Philadelphia Chromosome (Ph’) Negative, MLL-Rearranged AML Arising in a Patient Treated with Imatinib for CML.

Background: Imatinib has become standard front-line therapy for CML. In ~3% of patients treated with imatinib, abnormalities including trisomy 8 and/or monosomy 7 occur in Ph’ negative subclones and dysplasia occasionally is present, but transformation to AML is rare. We describe the first known case of AML with an MLL translocation during an imatinib-induced molecular remission of CML.

Methods: The Ph’ and the t(11;19)(q23;p13.1) were detected and monitored in sequential marrows using cytogenetic and FISH analyses. The BCR-ABL1 fusion transcript was traced by RT-PCR. The MLL translocation was identified and characterized in the AML blasts by Southern blot analysis, panhandle PCR-based methods and conventional PCR.

Clinical History and Results: The patient presented with chronic phase CML at age 53 and was treated with hydroxyurea for 6 weeks, IFN-α for 20 months and imatinib for 32 months. Complete cytogenetic response was achieved at 10 months. Molecular remission, as indicated by absence of the BCR-ABL1 transcript, occurred after 15 months of imatinib (37 months from CML diagnosis). Mild dysgranulopoiesis was noted 6 months after imatinib was started and increased on subsequent studies. After 28 months of imatinib (50 months from CML diagnosis), there was marked trilineage dysplasia and the karyotype showed t(11;19)(q23;p13.1) in cells that were Ph’ negative and negative for the BCR-ABL1 fusion transcript. FAB M5b AML was diagnosed four months later. The patient succumbed to AML despite aggressive management with chemotherapy and allogeneic stem cell transplantation. Southern blot analysis of the AML revealed two MLL bcr rearrangements. The reciprocal breakpoint junctions on the der (11) and der (19) chromosomes indicated a translocation of intron 8 of MLL and intron 1 of the known MLL partner gene ELL, which encodes a transcription elongation factor. The involved region of MLL was more 5′ than the secondary leukemia translocation breakpoint hotspot. The der (11) fusion transcripts joined MLL exon 7 to ELL exon 2, which is consistent with alternative splicing, and the der (19) fusion transcript joined ELL exon 1 to MLL exon 9.

Conclusions: Secondary leukemias with MLL translocations have been associated with topoisomerase II poisons, but not with the agents administered to this patient. The entity that we describe is distinct from blast crisis, in which Ph’ positive subclones evolve to acquire additional alterations. This case establishes that persistent clonal abnormalities and/or dysplasia in Ph’ negative cells following imatinib therapy may not be benign and may herald AML transformation. With effective and selective molecular eradication of the Ph’ positive clone, the emergence of leukemia with independent abnormalities may become more common. This is a highly concerning clinical complication to consider with BCR-ABL targeted agents.