CODOX-M/IVAC (NCI 89-C-41) for Children and Adolescents with Small Non-Cleaved and Large B-Cell Lymphomas. A 14 Years Monocentric Experience.
Authors: Moleti Maria Luisa , Testi Anna Maria , Malandruccolo Luigi , Todisco Elisabetta , Pescarmona Edoardo , Martino Pietro , Paoloni Francesca , Barberi Walter , Alfieri Cecilia , Palumbo Giovanna , Giona Fiorina , Foà Robert 
Published: October 2019

Abstract
Over the last 14 years, at our Institute, we have used the NCI 89-C-41 protocol designed by I. Magrath in children and adolescents with small non-cleaved cell (SNCL) and large B-cell (LBCL) lymphomas. In the 1996 paper (J Clin Oncol 1996, 14: 925–34), Magrath et al reported an event-free survival of 92% at 2 years, in adults and children with SNCL. In this protocol, patients with a single extra-abdominal mass or completely resected abdominal disease and LDH <350 IU/L are classified as low-risk; all other patients are defined as high-risk. Low-risk patients receive 3 cycles of the CODOX-M regimen, a combination of cyclophosphamide, doxorubicin, prednisone, vincristine, high-dose methotrexate and intrathecal therapy. High-risk patients receive 4 alternating CODOX-M and IVAC regimens. The IVAC protocol includes ifosfamide, etoposide, high-dose cytarabine and intrathecal methotrexate.
We describe hereby the results obtained in 35 patients younger than 21 years with SNCL and LCBL, seronegative for the HIV, treated with the NCI 89-C-41 protocol between September 1989 and March 2003 at our Institute. Median age at presentation was 12.1 years, ranging form 2.6 to 21 years. Thirty patients had SNCL and 5 LBCL. According to Murphy’s staging system, 17 were classified as stage II, 9 as stage III and 9 as stage IV (all with bone marrow involvement that was >25% in 3; 1 with associated CNS disease). Two patients were defined as low risk, while 33 were high-risk. The CNS+ patient received additional IT therapy. G-CSF was given in case of neutropenia associated to severe infections. Thirty-two of the 35 patients (91%) achieved a CR. The remaining 3 patients (SNCL, stages II, III and IV) obtained a PR after the first 2 cycles, but the disease rapidly progressed and led to death in all 3. One patient with stage IV SNCL died in CR of fungal meningitis, during the fourth cycle neutropenia. Three complete responders (SNCL, stage III) relapsed after 2, 2 and 33 months from the end of therapy. Only 1 of them is alive and well in second CR after a stem cell transplant. A life-threatening tumor lysis syndrome was observed in 2 patients; metabolic alterations caused seizures in 1 of them that resolved without sequelae. The hematological toxicity was acceptable; in low-risk patients no thrombocytopenias were observed and neutropenia lasted from 0 to 3 days. For high-risk patients, the median time to PMN >0.5 x 109/L after each cycle was 7, 6, 6 and 6 days (range 0–19), respectively, and to PLTS >50 x 109/L was 6 days (range 0–36). Infections were observed only in high-risk patients with 13 bacterial sepsis, 1 disseminated fungal infection and 12 localized infections. Mucositis (WHO >2) was the main extra-hematological side-effect occurring usually after the CODOX-M regimen; transient peripheral neuropathy occurred in 4 patients after the CODOX-M cycle. No acute and late liver, pulmonary and cardiac toxicities were registered. The 7-years overall survival and event free-survival are 83 and 80%. The results of our study indicate that the NCI 89-C-41 protocol, originally designed for SNCL patients, has confirmed its feasibility and documented its long-term efficacy in a series of children and adolescents with both SNCL and LBCL managed at a single center and with a median follow-up extended to 10 years.