Features and Outcome of Chronic Myeloid Leukemia (CML) at Very Young Age: Data from the International Pediatric CML Registry (I-CML-Ped Study)
Authors: Gunes Adalet Meral , Millot Frédéric , Kalwak Krzysztof , Lausen Birgitte , Sedlacek Petr , Versluijs Birgitte , Dworzak Michael , De Moerloose Barbara , Suttorp Meinolf 
Published: October 2019

Abstract
Introduction: CML is rare in the first two decades of life comprising only 3% of pediatric and adolescent leukemias. The overall annual incidence is approximately 1 per million children and adolescents and it increases with age (median: 12 yrs, range: 1-18) resulting in an extreme rarity of children affected in the first years of life. Data regarding the clinicopathologic characteristics and response to therapy of childhood CML diagnosed at age <3 years has not been reported yet.
Aims and objectives: We studied the epidemiologic and clinical features of patients(pts) with CML <3 years of age and evaluated treatment and long term outcome.
Material and Methods: Data from pediatric CML pts (age at diagnosis 0-18 yrs) registered from 2010 until 2017 into the International Pediatric CML Registry (Poitiers, France) under the umbrella of the I-BFM Study Group were retrospectively analyzed. Characteristics and treatment outcome of pts <3 yrs at diagnosis were evaluated from standardized forms.
Results: 22/479 pts (4.6%, ratio male/female: 14/8) were enrolled with a median age of 22 months (10-34) and a median weight and height were 9.3 kg (8.1-15.5) and 78 cm (73-98), respectively. The median time period from the first symptoms until final diagnosis was 21 days (2-182). Median spleen size was 12 cm (2-20) and median liver size was 3 cm (2-6) below the costal margins. Major complains and symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). Median WBC, Hb and platelet counts were 154 600/µl (23 000-892 000), 8.7 g/dl (5,6-11,5) and 311 000/µl (51 000-1 820 000), respectively. All pts underwent BM aspiration but, BM biopsy was performed only in 8/22 children. Philadelphia chromosome and BCR-ABL1 gene rearrangement were detected by cytogenetic and/or molecular techniques (FISH and RQ-PCR). In only 2 (9%) children, additional chromosomal abnormalities were detected by cytogenetics classifying one patient in accelerated phase. Overall 19/22 (86%) children were diagnosed in chronic phase and the remaining 3 pts were in advanced phase (CML-AP: n= 2, CML-BP: n= 1). Median follow-up of the cohort was 78 months (7-196).
Treatment: 21/22 pts initially received imatinib at the recommended dose of 260-300 mg/sqm/day while one child received IFN + ARA-C. Imatinib was changed to either dasatinib (n= 5) or nilotinib (n= 1) in 6 children (29%). Thus, 15 pts continued on imatinib. During follow-up, 9/22 (41%) pts underwent HSCT including 2 pts after switching to dasatinib.
Molecular response: Major molecular response (MR) was achieved in 10/21 (48%) children on TKI. One child (1/21) on TKI was not followed for MR, but he developed complete cytogenetic remission 4 mo after imatinib treatment. The remaining cohort (6/22; 27%) is alive on TKI without major MR with a median follow-up of 77 m (7-186) and 5/22 (23%) achieved complete MR following HSCT.
Adverse effects (AE): 194 AE episodes were reported in 18/22 (82%) pts. Most frequently observed AEs were hematologic (20%), gastrointestinal (16%), infectious (14%), musculoskeletal (14%), skin (12%), metabolic (6%), and HSCT-related (GvHD, 5%). Less frequently AEs comprised psychological (3%), edema (3%), tooth development delay (2%), allergic (2%), neurologic (PRESS syndrome,1%), and renal colic (1%). At last follow up, assessment of puberty status revealed that the majority of children were in Tanner stage 1 or 2 (17/22, 77%). Among these, 7 were >10 years old and showed puberty delay, while pubertal development was normal in the remaining 5/22 pts. Data on growth and development was available in 15/22 (68%) children. The majority had experienced decline of height (93%) and weight (73%). In 4 (27%) and 2 (13%) pts, respectively, measurements were found below the 3rd-10th percentiles. Delta z-score analysis for height and weight revealed that the z-scores in total 3 pts were below -2.
Survival: 21/22 (95%) children are alive while one patient died of GvHD. Two pts' last molecular status is unknown. 7/19 pts (37%) are in molecular CR following HSCT and the other 12/19 (63%) are still on TKI. Out of these, 3/12 pts achieved durable CMR with TKI (PCR negative) while the remaining 9/12 pts show either fluctuating (n= 3 ) or no major MR (n= 6).
Conclusion: This report demonstrates for the first time the efficacy and long term side effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age.

Disclosures
Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.