Response to Front-Line Imatinib Treatment in Children and Adolescents with CML - Data from a Large Pediatric Cohort
Authors: Suttorp Meinolf , Schulze Philipp , Glauche Ingmar , Göhring Gudrun , Von Neuhoff Nils , Metzler Markus , Sedlacek Petr , de Bont Eveline S. , Balduzzi Adriana , Lausen Birgitte , Aleinikova Olga , Sufliarska Sabina , Henze Guenter , Strauss Gabriele , Eggert Angelika , Kremens Bernhard , Groll Andreas H , Berthold Frank , Klein Christoph , Gross-Wieltsch Ute , Sykora Karl-Walter , Borkhardt Arndt , Kulozik Andreas E. , Schrappe Martin , Nowasz Christina , Krumbholz Manuela , Tauer Josephine Tabea , Claviez Alexander , Harbott Jochen , Kreipe Hans H , Schlegelberger Brigitte , Thiede Christian 
Published: April 2021

Abstract
Purpose
Results of the prospective trial "CML-PAED-II" assessing treatment efficacy and side effects in children and adolescents with newly diagnosed chronic myeloid leukemia (CML) are reported.
Patients and Methods
156 patients (age range 1.3-18.0 years, 91 male) with newly diagnosed CML (N= 146 chronic phase (CML-CP), N= 3 accelerated phase (CML-AP), N= 7 blastic phase (CML-BP)) received imatinib upfront (300 mg/m², 400 mg/m², 500 mg/m², respectively). Therapy response, progression-free survival, causes of treatment failure and proportion of patients undergoing stem cell transplantation were analyzed in 148 patients with complete data.
Results
Event-free survival rate at 18 months for pediatric patients diagnosed in CML-CP (median follow-up time 25 months, range: 0.1-120) was 97% (95% CI, 94.2%-99.9%). According to the 2006 ELN-criteria complete hematologic response at month 3, complete cytogenetic response (CCyR) at month 12, and molecular response (MR3.0) at month 18 were achieved in 98%, in 63%, and 59% of the patients, respectively. At month 36 on continuous first line imatinib or 2nd generation tyrosine kinase inhibitor treatment, 86% of the patients achieved CCyR and 74% achieved MR3.0.
66% of the patients experienced at least one side effect. Imatinib-related anemia was the most frequent toxicity observed if all grades were considered (N=98; 66%) while neutropenia was the most frequently reported grade 3/4 hematologic adverse effect (N=22; 15%). Among non-hematologic toxicities, all grades of gastrointestinal toxicity were observed most frequently (N=57, 38%), however, it occurred at lower grades 1/2 in all but one patient. Higher grade 3/4 musculoskeletal pain was also frequent (N=53, 36%). Twenty-seven patients (18%) had to discontinue treatment temporarily while nine patients permanently terminated imatinib due to non-tolerable side effects (neutropenia N= 4, muscle cramps N= 3, skin N= 1, liver N= 1).
Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response (N= 27) or intolerance (N= 9). 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N=3) or SCT-related complications (N=2).
Conclusion
This large pediatric trial provides evidence confirming that first line imatinib in children is highly effective. Observed adverse effects are acceptable and mainly comprise hematological side effects. Long term outcome and effects of a potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies.

Disclosures
Suttorp: Novartis: Research Funding. Schrappe: JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede: Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.