Characteristics, Treatment and Outcome of 15 to 18 Years-Old Adolescents with Chronic Myeloid Leukemia (CML): The Experience of the International Registry of Childhood CML (I-CML-Ped Study)

Introduction: CML is a rare disease in children and adolescents, accounting for 2-3% of leukemia cases in this population. Pediatric CML is more frequent in the 2 ^nd decade of life but data on adolescents are limited. Only response to treatment has been analyzed in few studies and seems to be poorer in this age cohort. The International Registry of Childhood Chronic Myeloid Leukemia gave us the opportunity to analyze the characteristics and outcome in a large cohort of adolescents.

Aims and objectives: To report on clinical features and response to treatment in adolescents (15-18 years of age at diagnosis) with CML in chronic phase (CML-CP).

Material and methods: The International Registry of Childhood CML (I-CML-Ped Study, registered at www.clinicaltrials.gov NCT01281735) enrolled patients less than 18 years of age at diagnosis of CML in all phases according to the criteria of the European Leukemia Net (ELN). Data from this registry collected from Jan 2011 - Mar 2021 into the I-CML-Ped Study (Poitiers, France) were retrospectively analyzed.

Results: Out of 614 patients (pts) registered in the I-CML-Ped Study, we identified 144 (23.4%) adolescents (15-18 years of age at diagnosis) with sufficient available data. Among them, according to the ELN criteria, 132 (92%), 7 (5%), and 5 (3%) pts presented with CML-CP, accelerated phase (AP), and blastic phase (BP), respectively. The median age of the cohort comprising 132 adolescents with CML-CP was 16.2 years [range, 15-18]. Ratio male/female was 1.75. Splenomegaly was reported in 66% of the pts with a median spleen size of 11.5 cm below the costal margin [range, 1-32]. Hepatomegaly was reported in 31% of the pts with a median liver size of 2.5 cm below the costal margin [range, 1-19]. Pain, asthenia and weight loss were the most frequent symptoms at diagnosis in 35%, 33%, and 20% of pts, respectively. The performance status according to the OMS and Karnofsky scores were 0 and 100% in 81% and 57% of the pts, respectively. At diagnosis, median leukocyte count was 181 G/L [range, 7-820]; median platelet count was 516 G/L [range, 102-2619], and median hemoglobin level was 10.45 g/dL [range, 4-17]. BCR-ABL1 transcript type b3a2 was present in 53% of the assessable pts. Additional chromosomal abnormalities and variants were found in 5% of the pts. 9% and 40% of pts were considered at high-risk according to the ELTS score and to the Sokal score (for pts less than 45 years), respectively. The majority of pts (97%) were treated with imatinib as first line treatment. After 12 months of treatment, in pts with data available, rate of complete cytogenetic response (CCyR) was 74/109 (68%) pts with imatinib first line. Overall, rate of CCyR was 101/109 (93%) pts with imatinib first line [88/109 (81%) pts receiving imatinib only, 13/109 (12%) pts after switching to another TKI, 8/109 (7%) pts did not achieve CCyR]. Median time to achieve CCyR was 8.2 months [range, 2.7-106.7]. The cumulative rate of MMR at month 12 was 40/111 (36%) pts. Overall rate of MMR was 91/111 (82%) pts [72/111 (65%) pts with first line imatinib only; 19/111 (17%) pts with another TKI]. Median time to achieve first MMR was 14.5 months [range, 0.9-63.1]. Out of all patients on first line imatinib, 11/123 (9%) pts progressed: 3/11 pts progressed to AP and 8/11 pts to BP. Further progress to BP was observed in 2 of the 3 pts with AP. BP phenotype was myeloid in 5/10 pts, lymphoid in 3/10 pts and bilineage in 1/10 pts (no data for 1/10 pts). With imatinib first line, deaths occurred in 5/123 (4%) pts, among them 4/5 due to complications associated with hematopoietic stem cell transplantation. With a median follow up of 37 months [range, 0.9-231], the overall survival rate was 89.2% [83.6%; 94.7%] for pts treated with imatinib first line (N = 123).

Conclusion: Our results are in line with publications describing adolescents and young adults (AYAs) as a risk population for a poorer treatment outcome: when comparing AYAs (15-29 yrs) to adults (>30 yrs), CCyR and MMR were inferior in AYAs (cumulative CCyR 84% vs 93%, cumulative MMR 75% vs 86%, respectively) [Pemmaraju N et al., Haematologica 2012] and rates of progression to AP and BP were 8.7% in AYAs (16-29 yrs) but only 5.3% and 6.1% in adults (45-59 yrs and >60 yrs, respectively) [Kalmanti L et al. , Ann Hematol. 2013]. Additional research is required in adolescents with CML to shed light on the cause(s) for the observed differences and to further improve the outcome.