Role of allo-HSCT in the treatment of patients with T315I mutation in the TKI era
Contact: Dr.Yulia Yu. Vlasova
Accepted 22 September 2016
Treatment of CML is based on the use of tyrosine kinase inhibitors (TKIs). Despite high effectiveness of the TKI, some patients in CP and significantly more patients in the AP and BC are resistant to it. Distinct point mutations at the kinase domain of ABL-tyrosine kinase are the most important mechanisms of TKI resistance. At present, T315I mutation is known to cause leukemia cells resistance for all known I and II generation TKIs.
Materials and Methods
We present cumulated results of 18 allogeneic bone marrow transplantations (allo-HSCT), performed in 16 patients with CML harboring T315I mutation, as well as data on pharmacological treatment of 37 patients that have been provided by hematological centers of the Russian Federation.
Four patients were in chronic phase 1 (CP1); 7 other cases, with CP≥2; five patients, in acceleration phase (AP); two patients were in blast crisis (BC) at the time of allo-HSCT. Fourteen patients were male, and two females. Their median age was 34 years (17-55 years old). HSCT was performed from HLA-identical siblings (n=7), or unrelated donors (n=11). Therapy before allo-HSCT consisted of the first-line treatment (n=2), ≥ 2 lines of therapy (n=3), ≥ 3 treatment lines (n=11). Median time from diagnosis to HSCT was 39 months (14 to 139 mo). Median time from detection of the mutation to allo-HSCT was 10 months (2 to 38 mo). EBMT scores were as follows: 3-4 points (n=12), 5-7 points (n= 4). Conditioning regimens included myeloablative therapy (MAC) for 5 cases, and reduced-intensity conditioning (RIC) in 13 patients. Seven patients out of 16 survived during the observation terms. At the time of HSCT, two patients were in CP1; 4, in CP2; one patient was in AP. At present time, all the patients are in complete molecular remission. Three patients in the 1st remission, and four, in remission achieved after prophylactic administration of TKI. So far, median observation time for living patients is 48 months (8-79 mo). Overall survival of the patients with allo-HSCT was 42.9%, with median follow-up of 18 months. 18 patients of 37 survived after receiving pharmacological therapy (male, 25, and female, 12). Their age was 17 to 77 years, with a median of 49 years. At the time of diagnosis, 29 patients were in CP, 8, in AP. When the T315I mutation was detected, 23 patients were in CP; AP was registered in 11 cases, and 3 patients were in BC. Prior to detection of the mutation, 5 patients received 1st line TKI therapy, 22, 2nd line TKIs, and 10 were treated with 3rd line TKI. Appropriate therapy was as follows: ponatinib (n=3), I-II generation TKI (n=8), Chemotherapy+TKI\ hydroxyurea+IFN (n=17). At present time, six patients are in CP≥1, nine patients have developed CHR, ССR, or partial cytogenetic response. Current observation terms in living patients are 53-250 months, a median of 81 months. Overall survival among patients receiving pharmacological therapy is 48.4%, with a median follow-up of 81 months.
Interpretation of the newly found T315I mutation is important in view of clinical phase assessed at the time of this molecular diagnosis. The patients in CP1 may continue therapy with TKI. Allo-HSCT is a potential therapeutic option for CML patients in the AP and BC carrying T315I mutation, especially for patients in CP ≥2.
Tyrosine kinase inhibitors, allo-hsct, chronic myeloid leukemia, t315 mutation, resistance
Accepted 22 September 2016