Intensification of postconsolidation therapy in patients with high-risk neuroblastoma

Introduction . The results of treatment of high-risk neuroblastoma (NB) patients at the current stage remain unsatisfactory and overall survival does not exceed 50–60 %. Response to induction therapy, including response from distant metastases, is an important prognostic factor. Worse treatment outcomes are noted in patients who have not achieved complete resolution of metastatic foci. Intensification of postconsolidation therapy with the addition of cytostatic drugs not used at the induction treatment stage to 13-cis-retinoic acid (13-cis-RA) is a possible treatment option aimed at overcoming tumor cell resistance and improving both objective response and long-term prognosis in these patients. Materials and methods . We conducted a multicenter prospective study of the use of 12 courses of temozolomide in combination with 9 courses of 13-cis-RA as part of postconsolidation therapy in high-risk NB patients who achieved an unsatisfactory response to induction therapy (persistence of metastatic foci) within the modified protocol of German Society for Pediatric Oncology and Hematology GPOH NB-2004, who received this therapy from January 2020 to January 2022. Temozolomide therapy was administered at a dosage of 150 mg/m 2 /day per os (intravenous administration was allowed) for 5 days and started on day 29 of the first cycle of 13-cis-RA. Another course of 13-cisRA was started on day 6 of temozolomide administration. During the 3-month break between the courses of 13-cis-RA (6 and 7 courses), temozolomide was continued for 5 days (the courses were repeated every 28 days). Results. Fourteen high-risk NB patients with a median age at the time of diagnosis of 62 months (range – 9–173 months) were included in the study. Thirteen patients with newly diagnosed NB were verified with INSS stage 4 disease and INRGSS stage M; 1 patient with initial localized low-risk NB subsequently developed a combined relapse. 9/14 (64 %) patients received standard induction therapy and 5/14 (36 %) received intensified therapy due to an unfavorable response to the first six courses of induction chemotherapy. The response after completion of induction therapy was evaluated as partial response (PR) in 6/14 patients, mixed response (MR) in 6/14, and stable disease (SD) in 2/14. All patients received high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) during the consolidation phase. Postconsolidation therapy included a total of 134 cycles of temozolomide. Postconsolidation therapy including 12 cycles of temozolomide was completed by 10/14 (71 %) patients. 4/14 (28 %) patients did not complete therapy (2/4 – parental refusal of therapy and 2/4 – progression (PR)). 4/14 (29 %) patients included in the study fully completed the proposed regimen of post-consolidation therapy (13-cis-RA and temozolomide) without the addition of other therapeutic agents. 6/14 (43 %) patients received all 12 courses of temozolomide in combination with anti-GD2 targeted monoclonal antibodies (mAbs) immunotherapy and/or molecularly targeted therapy. In 3/14 (21 %) patients, manifestations of hematologic toxicity were observed, requiring reduction of temozolomide dosage and increasing the course interval. One out of 3 patients experienced thrombocytopenia on courses 2–5 and 2 out of 3 patients experienced grade II–III neutropenia on courses 5 and 2, 6, respectively. No unexpected serious toxicities, including deaths, were reported during all courses evaluated. Overall, 11/14 (79 %) patients completed first-line therapy (complete response (CR) – 2/11, PR – 7/11, SD – 1/11, PR – 1/11), 3/14 (21 %) did not complete due to disease progression. Currently, 11/14 (79 %) patients are alive (3/11 – after PR/relapse and 8/11 – alive without events). 2/14 (14 %) patients died from disease progression, 1/14 (7 %) – from non-tumor related causes. Median follow-up from diagnosis was 39.3 months for all patients (range – 12.5–62.5) and 42.5 months for survivors (range – 24.4–62.5). Conclusions . For high-risk NB patients who have not achieved a complete metastatic response to the induction therapy phase, intensification of the postconsolidation phase of treatment may be suggested. The addition of temozolomide to the differentiation agent 13-cis-RA in our study demonstrated minimal toxicity, good tolerability, and improved response in a subset of patients. Further studies are needed to select the optimal regimen of postconsolidation therapy for patients with an unsatisfactory response to the induction phase.