High-dose polychemotherapy with autologous hematopoietic stem cell transplantation in children with non-Hodgkin lymphomas
Authors: Kozlov A. V. , Kazantsev I. V. , Yukhta T. V. , Tolkunova P. S. , Gevorgyan A. G. , Nikolayev I. Yu. , Galibin A. N. , Bogdanova O. I. , Zvyagintseva D. A. , Golenkova M. S. , Yudintseva O. S. , Sviridova U. V. , Shvetsov A. N. , Baykov V. V. , Babenko E. V. , Estrina M. A. , Punanov Yu. A. , Morozova E. V. , Kulagin A. D. , Mikhaylova N. B. , Zubarovskaya L. S. 
Published: May 2021

There is no doubt that autologous hematopoietic stem cell transplantation (auto-HSCT) with high-dose polychemotherapy (PCT) is a standard method for the second remission consolidation in case of relapse or for the fist remission consolidation in refractory disease in adult patients with non-Hodgkin lymphomas (NHL) (with the exception of lymphoblastic lymphoma in which allogeneic transplantation is preferable). Similar to patients older than 18 years of age, an identical algorithm is applied in pediatric patients, however in the absence of randomized clinical trials and due to a small number of patients, the evidence base in children is weaker compared to adults, which complicates the analysis. Due to a signifiant number of nonrandomized studies confiming the benefis of transplantation, it is impossible to plan and make a direct comparison of auto-HSCT and standard chemotherapy in pediatric patients within a randomized study primarily because of ethical reasons. Although transplantation is not able to fundamentally change the prognosis in all children with relapsed or refractory (R/R) NHL, a cure cannot be achieved without this method. Taking into account that most of the works devoted to auto-HSCT in children with R/R NHL were published more than 10 years ago, current data on this issue are of great interest due to the large-scale implementation of the effective methods of targeted and immunotherapy over the past decade. This study was approved by the Independent Ethics Committee and the Scientifi Council of the I.P. Pavlov First Saint-Petersburg State Medical University, Ministry of Healthcare of the Russian Federation. At the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, 31 children with R/R NHL underwent auto-HSCT from 2008 to 2020. The median age at the time of transplantation was 14 (2–18) years. At the onset of the disease, most patients were diagnosed with stage III or IV cancer (n = 30, 97%), the CNS involvement was registered in 4 patients (13%), the bone marrow involvement was registered in 2 patients (6%). The histological variants were as follows: primary mediastinal large B-cell lymphoma (n = 11, 35%), anaplastic large cell lymphoma (n = 6, 9%), Burkitt's lymphoma (n = 5, 16%), diffse large B-cell lymphoma (n = 5, 16%), peripheral T-cell lymphoma (n = 2, 7%), unspecifid B-NHL (n = 1, 3%) and lymphoblastic lymphoma (n = 1, 3%). The Karnofsky performance status prior to transplantation was ≥ 90% in all patients. The median time from diagnosis to auto-HSCT was 304 (122–3888) days. The median number of prior lines of therapy was 2 (1–4). In the majority of the patients (n = 27, 87%), a fist-line treatment was carried out according to the principles developed by the BFM group and in 4 older children (13%), we used regimens based on CHOP. As a second-line treatment, 18 (58%) patients received R-ICE (rituximab, ifosfamide, carboplatin, etoposide); the rest of the patients were treated with other regimens. NHL was relapsed (n = 14, 45%) or refractory (n = 17, 55%). A histological confimation of R/R NHL was carried out in 11 (35%) patients; in the rest of the cases, the diagnosis was made based on the imaging results and their correlation with the clinical presentation. Remission prior to auto-HSCT was achieved in 90% (n = 28) of cases: complete remission was observed in 39% (n = 8) of cases, and partial remission was observed in 51% (n = 16) of cases. In addition, transplantation was carried out in three patients (10%) who did not achieve remission. The graft sources were peripheral hematopoietic stem cells (n = 19, 61%) and bone marrow (n = 12, 39%). The median CD34+cells/kg was 3.85 (2–7.6). As conditioning regimens we used BEAM (n = 13, 42%) and BeEAM (n = 18, 58%). Both regimens consisted of etoposide 200 mg/m2/day from D5 to D2, cytarabine 400 mg/m2/day from D5 to D2, melphalan 140 mg/m2/day on D1. The regimens diffred in the following: we used carmustine 300 mg/m2/day on D6 in BEAM or bendamustine 160 mg/m2/day on D7 and D6 in BeEAM. Immunotherapy or targeted therapy prior to auto-HSCT was carried out in the majority of the patients (n = 25, 80%). The following medications were used: rituximab (n = 20, 65%), brentuximab vedotin (n = 6, 19%), nivolumab (n = 3, 10%), crizotinib (n = 2, 6%). Temporary three-lineage grade IV cytopenia was observed in all patients after auto-HSCT. Grade III–IV mucositis was registered in 10 (30%) patients, and 3 (10%) children developed grade III–IV infectious complications. Transplant-related mortality was not registered. During the follow-up period, six (19%) patients died due to the underlying disease progression. At the median follow-up of 888 (66–3375) days, the 5-year overall (OS) and event-free (EFS) survival rates were 70% (95% CI: 43–86) and 62% (95% CI: 41–80), respectively. The cumulative incidence of relapse was 38% (95% CI: 20–58). Based on the data obtained in our work, we can conclude that the use of targeted or immunotherapy provides a statistically signifiant improvement in overall survival (OS) (p = 0.013). This is associated with both factors: a more sustained remission prior to auto-HSCT and the availability of effctive treatment for some patients (mainly for the patients with anaplastic large cell lymphoma) in case of relapse after auto-HSCT. The achieved long-term survival rate is comparable or even slightly superior to the data previously obtained by other researchers. Almost one third of the patients suffred from primary mediastinal large B-cell lymphoma, and this is one of the possible reasons for higher long-term OS and EFS rates compared to the previously published results. Moreover, the presence of 6 patients with R/R anaplastic large cell lymphoma with a more favorable prognosis, and, probably, the absence of the morphological confimation of R/R NHL (“second look”) in some patients (n = 20, 65%) could have inflenced the survival rates, which does not exclude the possible inclusion of a number of cured patients in the work. The importance of our work lies in the fact that a signifiant part of the patients (n = 25, 80%) underwent targeted or immunotherapy. This allowed us to show the effctiveness of transplantation in different types of NHL in children in the so-called era of immunotherapy. Auto-HSCT is an effctive and relatively safe treatment strategy for children with R/R NHL which makes it possible to achieve a cure in a signifiant number of patients. The use of targeted and immunotherapy improves the prognosis in transplanted patients. A second biopsy is recommended to confim R/R NHL.