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Journal of Postgraduate Medicine, Vol. 56, No. 3, July-September, 2010, pp. 221-222 Case Snippet Is b3a2 a better prognostic variant in childhood chronic myeloid leukemia? Malhotra KP, Sharma CB, Jain J1 , Grover RK1 Department of Pathology, 1 Clinical Oncology, Delhi State Cancer Institute, Dilshad Garden, Delhi - 95, India Correspondence Address: Dr. Kiran Preet Malhotra, Department of Pathology, Delhi State Cancer Institute, Dilshad Garden, Delhi - 95, India, drkiranpreetmalhotra@yahoo.co.in Code Number: jp10064 PMID: 20739774 DOI: 10.4103/0022-3859.68640 A three-year-old girl presented with low-grade fever and generalized weakness of five months duration. On examination, she was febrile with moderate degree of pallor and massive splenomegaly. There was no hepatomegaly, lymphadenopathy or evidence of mucosal bleeds or skin rash. Routine hemogram showed hemoglobin of 8.4 g%, elevated total leukocyte count of 265 x 109/L and a platelet count of 1063 x 109/L. A peripheral blood differential count revealed 60% polymorphs and band forms, 4% blasts, 4% promyelocytes, 17% myelocytes, 6% metamyelocytes and 6% basophils. Bone marrow aspirate revealed a similar picture. Leukocyte alkaline phosphatase score was 20 (control 41). Fetal hemoglobin levels were not elevated. Nested reverse transcription polymerase chain reaction showed presence of Philadelphia chromosome with b3a2 transcript variant of bcr-abl fusion gene. The case was hence diagnosed as adult type chronic myeloid leukemia (CML) in chronic phase and imatinib was titrated to response (200 mg/day). Two months post-imatinib therapy, the leukocyte and platelet counts normalized to 9.2 x 109/L and 332 x 109/L, respectively and the spleen was not palpable. Fluorescence in situ Hybridization analysis performed after six months showed bcr-abl fusion negativity in 100% of the interphase cells. After a follow-up period of 18 months, the patient is well maintained on imatinib therapy with no event of acceleration or blast transformation. Among childhood leukemias, CML is a rare entity with an annual incidence of one case per million children[1] Adult type CML in children is even rarer and is characterized by Philadelphia chromosome positivity. A patient may exhibit either b2a2 or b3a2 or both transcripts simultaneously, or less common ones like b2a3, b3a3 or b1a2, depending upon the breakpoint within or outside the major breakpoint cluster region. The transcribed mRNA subsequently is translated into a fusion protein with increased tyrosine kinase activity.[2],[3] Cytogenetic variants of the bcr-abl gene have been analyzed in some pediatric cases but their frequency, prognostic relevance and significance for therapy and long-term survival have not been well defined. An increased frequency of b2a2 [2,4] and b3a2 variant have been variously reported.[1] In a recent large study, the frequency of both variants has been reported to be similar and interestingly 26% cases were reported to have both variants simultaneously whereas earlier studies report only 0-1% of such cases.[3] Our patient showed b3a2 variant which has been reported to be a rare variant in India.[4] Among statistically significant differences observed, higher platelet and leucocyte counts and lower hemoglobin values have been reported with b3a2 variant which were also observed in our patient.[3] Our patient with b3a2 variant showed complete hematologic and cytogenetic response to imatinib, and continues to be in remission after 18 months of follow-up. While preliminary reports in adults suggest a better response to imatinib in patients with b2a2 variant, no such studies on prognostic or therapeutic implications of the transcript variants have been conducted in children.[5] The good outcome in our case suggests that b3a2 transcript may portend a better prognosis in children with good response to imatinib; a larger study in this context is however warranted. References
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