Management of Chronic Myeloid Leukemia in Children and Adolescents According to Local Guidelines.the Italian Experience
Authors: Giona Fiorina , Santopietro Michelina , Menna Giuseppe , Putti Maria Caterina , Micalizzi Concetta , Santoro Nicola , Ziino Ottavio , Mura Rosamaria , Ladogana Saverio , Iaria Grazia , Sau Antonella , Burnelli Roberta , Vacca Nadia , Nardi Margherita , Consarino Caterina , Moleti Maria Luisa , Nanni Mauro , Diverio Daniela , Leszl Anna , Biondi Andrea , Locatelli Franco , Saglio Giuseppe , Foà Robin 
Published: October 2019

Abstract
Before 2000, allogeneic hematopoietic stem cell transplantation (HSCT) was the only potentially curative treatment for children with chronic myeloid leukemia (CML) in chronic phase (CP). The availability of imatinib (IM) and thereafter of second-generation (2G) tyrosine kinase inhibitors (TKIs) has extended therapeutic options for childhood CML. Experience with IM in managing children and adolescents with CP-CML resistant or intolerant to interferon treatment treated prompted us to outline guidelines with the aim of offering a uniform management approach for this category of patients (pts). IM was scheduled in newly diagnosed pts with CML in CP, including those with an HLA identical sibling (HLA+). Cytogenetics on bone marrow (BM) and molecular analysis on peripheral blood (PB) and on BM were suggested at planned time-points. These guidelines have been shared with both pediatric referral centers (P Centers) and reference center for adults and children (AP Centers) in Italy. The guidelines, summarized in Figure 1, have been updated over the years (yrs), with the contribution of colleagues managing adult CML.
Fifty-seven CP-CML pts with a median age of 11.4 yrs, diagnosed between March 2001 and June 2015, were managed at 9 P centers (34 pts) and at 4 AP Centers (23 pts). All pts, including 16 with an HLA+, started IM that was discontinued early in 2 pts due to toxicity. HSCT from an HLA+ donor was performed in 2 pts in CP. A bone marrow aspirate at 3, 6, 9, 12, 18, 24 months was carried out in 85.5%, 98%, 83.5%, 100%, 95% and 94% of pts, respectively. Rates of molecular assessments on BM at 3, 6, 9, 12, 18 and 24 months were 73%, 78%, 92%, 84%, 86% and 100% of pts, respectively, significantly higher at 6 and 9 months in pts followed at P centers compared to those followed at AP centers. Cytogenetic evaluation rates at the same time points were 69%, 80%, 81%, 82% 73% and 75%, respectively, significantly higher in pts followed at AP centers compared to those followed at P centers. Rates of molecular assessments on PB at 3, 6, 9, 12, 18 and 24 months were 50%, 54%, 57%, 60%, 64% and 69% of pts, respectively, higher in pts followed at AP centers compared to those followed at P centers. Four pts (1 with HLA+) resistant to IM were rescued with 2G TKI and 3 of them then underwent a HSCT. Fifty pts (92.5%), including 13 HLA+ pts, achieved a cytogenetic or molecular (MR). Seven of the 50 responders (14%) underwent a HSCT from an HLA+ (6 pts) or from a matched unrelated donor (MUD), all in P centers before 2009. Seven HLA+ pts continued IM: in 3 it was given intermittently and thereafter discontinued in 1. Among the 36 responders without a HLA-identical sibling (HLA-), 10 pts (persistent MR, 2 pts; late side effects, 5 pts; poor compliance, 3pts) started intermittent IM, that was discontinued in 3 of them with deep MR. Overall, 18/36 (50%) pts failed IM: 2 had late toxicity and 16 (44%) developed disease recurrence (5 on intermittent IM and 1 pt after IM discontinuation). BCR-ABL1 mutation analysis was carried out in 11 pts: BCR-ABL1E255K combined with BCR-ABL1F359Vmutations were found in 1 pt and BCR-ABL135INS in 5 pts. Eleven pts were rescued with 2G TKIs (Dasatinib, 5 pts; Nilotinib, 6 pts), 5 pts restarted continuous IM and 2pts underwent a HSCT from a MUD. All 57 pts are alive at a median follow-up of 72 months (range, 12-184): 15 pts (26%) after a HSCT (HLA+, 9 pts; MUD, 6), 4 pts (7%) are treatment-free (1 pt after nilotinib), 27 pts (47.5%) are still receiving IM (continuous, 22 pts; intermittent, 5 pts), 10 pts (17.5%) are on treatment with 2G TKIs (dasatinib, 5 pts; nilotinib, 5 pts) and 1 pt with BCR-ABL1E255K and BCR-ABL1F359Vmutations is on third-line treatment with ponatinib.
Our experience shows that pediatric guidelines are an important management tool for children and adolescents with CP-CML. Over the years, exchange of experience for monitoring and treatment of pediatric CP-CML with colleagues managing adult pts has contributed to update management strategies for this particular category of pts. Furthermore, exchange of knowledge and debate concerning some clinical situations within our network has allowed to have a progressively uniform approach for children and adolescents followed in these 13 Italian centers. Taking into account the rarity of the condition, shared pediatric guidelines and exchanges of experience and knowledge with adult hematologists will further contribute to an optimal management of childhood CML.

Disclosures
Biondi: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Foà:BMS: Consultancy; Ariad: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.