Can Children and Adolescents With Chronic Myelogenous Leukemia Be Cured Without Stem Cell Transplant? A Single Center Experience
Authors: Giona Fiorina , Siniscalchi Benedetta , Moleti Maria Luisa , Rea Massimiliano , Marzella Deborah , Nanni Mauro , Gottardi Enrico , Iori Anna Paola , Diverio Daniela , Testi Anna Maria , Saglio Giuseppe , Foa' Robin 
Published: October 2019

Abstract
For many years stem cell transplant (SCT) has been considered the only curative treatment for adults and children with chronic myeloid leukemia (CML). The availability of therapies, potentially capable of eradicating the Ph+ clone, has changed the treatment approach to CML patients. In this study, we report the long-term outcome of CML patients aged <20 years treated with interferon alpha (IFN) and/or imatinib (IM), and of those submitted to SCT.
From 1990 to 2011, 35 consecutive CML patients in chronic phase (CP) (20 males, 15 females; median age1210/12 years) were treated according to the local guidelines. Before 2002, CML patients with a HLA-matched sibling underwent an allogeneic SCT, while the remaining patients were systematically treated with IFN. Since 2002, IM at a dose of 340 mg/m2/day was used in all newly diagnosed patients in CP, including those with a HLA-matched sibling. Cytogenetic analysis and qualitative RT-PCR were performed on bone marrow (BM) cells before and during IM therapy, at planned intervals, while FISH was carried out at complete cytogenetic response (CCyR). Since 2000, 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. The terms of MR4, MR4.5 and MR5 are used to indicate levels of disease <0.01% BCR-ABLIS,<0.0032% BCR-ABLIS,<0.001% BCR-ABLIS, respectively.
From 1990 to 2001, 23/27 patients received IFN at a median dose of 6 ML IU/day (range: 2.5–9) and 4/27 patients with a HLA-matched sibling underwent a SCT. Twelve of 23 patients treated with IFN (52%) obtained a cytogenetic response (6 complete) and 5 of them (22%) achieved a molecular response (4 CMR and 1 MMR) after a median of 76 months (range: 43-122). IFN was stopped in 20/23 patients (87%) because of: no response (n=7), recurrent disease (cytogenetic relapse [n=1], blast crisis [BC] [n= 5], accelerated phase [AP] [n=1]), SCT (n=1 in CP), intolerance (n=3, with molecular response), autoimmune disease (n=1), lack of compliance (n=1). The remaining 3 patients continued IFN, that was discontinued in 2 of them in CMR5lasting >99 and 120 months, respectively.
Since 2002, IM was started in 8 newly diagnosed patients in CP, including 3 with a HLA-matched sibling, and in 7 patients previously treated with IFN (1 in MR4.5, 1 in MMR, 5 in CP). Twelve of 13 evaluable patients (92%) obtained a CCyR after a median of 6 months (range 3-12). Of 12 patients evaluable for molecular response, 8 achieved a CMR after a median of 13 months and 3 a MMR; 1 patient had a MR4 on PB and a MMR on BM. Two patients stopped IM because of extra-hematologic toxicity after 1 and 2 months, respectively; 2 patients had a disease recurrence (cytogenetic relapse [n=1] and BC [n=1]). IM was discontinued in 4/8 patients (including 1 with a HLA identical sibling) in sustained CMR (MR4.5-MR5) lasting >75, 88, 89 and 123 months, respectively.
Overall, 15 patients underwent a SCT after a median of 17 months: 5 from an identical sibling (4 in 1st and 1 in 2nd CP), 6 from a MUD (3 in CP, 2 in AP and 1 in CCyR), 2 from UCB (1 in aplasia and 1 in 2ndCCyR ), 1from a haploidentical-related donor and 1 autologous. Two patients (1 MUD and 1 UCB) died of SCT-related toxicity and 4 patients had disease recurrence (BC [n=3] and AP [n=1]).
At the last follow-up, 5/15 transplanted patients have died (3 of disease progression) after a median of 29 months (range 19-216), 2 are lost to follow-up and 8 patients are alive in CMR (4 in MR4.5-5) at a median of 205 months (range: 48-236). Of 20 patients treated with IFN and/or IM, 5 have died of disease progression after a median of 41 months (range 27-72), 1 is lost to follow-up, and 14 patients are alive at a median of 161 months (range: 22-246): 2 are in treatment with IFN, 6 with IM and 6 are in CMR (7 in MR4.5-5) without any treatment at 31, 31, 37, 38, 50 and 60 months from IFN (n=2) + IM (n=2) or IM (n=2) discontinuation.
In our experience, IM + IFN has proven to be an effective therapy in CML children and adolescents in CP, offering a valid alternative to SCT. These drugs provide sustained responses and can be safely discontinued in CML patients with a deep sustained CMR (MR4.5-MR5). Larger cohorts of pediatric patients are necessary to confirm these promising results which raise the possibility that children with CML might be cured without SCT.

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