Effectiveness of tyrosine kinase inhibitor therapy and allogeneic hematopoietic stem cell transplantation in pediatric patients and adolescents with chronic myeloid leukemia (experience of R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology, and Transplantation)

Summary

Despite the fact that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only method able to cure the disease completely in pediatric and adolescent patients (pts) with chronic myeloid leukemia (CML), it is associated with life-threatening complications. Therefore, the tyrosine kinase inhibitors (TKIs) are a standard option for first-line therapy. In our study we summarize a single-center experience in TKIs therapy for children and adolescents with CML and try to establish the indications for allo-HSCT in this group.

Patients and methods

A total of 35 children and adolescent with CML received therapy TKIs +/- allo-HSCT at the R. Gorbacheva Memorial Research Institute were included into the analysis from April 2005 to August 2019. 23 males (66%) and 12 females (34%) participated in the study. The median age at the time of diagnosis was 10.7 years (range 7 months to 18 years). At the time of diagnosis 30 patients were in chronic phase (CP), four patients were in accelerated phase (AP), and one, in lymphoid blast crisis (LBC). Before imatinib (IM) treatment was initiated, 21 patients received hydroxycarbamide, five of them were subject to combined therapy with other drugs (α-interferon in two cases). Two of these pts had CHR prior to first-generation TKIs (1G-TKIs) initiation. The median starting IM dose was 300 mg/m²/day. The therapy toxicity was assessed based on WHO criteria according to CTCAE scale. The TKIs therapy response was evaluated according to ELN criteria.

Results

The complete hematological remission (CHR) at the 3rd month (mo) of IM therapy was achieved in 31 cases (89%). Among them, 24 (69%) had subsequently reached CCyR (7, at 3 mo; 8, at 6 mo; 8, at 12 mo; and 1, after12 mo of the therapy). Molecular remission (MR) was achieved in 17 of 35 (49 %) pts. In 7 cases it was the MMR seen at mo 3 in 2, 6 in 1, 12 in 1 and after mos 12 in 3 cases. Ten patients had CMR observed at mo 3 in 2 cases; 12 in 1, and 12 mo later, in 7 cases. The hematological toxicity to 1G – TKIs was seen in 7 (20%) patients, grade I-II non-hematological toxicity in 10 (28%) cases. The optimal response to IM was seen in 10 (29 %), suboptimal in 11 (31%) pts. In 4 (11%) cases, the therapy was interrupted before 1 year, in 10 (29%), the primary treatment failure was observed. Also, 13 (37%) patients had to be switched to 2G -TKIs (dasatinib in 8, and nilotinib in 5) due to toxicity (n=2), primary/secondary resistance (n=11). In 14 (40%) patients, allo-HSCT was performed, in 8 of them, 2G-TKIs were applied. At the moment of allo-HSCT, 5 patients were in CP, 7 in AP, and 2 in LBC. Indications for allo-HSCT were as follows: lack of MR and/or CyR in 4, loss of CHR and CyR and/or MR in 4, LBC in 1; disease progression to AP in 2 cases; disease progression to LBC with M244V and M351 mutation in 1 case; AP with T315I mutation in two cases. Two patients were lost from the follow-up (1 patient developed transformation to AP with Y257C mutation, the extramedullary BC with myeloid lineage in 1 case). Overall survival (OS) in 1G- +/- 2G-TKIs patients (n=21) with a median follow-up of 49 (10-126) months was 100%, OS in allo-HSCT recipients +/- 2G-TKIs was 79% (n=11,) at the median follow-up of 82 (1-140) mo. Three patients died due to transplant-related complications (aGVHD in 1 case, cGVHD in 1 patient, and infection in 1 case).

Conclusions

Despite the frequent Grade I-II toxicity (in 28% of cases), the TKIs therapy proved to be still a safe and effective treatment modality in children and adolescents with CML and should be employed as first-line treatment. However, loss of clinical response, toxicity, and resistance-associated additional mutations are possible indications for allo-HSCT, although there are still no universal guidelines, and each case should be viewed individually.

Keywords

Chronic myeloid leukemia, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, children, adolescents.