Controversies in the Treatment of CML in Children and Adolescents: TKIs versus BMT?

In summary, the relative role of HCT versus prolonged TKIs is very uncertain in the pediatric and adolescent populations. The long-term effects of prolonged TKI usage appears to be lower than that seen with HCT, although only HCT can achieve a permanent remission. Any recommendation in children and adolescents is difficult to defend because of the lack of available clinical data. Based on the adult data and what little is known in children, a reasonable approach appears to be initial treatment with imatinib in children and adolescents with CML-CP, with a change to a second-generation TKI if there is an incomplete response or recurrence after an initial response. At the time of a change to the second-generation TKI, an allogeneic HCT from either a matched sibling or closely matched unrelated donor should be implemented. Monitoring recommendations of BCR-ABL for CML on TKI therapy or after HCT can at this time only be extrapolated from adult data with the caveat that these populations should be more closely monitored until additional data are obtained (Table 1). The long-term effects of TKI usage lasting for a number of decades represent a very big unknown factor as pediatric oncologists consider the most appropriate treatment for their patients with CML. We also conclude that randomized international trials are urgently needed to evaluate the best therapies for pediatric CML.Table 1Response Assessment, Warnings, Monitoring Intervals, and Interventions for CML Patients Treated with Imatinib and after SCT (see 16Suttorp M. Thiede C. Tauer J.T. Roettgers S. Sedlacek P. Harbott J. Chronic myeloid leukemia in pediatrics—first results from study CML-PAED II (ASH Annual Meeting abstract).Blood. 2009; 114: 145Google Scholar) Criteria for Response AssessmentTime Point∗During the first 2 years, monitoring should occur every 3 months. If a major molecular response (≤0.1%) is achieved, the monitoring interval may be prolonged. However, there are no pediatric data in support of this practice, and until further pediatric data are available, we recommend that peripheral blood be monitored for BCR-ABL every 3 months indefinitely.Insufficient Imatinib ResponseImatinib FailureWarningsMonitoring During TKI Therapy: At diagnosis——High-risk disease according to Sokal/Hasford risk scoreNot first chronic phase Add. cytogenetic abnormalities in Ph+ cells (Del 9q+) At 3 monthsLess than complete hematology responseNo hematologic response (stable disease or disease progression)Any new cytogentic abnormality in Ph+ or Ph− cells At 6 monthsLess than partial cytogenetic response (Ph+ >35%)No cytogenetic response (Ph+ >95%)Any new cytogenetic abnormality in Ph+ or Ph− cells At 12 monthsNo complete cytogenetic response (Ph+ >95%)No major cytogenetic response (Ph+ >35%)Any new cytogenetic abnormality in Ph+ or Ph− cells At 18 monthsLess than major molecular response (no 3 log reduction)No complete cytogenetic responseAny new cytogenetic abnormality in Ph+ or Ph− cells At any timeLoss of responseDisease progressionAny new cytogenetic abnormality in Ph+ or Ph− cellsMutation?Mutation?Intervention: SCT might be considered, depending on EBMT risk score at time of warning, insufficient response, or failure.Monitoring∗During the first 2 years, monitoring should occur every 3 months. If a major molecular response (≤0.1%) is achieved, the monitoring interval may be prolonged. However, there are no pediatric data in support of this practice, and until further pediatric data are available, we recommend that peripheral blood be monitored for BCR-ABL every 3 months indefinitely. post-SCT:Analysis of bone marrow aspirates by real-time quantitative RT-PCR at +1, +2, +3, +6, +9, +12 months after SCT; increase the assay frequency as needed.Definition of low-risk patient:1)Reduction of BCR-ABL mRNA levels by at least 2 log from baseline at 1 month post-SCT and continuous decline thereafter following SCT.2)Achievement of MMolR (ratio abl/bcr-abl ≤0.1%) and maintenance of this stable BCR-ABL transcript level post-SCT or continuous decline thereafter following SCT.3)Development of aGVHD grade II-IV or extensive cGVHD and Ph+ chromosome negative and stable or decreasing BCR-ABL transcript levels after SCT.4)CMolR (RT-PCR negative) after SCT.Intervention: No intervention for low-risk patients.Definition of high-risk patient:Not qualifying for any criteria of the low-risk group.Intervention: Based on individual decisions including withdrawal of immunosuppression, escalating donor lymphocyte infusions, and imatinib mesylate.SCT indicates stem cell transplantation; GVHD, graft-versus-host disease.∗ During the first 2 years, monitoring should occur every 3 months. If a major molecular response (≤0.1%) is achieved, the monitoring interval may be prolonged. However, there are no pediatric data in support of this practice, and until further pediatric data are available, we recommend that peripheral blood be monitored for BCR-ABL every 3 months indefinitely. Open table in a new tab

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