complete cytogenetic response rates were similar among groups. Patients expressing e14a2 transcripts compared to e13a2 transcripts had deeper and faster molecular responses, when considering MMR (100% vs 84.1%, p = .007) with a median time of 6.7 and 17.1 months or MR4.5 (100% vs 59.9%, p = .005) with a median time of 39.7 and 70.9 months, respectively. A sustained treatment free remission was observed in 10/10 patients with e14a2 versus 1/3 with e13a2 transcript (p = .04).In conclusion, even treated with nilotinib first line, patients with chronic phase CML expressing BCR-ABL1 e13a2 transcript have a lower rate of deep molecular responses.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia characterized in chronic phase by increases in myeloid and platelets cells in the peripheral blood and myeloid hyperplasia in the bone marrow [1, 2].The pathophysiology of CML has been well established since the description of the Philadelphia chromosome by Nowell and Hungerford in 1960 [3]
The disease is characterized by a translocation [4] that consists of a juxtaposition of the ABL1 gene from chromosome 9 and the BCR gene from chromosome 22, coding for a protein with constitutive tyrosine kinase activity, able to be targeted by tyrosine kinase inhibitors [5, 6]
polymerase Chain reaction (PCR) efficiencies were the not different (p = .34) when we used a specific e14a2 primer or the European Against Cancer (EAC) primers on a e14a2 cell line, suggesting that amplification is comparable between the two transcripts with EAC protocol
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia characterized in chronic phase by increases in myeloid and platelets cells in the peripheral blood and myeloid hyperplasia in the bone marrow [1, 2].The pathophysiology of CML has been well established since the description of the Philadelphia chromosome (or Ph1) by Nowell and Hungerford in 1960 [3]. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia characterized in chronic phase by increases in myeloid and platelets cells in the peripheral blood and myeloid hyperplasia in the bone marrow [1, 2]. The disease is characterized by a translocation [4] that consists of a juxtaposition of the ABL1 gene from chromosome 9 and the BCR gene from chromosome 22, coding for a protein with constitutive tyrosine kinase activity, able to be targeted by tyrosine kinase inhibitors [5, 6]. Depending on the site of the breakpoint in the BCR gene, the fusion protein can vary in size from 185 kDa to 230 kDa. The break most commonly occurs between exon (e13) and exon (e14 formerly known as b2) or between e14 and exon (e14, formerly known as b3) in a region of approximately 5.8 kb called the major breakpoint cluster or M-BCR. The breakpoint in the ABL1 gene is generally located between exons a1 and a2
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