Interferon-α or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation

To the editor:

We report here the clinical outcome for 2 chronic myeloid leukemia (CML) patients who acquired the T315I mutation while on imatinib, both of whom were treated successfully, one with recombinant interferon-alpha (rIFN) and the other with semisynthetic homoharringtonine (HHT).

Patient 1 was a 75-year-old man with CML diagnosed in October 2003 who started imatinib 400 mg daily. After 4 months he achieved a complete cytogenetic remission (CCyR) with low BCR-ABL transcript numbers (0.3%) quantified by real-time quantitative polymerase chain reaction (RQ-PCR).¹  He maintained a good response for 12 months but then BCR-ABL transcripts started to increase progressively and a T315I mutation was identified. The earlier samples were then analyzed retrospectively. Thirty months after starting imatinib, cytogenetics revealed loss of CCyR (2% Philadelphia chromosome [Ph]–positive cells) and the patient started rIFN 9 MU/week. Ten months later the patient was still in complete hematologic remission (CHR) with low BCR-ABL transcripts (3%), a level that is just consistent with CCyR. Interestingly, on rIFN, the percentage of mutant transcripts measured by quantitative single-nucleotide polymorphism pyrosequencing¹  decreased from 100% to 30% (Figure 1A).

The second patient was a 60-year-old woman diagnosed with chronic-phase CML in 1997. She received rIFN and thereafter imatinib 400 mg daily from October 2002. She achieved a major cytogenetic response (15% Ph-positive cells) at 12 months but lost her response 2 years later. Bone marrow examination then revealed myelofibrotic transformation with 100% Ph positivity. Imatinib was increased to 600 mg/day, but she went into accelerated phase at 40 months, and thus received dasatinib 70 mg twice a day. Four months later a bone marrow aspirate still showed accelerated-phase leukemia, and a T315I mutation was identified. The earlier samples were then analyzed and the mutated clone was detected before starting dasatinib. The patient started on HHT at 1.25 mg/m² subcutaneously twice daily for 5 consecutive days every month. Five months later she achieved a CHR. The marrow showed a minor cytogenetic response, and at 10 months the percentage of the mutant clone had decreased from 100% to 27% (Figure 1B).

The finding of a T315I mutation in the BCR-ABL gene characteristic of CML is associated with clinical resistance to imatinib, nilotinib, and dasatinib.^2,–4  The only established salvage option for patients harboring this mutation is allogeneic stem cell transplantation (allo-SCT)⁵ ; the role of the aurora kinase inhibitor MK-0457 is not yet clear.⁶  Because the mechanisms of action of rIFN and HHT differ from that of tyrosine kinase inhibitors (TKIs), we evaluated their effect in these 2 patients with a predominant T315I clone.^2,7,8  Although longer follow-up is needed, both patients showed a significant decrease in the percentage of the mutated clone along with a continuing disease response for a follow-up of 10 months. The question whether T315I-expressing CML cells are more “aggressive” than cells expressing native protein is still debated.^9,10  However, it is possible that the decrease in size of the mutant subclone was a consequence of removing the selection pressure by stopping TKI. Thus rIFN or HHT should be considered for CML patients harboring the T315I mutation.²