Abstract
The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors in the therapeutic arsenal. Disease response and survival have been dramatically improved with these agents, however a significant cohort of patients may resist to such inhibitors. In tyrosine kinase inhibitors (TKIs)-resistant CML patients, the identification of the BCR-ABLT315I mutation is a rare event, but usually translates into poor survival rates and therapeutic options remain few in the absence of a suitable allogeneic donor. In this study, within the CGX-635 CML 202 trial or not, we investigated the impact of cycles of sub-cutaneous Homo-harringtonine (HHT) [Omacetaxine mepesuccinate] as monotherapy on wild-type and mutated transcripts in 7 chronic phase CML patients resistant to TKIs, harbouring a BCR-ABLT315I mutation. Patients were monthly monitored in a centralized manner for total disease burden (RQPCR) and BCR-ABLT315I transcripts (PCR-RFLP, sensitivity threshold 1%) for up to 14 cycles. There were 4 M and 3 F, median age: 51 (38–79) at HHT start. All patients were in chronic phase (CP) at diagnosis, Sokal score was high for 5, intermediate for 1 and unknown for 1 patient. One patient had a Ph1 duplication at diagnosis. Two patients had short term IFN before imatinib. Median time of imatinib treatment was 27 (15–54) months with, as best responses: CHR for 2, a minor CyR for 1, PCyR for 2, CCyR without MMR for 2. Three patients had a second generation TKI for a median of 1 (1–22) month for unsatisfactory response to imatinib. At T315I identification, all patients were in CP CML, 4 in hematological relapse, 3 in CHR (1 molecular progression in CCyR, 1 in cytogenetic progression, 1 with no cytogenetic response). The proportion of T315I transcripts among total BCR-ABL transcripts was 95 (20–100) % and the BCR-ABL/ABL ratio (IS) was 67 (26–112) % at T315I discovery. Three patients had clonal evolution (Ph1 duplication, -7, -Y+variant Ph1). The median interval imatinib start-T315I was 27 (10–65) months. After T315I discovery, imatinib was withdrawn and, if necessary, patients went on hydroxyurea. The median time between T315I detection and HHT start was 2 (1–4.3) months. All patients demonstrated hematologic or cytogenetic improvements to HHT (7 patients in CHR, 1 in CCyR, after a median follow-up of 11 months). A rapid decline and a sustained disappearance of T315I mutated transcripts was observed in 6 out of 7 patients, median proportion of T315I transcripts was 65 % at Cycle 2, 19 % at cycle 3, 1 % at cycle 4, < 1 % at cycle 5 and beyond, The total tumour burden reduction was moderate with one patient converted to a CCyR after 3 cycles, but with no other cytogenetic improvement. A moderate decline was observed in BCR-ABL/ABL ratios from a median of 67 before HHT to 39 % at cycle 10, suggesting a differential activity of HHT on wild-type versus BCRABLT315I cells. Patients received a median of 8 (4–17) cycles of HHT at last follow-up and none of the patients have progressed. Transient grade 3–4 hematological toxicities after the first cycle and grade 0–2 after maintenance cycles were observed in all patients. Nonhematological toxicities were grade1–2 (site pain after injections, nausea, diarrhea). Since high levels of BCR-ABLT315I transcripts in CML are thought to be associated with disease progression, HHT (i. e. a non-targeted therapy) in these cases seems to exert a somewhat preferential activity on T315I mutated CML cells through an unknown mechanism yet. Therefore, by reducing the T315I+ tumor burden, this treatment is expected to decrease progression rates, and improve survival.
Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors