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Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial
Lia Gore1, Pamela R Kearns1, Maria Lucia de Martino1
1Lia Gore, University of Colorado School of Medicine/Children's Hospital Colorado, Aurora, CO; Pamela R. Kearns, University of Birmingham, Birmingham, West Midlands; Donna Lancaster, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; Maria Lucia de Martino Lee, Support Group for Children and Adolescents with Cancer; Carmino Antonio De Souza, University of Campinas, São Paulo, Brazil; Yves Bertrand, L'Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France; Nobuko Hijiya, Ann and Robert H. Lurie Children's Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL; Linda C. Stork, Oregon Health & Science University, Portland, OR; Nack-Gyun Chung, The Catholic University of Korea, Seoul St. Mary's Hospital; Jong Jin Seo, University of Ulsan College of Medicine, and Asan Medical Center, Seoul, Republic of Korea; Rocio Cardenas Cardos, Instituto Nacional De Pediatria, Mexico City, Mexico; Tapan Saikia, Prince Aly Khan Hospital, Mumbai, India; Franca Fagioli, Regina Margherita Hospital, Turin, Italy; Judith Landman-Parker, Hôpital Enfants Armand-Trousseau, Paris, France; Andrew E. Place, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Karen R. Rabin, Texas Children's Cancer Center, and Baylor College of Medicine, Houston, TX; Mariana Sacchi and Rene Swanink, Bristol-Myers Squibb, Princeton, NJ; C. Michel Zwaan, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands; Pamela R. Kearns and C. Michel Zwaan, Innovative Therapies for Children with Cancer Consortium, European Union.
Insights
This study shows dasatinib is a safe and effective treatment for pediatric chronic myeloid leukemia (CML) in chronic phase. Early and deep responses were observed in children with CML-CP, including those resistant to imatinib.
Area of Science:
- Pediatric Hematology Oncology
- Pharmacology and Therapeutics
- Clinical Trial Research
Background:
- Chronic myeloid leukemia in chronic phase (CML-CP) requires safe and effective pediatric treatments.
- Dasatinib is an approved tyrosine kinase inhibitor for adult and pediatric CML-CP.
- A prior phase I study established appropriate dasatinib dosing for pediatric Philadelphia chromosome-positive (Ph+) leukemias.
Purpose of the Study:
- To evaluate the safety and efficacy of dasatinib in pediatric patients with CML-CP.
- To assess treatment responses in children with imatinib-resistant/intolerant CML-CP and newly diagnosed CML-CP.
- To compare outcomes in different treatment cohorts within the pediatric population.
Main Methods:
- A phase II, open-label, nonrandomized prospective trial (CA180-226/NCT00777036) involving pediatric patients (<18 years) receiving dasatinib.
- Three cohorts were studied: imatinib-resistant/intolerant CML-CP, imatinib-resistant/intolerant accelerated/blast phase CML or Ph+ acute lymphoblastic leukemia, and newly diagnosed CML-CP.
- Key efficacy endpoints included major cytogenetic response (>30%) for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) (>55%) for newly diagnosed patients.
Main Results:
- Of 113 CML-CP patients, 14 (48%) in the imatinib-resistant/intolerant group and 61 (73%) in the newly diagnosed group remained on treatment.
- Major cytogenetic response was achieved by 3 months (imatinib-resistant/intolerant) and CCyR by 6 months (newly diagnosed).
- By 12 months, CCyR rates were 76% (imatinib-resistant/intolerant) and 92% (newly diagnosed); major molecular response rates were 41% and 52%, respectively. Progression-free survival at 48 months was 78% and 93%.
Conclusions:
- Dasatinib demonstrates safety and efficacy in pediatric CML-CP, as evidenced by the largest prospective trial to date.
- Target responses were achieved early with dasatinib in both first- and second-line settings.
- Pediatric safety profiles were comparable to adults, with no reported instances of pleural/pericardial effusion or pulmonary arterial hypertension; bone growth events occurred in 4%.
Abstract:
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.
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