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Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.

ABSTRACT: Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.

SUBMITTER: Hijiya N

PROVIDER: S-EPMC4915793 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.

Hijiya Nobuko N Schultz Kirk R KR Metzler Markus M Millot Frederic F Suttorp Meinolf M

Blood 20151028 4

Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic d ...[more]

PMID: 26511135

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Project description:Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

Dataset Information

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.

Publications

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.

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