High Dose Imatinib Is Effective In Children and Adolescents With Chronic Myelogenous Leukemia In Chronic Phase. The Italian Experience
Authors: Giona Fiorina , Putti Maria Caterina , Menna Giuseppe , Micalizzi Concetta , Santoro Nicola , Iaria Grazia , Ladogana Saverio , Burnelli Roberta , Consarino Caterina , Siniscalchi Benedetta , Rea Massimiliano , Marzella Deborah , Tucci Francesca , Nanni Mauro , Messina Chiara , Varotto Stefania , Diverio Daniela , Biondi Andrea , Pession Andrea , Zecca Marco , Locatelli Franco , Saglio Giuseppe , Foa' Robin 
Published: October 2019

Abstract
Imatinib (IM) is an established first-line treatment for children with chronic myeloid leukemia (CML). However, the most effective dosage and duration of IM treatment are not well defined. This study was designed to evaluate the response to high-dose IM and long-term outcome in pediatric CML patients, previously untreated or resistant to IFN. Patients aged <18 years with a diagnosis of CML in chronic phase (CP) were treated with IM at a dosage of 340 mg/m2/day. Cytogenetic analysis was performed on bone marrow (BM) cells before and during IM therapy, at planned intervals; quantitative RT-PCR was assessed on peripheral blood (PB) monthly and on BM every 3 months, according to the European LeukemiaNet recommendations for minimal residual disease quantification. Major molecular response (MMR) is defined as <0.1% BCR-ABLIS, while complete MR (CMR) is considered as <0.01% BCR-ABLIS.
From March 2001 to February 2013, 45 CML patients in CP (18 females, 27 males; median age: 119/12 years) were recorded from 9 Italian pediatric centers. Eight patients had previously received IFN. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage was modulated according to hematologic toxicity and/or appearance of WHO >2 side- effects, mostly during the first 6 months of treatment (median administered dose: 309 mg/m2/day). Hematologic toxicity (medullary hypoplasia[n=1], neutropenia [n=11] and/or thrombocytopenia [n=6], anemia [n=1]) was observed in14/44 evaluable patients (32%); 13 patients (29.5%) experienced isolated or combined side effects: arthralgia/myalgia (n=10), nausea (n=1), vomiting (n=1), diarrhea (n=1), hepatitis (n=1), edema (n=1). After 3 months of IM treatment, 7/25 of tested patients (28%) obtained complete cytogenetic response (CCyR). Overall, 34/36 evaluable patients (94%) obtained a CCyR at a median time of 6 months.
A molecular response (<0.1% BCR-ABLIS) was achieved in 21/26 tested patients (81%) on PB and in 30/33 evaluable patients (91%) on BM. Seventeen of 26 patients (65%), including 2 with a HLA-matched sibling, obtained a CMR on PB cells and 19/33 (55%) on BM cells at a median time of 15 and 19 months, respectively. With the aim of reducing the risk of longitudinal growth impairment or to improve treatment compliance, 9 patients with sustained CMR and 2 adolescents with MMR lasting >12 months received IM at the same daily dosage for 3 weeks a month (intermittent therapy). IM given without interruption was resumed in 3 of these 9 patients because of an increased BCR-ABL transcript. The growth rate showed a delay in height, which recovered over time, in 6 children who received IM prior to puberty.
Overall, IM was stopped in 22/44 evaluable patients (50%) because of various reasons: stem cell transplant (SCT) in 8 patients (3 in CP, 1 in CCyR, 3 in MMR, 1 in CMR); hematologic (n=2) or extra-hematologic toxicity (n=2) (WHO grading >3) during the first 6 months in 4; recurrent disease in 6 (3 increased BCR-ABL transcript, 2 cytogenetic relapse,1 blast crisis [BC]); no response in 1; CMR ( <0.0032% BCR-ABL IS) lasting >88 months in 2 and pancreatitis in 1 patient in CMR for 75 months.
Twelve patients underwent a SCT after a median time of 8 months: 8 from an identical siblings (5 responders to IM [1 CMR, 3 MMR, 1 CCyR]), 3 MUD (2 in CCyR and 1 in MMR) and 1 cord blood in CCyR after chemotherapy for CB. Three patients, transplanted from an identical sibling, had disease recurrence after 24 (molecular relapse), 36 (cytogenetic relapse) and 83 (BC) months, respectively.
At the last follow-up, all patients are alive (CMR= 25; MMR=14; CCyR=3; minor CyR=2; too early=1) at a median of 52 months (range: 3-146). Of 42 patients evaluable for treatment, 23 are receiving IM at a dosage of 340 mg/m2 (4 intermittent IM); 11 are in CMR without any treatment (8 after SCT; 3 at 32, 33 and 50 months after IM discontinuation); 4 are in treatment with dasatinib, 3 with nilotinib and 1 with IFN.
In our experience, higher dose IM is an effective treatment for childhood CP CML, associated with sustained responses. Moreover, IM can be safely discontinued in pediatric CML patients with a deep CMR lasting more than 7 years. For patients candidates to a SCT, IM provides a safe bridging option to transplant, at no increased risk. Since patients may lose their response, a close and regular monitoring should be performed, mostly for those who stop IM, as SCT and new TK inhibitors may be successfully employed in patients failing IM.

Disclosures:
Saglio: Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.