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A 64-year-old gentleman, who had been diagnosed with intrahepatic cholangiocarcinoma 3 years back and was in remission following resection and adjuvant chemotherapy with a combination of 5-fluorouracil (5-FU) and gemcitabine, presented to us with shortness of breath and weakness for 2 weeks. On examination, he had hepatosplenomegaly. Complete blood count revealed anaemia (Hb 8.5 g/dL), thrombocytopenia (39 × 109/L) and leucocytosis (63.9 × 109/L). Peripheral blood smear and bone marrow aspirate revealed 65% and 78% blasts, respectively. Intriguingly, there were two morphologically distinct population of blasts. The larger blasts (3–3.5 times the size of mature lymphocytes) had opened-up chromatin and prominent nucleoli while the smaller blasts had condensed chromatin with indistinct nucleoli. On cytochemistry, only the larger blasts were positive for myeloperoxidase stain (Fig. 1A). On flow cytometry, a single population of precursor cells were identified which showed simultaneous expression of both myeloid (CD13, CD33, CD117, myeloperoxidase) and B-cell lineage (CD10, CD19, cytoplasmic CD22 and cytoplasmic CD79a) markers (Fig. 1B–G), thereby establishing the diagnosis of mixed phenotype acute leukaemia. Monosomy 7 and BCR-ABL1 translocation were identified on fluorescence in-situ hybridisation (Fig. 1H–J). Reverse transcriptase polymerase chain reaction (RT-PCR) corroborated the presence of BCR-ABL1 translocation with p190 transcript (Fig. 1K).
Therapy-related myeloid neoplasm (t-MN) is a recognised entity in the WHO 2016 classification. Recently, there has been much interest in unravelling the drivers of therapy-related lymphoid neoplasm which has been reported to comprise 9–13% of all therapy-related leukaemias. Current evidence suggests that t-ALL arises de novo as an effect of genotoxic therapy, and inherited cancer susceptibility genes play a role in only a small subset of patients [1]. Therapy-related mixed phenotype acute leukaemia (t-MPAL) is an even rarer entity and has been described only in prior case reports [2,3,4,5,6,7,8]. The origin, incidence, cytogenetic aberrations, biology and prognosis of t-MPAL remains unexplored because of the rarity of this entity. The exact phenotype profile (B/myeloid versus T/myelod and biphenotypic versus bilineal t-MPAL) is also not known. To the best of our knowledge, this is the first report of the development of B/myeloid MPAL following chemotherapy with antimetabolites (5-FU and gemcitabine) for intrahepatic cholangiocarcinoma.
The occurrence of therapy-related leukaemias after alkylating agents and topoisomerase II inhibitor therapy is well known. The latent period post-exposure to chemotherapy is prolonged with alkylating agents (5–10 years) and shorter following topoisomerase II inhibitors (1–5 years). Therapy-related leukaemias secondary to antimetabolites have been well documented although their incidence remains undetermined. The biology, cytogenetic and molecular profiles of these neoplasms are also underexplored. Our patient developed t-MPAL 3-years after treatment with 5-FU and gemcitabine which is consistent with the relatively short latency that has been previously reported with therapy-related leukaemias post-exposure to 5-FU based antimetabolite therapies [9,10,11].
Unbalanced chromosomal aberrations like monosomy 7 are common after therapy with alkylating agents while topoisomerase II inhibitors lead to balanced translocations including t(9,22)(q34;q11.2). Presence of Philadelphia chromosome i.e., t(9,22)(q34;q11.2), is a poor prognostic feature in MPAL regardless of the presence of other cytogenetic abnormalities. Monosomy 7 has also been described in around 10% patients with MPAL. However, the concurrent presence of a t(9;22)(q34;q11.2) and monosomy 7 is rare in MPAL. There is little data on the cytogenetic and molecular aberrations of t-MPAL [2,3,4,5,6,7,8]. To the best of our knowledge, this is the first report of the concomitant presence of monosomy 7 and BCR-ABL1 in t-MPAL.
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Ray, D., Naseem, S., Sreedharanunni, S. et al. Mixed phenotype acute leukaemia with monosomy 7 and BCR-ABL1 translocation following antimetabolite therapy for intrahepatic cholangiocarcinoma. J Hematopathol 15, 41–43 (2022). https://doi.org/10.1007/s12308-022-00486-8
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DOI: https://doi.org/10.1007/s12308-022-00486-8