Improved Outcome and Decreased Morbidity and Mortality Rates of B-Cell Malignancies with Less Intensive Chemotherapy Induction: Experience in a Single Institution

Abstract

Background: High-Dose chemotherapy is necessary one of the most important tools for improving response rates and for decreasing relapse rate in childhood B-cell malignancies. However, deaths during induction or in Complete Remission (CR) in children with higher disease burden had adversely influenced pEFS in our setting, and for this reason an accomplished clinical support is mandatory for achieving these better results. Objective: Our aim was to diminish morbidity and mortality of patients with B-cell malignancies with the administration of a reduced intensity BFM-based induction phase, plus the addition of rituximab in a pilot study. We also retrospectively analyzed the outcome of this group of patients. Methods: This is a prospective study, single arm, non-randomized local trial for treatment of B-cell malignancies. Between December-2008 and March-2016, 81 pts consecutive (<16 years/old) (52:M/29:F) were enrolled in a protocol HPG-09, and 70 of them resulted evaluable. Patients were stratified according stage and DHL level in Risk-1, Risk-2, Risk-3 and Risk-4. Risk-4 included patients with stage IV and stage III with DHL levels higher than 1,000 U/dl. The pathology, flow-cytometry and cytogenetic findings disclosed 60 cases of Burkitt Lymphoma, 11 diffuse large B cell Lymphomas, 9 mature-B acute lymphoblastic leukemia, and 1 Precursor-B ALL with with t(8;14). The treatment locally-none BFM-counterpart included 4 doses of Rituximab administered to Risk-4 cases during early phases of treatment and intensified chemotherapy with HDMTX (24 hr) 5 g/m2, plus reduced intensity induction with pre-phase followed by A1 block (MTX 1 g/m2 4 hr infusion), in order to decrease morbidity and early mortality rates. Results: Distribution of patient according to risk-groups was: Risk-1 (n=2) 2%, Risk-2 (n=9) 11%, Risk-3: (n=13) 16% and Risk-4 (n=46) 57% of cases. Median DHL= 3,642 (range: 396-33,673) UI/dl, CNS+ cases was observed in 6 cases. Complete remission (CR) was achieved in 95.1% of the cases and 4.9% of patients died in early phases of treatment. From patient who achieve CR, 6 adverse events were observed (all of them in Risk-4 group): 2 relapses and 4 death in CR (1 Steven´s-Johnson Syndrome, 2 tumor lysis syndrome plus CID and 1 patient died after extensive initial surgery) The pEFS for R1, R2, and R3 was 100%. With a median follow-up of 48 (range:6-61) months, the pEFS (SE) for all risks groups was 91 (4)% and for Risk-4 85 (6)%. Conclusions: Risk-4 group accounted for 66% of the total population of patients, defining a more aggressive disease prevalence in our setting. Locally-adapted strategy based on BFM experience was successfully implemented, reducing induction intensity and with the incorporation of 4 doses of Rituximab. The outcome of this group of patients was very good. Reduction of induction intensity and addition of Rituximab resulted in low mortality rate and excellent survival outcome. Disclosures No relevant conflicts of interest to declare.

Optimizing outcomes for children with non‐Hodgkin lymphoma in low‐ and middle‐income countries by early correct diagnosis, reducing toxic death and preventing abandonment

“…In some settings, as adopted by the French‐African Paediatiric Oncology Group (GFAOP), intestinal parasite therapy is routinely given prior to the start of lymphoma therapy, with standardized recommendations for antimicrobial management during therapy (Traore et al , ). Generally, modified (reduced intensity) induction regimens were associated with lower fatal toxicity rates when compared to previous experience in the same centres (Sanchez La Rosa et al , ). However, shorter methotrexate infusions are not only less toxic, but also less effective in controlling the lymphoma, and this approach to improve patient survival has not been studied in a randomized trial.…”

“…In most LMIC there is a higher prevalence of advanced disease, as high as 80–90% of patients in some studies compared to 66% in the BFM‐95 protocol (Woessmann et al , ; Ahmad et al , ; Gaytan‐Morales et al , ). Some results from single institutions in UMIC also document a high prevalence of advanced disease, while others showed a similar pattern to HIC (Klumb et al , ; Sanchez La Rosa et al , ). Finally, the BFM‐95 intense chemotherapy block CC, containing high‐dose cytarabine, steroids and etoposide, is not uniformly used, or is used with lower doses in order to avoid its higher haematopoietic and gastrointestinal toxicity in many MIC (Cervio et al , ).…”

“…Unfortunately, its high cost makes it unaffordable in many settings. Results from a single centre in Argentina, where the dose of methotrexate in the first induction block was reduced to 1 g/m 2 in a 4‐h infusion while adding rituximab (4 weekly doses starting from week 1) for high risk patients demonstrated a decrease in early death and improved survival (Sanchez La Rosa et al , ). However, it is important to be aware of the high risk of hypogammaglobulinaemia associated with rituximab administration, and the importance of immunoglobulin replacement therapy for deficient patients to reduce the risk of severe infections.…”

Science and health for all children with cancer

“…So-called "adapted treatment regimens" are widely used in LMIC. These are typically lower intensity regimens that can be associated with higher overall survival by causing fewer toxic deaths (44). For instance, patients with Burkitt lymphoma who have bulky disease and significant morbidity after initial treatment may be managed with an additional few weeks of reducedintensity treatment before continuing standard therapy (45).…”