Abstract
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.
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References
Schlieben S, Borkhardt A, Reinisch I, Ritterbach J, Janssen JW, Ratei R, et al. Incidence and clinical outcome of children with BCR/ABL-positive acute lymphoblastic leukemia (ALL). A prospective RT-PCR study based on 673 patients enrolled in the German pediatric multicenter therapy trials ALL-BFM-90 and CoALL-05-92. Leukemia. 1996;10:957–63.
Aricò M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med. 2000;342:998–1006.
Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27:5175–81.
Chang BH, Willis SG, Stork L, Hunger SP, Carroll WL, Camitta BM, et al. Imatinib resistant BCR-ABL1 mutations at relapse in children with Ph+ ALL: a Children’s Oncology Group (COG) study. Br J Haematol. 2012;157:507–10.
Tamamyan G, Chao YH, Wang CH, Wu HP, Weng T, Peng CT, Wu KH. Dasatinib plus chemotherapy to achieve full donor chimerism and complete molecular remission in a child with relapsed philadelphia chromosome-positive acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:1727–8.
Kanda J. Effect of HLA mismatch on acute graft-versus-host disease. Int J Hematol. 2013;98:300–8.
Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–6.
Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007;110:727–34.
Lee S, Kim DW, Cho BS, Yoon JH, Shin SH, Yahng SA, et al. Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2012;26:2367–74.
Schultz KR, Bowman WP, Aledo A, et al. Continuous dosing imatinib with intensive chemotherapy gives equivalent outcomes to allogeneic BMT for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with longer term follow up: updated results of Children’s Oncology Group (COG) AALL0031 [Abstract]. Pediatr Blood Cancer. 2010;54:788.
Hochhaus A, La Rosée P, Müller MC, Ernst T, Cross NC. Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle. 2011;10(2):250–60.
Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–9.
Jones D, Thomas D, Yin CC, O’Brien S, Cortes JE, Jabbour E, et al. Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. Cancer. 2008;113:985–94.
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88.
O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.
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Supported in part by a Grant-in-Aid for Cancer Research and a grant for Clinical Cancer Research and Research on Children and Families from the Ministry of Health, Labor and Welfare of Japan.
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12185_2014_1565_MOESM1_ESM.docx
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)
12185_2014_1565_MOESM2_ESM.docx
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)
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Aoe, M., Shimada, A., Muraoka, M. et al. ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases. Int J Hematol 99, 609–615 (2014). https://doi.org/10.1007/s12185-014-1565-3
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DOI: https://doi.org/10.1007/s12185-014-1565-3