Aoe, M., Shimada, A., Muraoka, M. et al. Int J Hematol (2014) 99: 609. doi:10.1007/s12185-014-1565-3
The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.
Supplement Fig. 1. Treatment schedule for JPLSG Ph-ALL 04. Following the induction therapy, intensification therapies (1st and 2nd phase), re-induction therapy, and administration of imatinib mesylate alone for 2 weeks, stem cell transplantation (SCT) is performed immediately if a donor is obtained. If bone marrow donor cannot be obtained, or co-ordination stopped, cord blood transplantation (CBT) is performed. 1, intensification-1 therapy; 2, intensification-2 therapy (DOCX 72 kb)
Supplement Fig. 2. Treatment schedule for JACLS-TCCSG Joint Study of Ph-ALL 2002. Following induction therapy and one cycle of intensification therapies (1-3 phases), SCT is performed as soon as a donor is obtained. If bone marrow donor cannot be obtained, or co-ordination stopped, CBT is performed. Treatment will be terminated with chemotherapy only if the SCT is not performed at the time of 104 weeks. Cranial irradiation is not performed. Triple IT is performed once per 4 weeks to 52 weeks. 1, intensification-1 therapy; 2, intensification-2 therapy; 3, intensification-3 therapy (DOCX 79 kb)