Response to High Dose Imatinib and Long-Term Outcome in Children and Adolescents with Previously Untreated Chronic Myeloid 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 , Moleti Maria Luisa , Mariani Sabrina , De Benedittis Daniela , Marzella Deborah , Varotto Stefania , Tucci Francesca , Nanni Mauro , Messina Chiara , Diverio Daniela , Biondi Andrea , Pession Andrea , Zecca Marco , Locatelli Franco , Saglio Giuseppe , Foà 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 of IM and overall management of newly-diagnosed childhood CML in chronic phase (CP) are not well defined.
This study was designed to evaluate (a) the response to IM at a dosage equivalent in terms of drug exposure to the 600 mg daily utilized in adults and (b) the long-term outcome in newly-diagnosed children and adolescents with CML. Patients aged <18 years with a diagnosis of CML in CP were treated with IM at a dosage of 340 mg/m2/day. Cytogenetic analyses were planned on bone marrow (BM) cells before and during IM therapy as well as quantitative RT-PCR on peripheral blood (PB) monthly and on BM every 3 months. Partial cytogenetic response (PCyR) was considered as the presence of Ph+ cells between 0 and 35%. Molecular response (MR) was considered as <0.01% BCR-ABL1 IS, while major MR (MMR) was defined as <0.1% BCR-ABL1 IS. This study was approved by the Istitutional Review Boards of each participating Institution.
Between December 2002 and February 2014, 41 CML patients in CP (females: 13, males: 28; age <10 years: 13 patients) were recorded from 9 Italian pediatric centers. Twenty-seven patients (66%) have a follow-up >24 months. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage of IM was modulated according to the occurrence of >2 WHO side-effects or response, mainly during the first 6 months of treatment. Forty patients are evaluable for treatment results. Median administered dosage of IM was 309 mg/m2/day, higher in males than in females (326 mg/m2vs 245 mg/m2, p .015) and in those younger than 10 years (314 mg/m2vs 262 mg/m2). Twenty-four patients (60%) experienced isolated or combined side effects: hematologic toxicity (medullary hypoplasia [n=1], neutropenia [n=7] and/or thrombocytopenia [n=6], anemia [n=1]) and/or extra-hematologic toxicity (arthralgia/myalgia [n=8], nausea [n=1], vomiting [n=1], diarrhea [n=1], abdominal pain [n=2], hepatitis [n=1], skin rash [n=2]. Persistent >3 WHO adverse events led to IM discontinuation in 6 patients (15%).
At 3 months of IM treatment, hematologic response and PCyR rates were 91% and 54%, respectively; BCR-ABL1 transcript levels <10% were found in 69% and 75% of patients on BM and on PB cells, respectively. At 6 months, 77% of patients was in CCyR; 56% and 66% of patients showed BCR-ABL1 transcript levels <1% on BM and on PB cells, respectively. At 12 months, MMR was detected in 66.4% and 71.4% of patients on BM and on PB cells, respectively; BCR-ABL1 IS <0.0032% was found in 21% and 14% of patients on BM and on PB cells, respectively. All but 1 patient achieved a response. Overall, 94% obtained a CCyR at a median time of 6.4 months. Fourteen of 25 (56%) and 13/17 (76%) evaluable patients obtained a MR on BM and on PB cells at a median time of 13 and 15 months, respectively. Intermittent therapy (IM at the same daily dosage for 3 weeks a month) was started in 6 patients with a sustained MR; thereafter, 2 adolescents with <0.0032% BCR-ABL IS lasting >7years successfully discontinued IM and 2 patients resumed continuous IM because of an increased BCR-ABL transcript. IM was interrupted in 8/33 (24%) responder patients, 4 of them in BCR-ABL1 IS<0.1%, after a median time of 7 months because they underwent an allogeneic stem cell transplant (SCT). Treatment was also discontinued in 6 patients in continuous IM because of a disease recurrence (median response duration: 37 months; range, 21-115). Overall, 12 patients (30%) underwent a SCT after a median of 7.7 months: 8 from an identical sibling (BCR-ABL1 IS <0.1% in 3), 3 from a MUD and 1 from an umbilical cord blood. Three patients, transplanted from an identical sibling, had disease recurrence after 24, 36 and 83 months, respectively. Estimated probabilities of failure-free survival was 50% at 8 years for patients submitted to an SCT and 60% at 10 years for those still receiving IM. At the last follow-up, all patients are alive at a median of 44.6 months.
In our experience, IM at a daily dose of 340 mg/m2 is effective in newly-diagnosed CML children with responses rates higher than those reported in children treated with IM at lower dosage. Considering the long-term follow-up, high-dose IM allowed to safely discontinue treatment in some patients with a deep MR; furthermore, it did not worsen the outcome both in patients submitted to a SCT and in those with disease progression or side-effects.

Disclosures
Saglio: BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.