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Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous Or Allogeneic Stem Cell

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Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous Or Allogeneic Stem Cell Biol Blood Marrow Transplant 25 (2019) 1792À1797 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma Elzbieta_ Wawrzyniak-Dzierzek_ 1, Kornelia Gajek1, Blanka Rybka1, Renata Ryczan-Krawczyk1, Jadwiga Wec˛ »awek-Tompol1, Anna Raciborska2, Monika Mielcarek-Siedziuk1, Jowita Fraczkiewicz˛ 1, Ma»gorzata Salamonowicz1, Krzysztof Ka»wak1, Monika Rosa1, Aleksandra Slezak˛ 1, Marek Ussowicz1,* 1 Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland 2 Department of Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, Warsaw, Poland Article history: ABSTRACT Received 6 December 2018 The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new Accepted 6 May 2019 therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regi- men in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). Key Words: For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 Neuroblastoma patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic Autologous toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive dis- Haploidentical ease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in Treosulfan patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; Melphalan P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% Thiotepa versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma. © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. INTRODUCTION According to data from the Center for International Blood Neuroblastoma is the most common extracranial tumor in and Marrow Transplant Research, allogeneic stem cell trans- children. Multimodal treatment in the high-risk neuroblas- plantation (SCT) after autologous SCT does not seem to offer an toma subgroup includes standard-dose chemotherapy, tumor advantage, with only 19% and 6% of patients alive and in remis- resection, megachemotherapy, radiotherapy, and immuno- sion at 1 year and 5 years after allo-SCT, respectively [1]. Cur- therapy with dinutuximab; however, up to 70% of treated rently, busulfan-based megachemotherapy is the preferred patients die of the disease. The prognosis of resistant or relaps- first-line treatment for neuroblastoma, despite the reported ing neuroblastoma remains very poor. Reports on the survival 22% incidence of sinusoidal obstruction syndrome (SOS)/veno- of patients who relapse after high-dose chemotherapy and occlusive disease (VOD) [2]. stem cell rescue are uniformly dismal. Due to poor outcome in resistant and relapsing neuroblas- toma the need for optimized high dose chemotherapy to improve survival is warranted, but toxicity and increased risk Financial disclosure: See Acknowledgments on page 1796. of non-relapse mortality (NRM) must be considered in the * Correspondence and reprint requests: Marek Ussowicz, MD, PhD, Depart- heavily pretreated patients. The popular revival of high-dose ment of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland. thiotepa in recent years raises a question concerning the opti- E-mail addresses: [email protected], [email protected] (M. Ussowicz). mal use of the drug in the transplantation setting. The oldest https://doi.org/10.1016/j.bbmt.2019.05.006 1083-8791/© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. E. Wawrzyniak-Dzierzek_ et al. / Biol Blood Marrow Transplant 25 (2019) 1792À1797 1793 reports on high-dose thiotepa (TT) with auto-SCT in neuroblas- Post-Transplantation Therapy toma date back to the early 1990s, but the observed efficacy Four patients received radiation therapy to the primary tumor at a total was low [3À6]. The combination of TT with a second alkylator, dose of 21 to 36 Gy fractioned into 1.5-Gy single doses. Post-transplantation dinutuximab beta therapy was administered to 6 patients at a dose of 100 such as high-dose carboplatin, was found to produce better mg/m2 as a continuous infusion over 10 days, repeated for 5 cycles. Patients outcomes for patients with neuroblastoma, although the fol- treated with dinutuximab beta received isotretinoin (13-cis-RA) 160 mg/m2/ low-up was short [7]. In another study, the combination of TT day divided into 2 equal doses given orally twice daily for 14 days, followed with etoposide and cyclophosphamide produced inferior 5- by a 14-day rest, for a total of 6 cycles. In 3 patients not eligible for dinutuxi- mab beta, temozolomide-irinotecan (TEMIRI) chemotherapy was adminis- year event-free survival (EFS) compared with busulfan-mel- tered as a 5-day course of irinotecan 50 mg/m2 (1-hour infusion) and phalan (21% versus 88%), although the study included only 8 temozolomide 150 mg/m2 (oral) every 3 to 4 weeks, for up to 6 cycles [13]. patients in the busulfan-melphalan group, for whom the results were unexpectedly good [8]. Recently, treosulfan has Statistical Analysis been viewed as a promising option, especially because the The main study endpoint was the evaluation of the organ-specific toxic- ’ data support the in vitro activity of treosulfan on neuroblas- ities. Toxicity data from the patients medical records were graded in accor- dance with the Common Toxicity Criteria, version 5 from the National toma lines [9]. However, to date only a few reports have inves- Institutes of Health [14]. SOS/VOD was diagnosed and graded according to tigated megachemotherapy with treosulfan in neuroblastoma, the 2018 European Group for Blood and Marrow Transplantation pediatric and these reports are limited to single patients [10,11]. Experi- criteria [15]. fi ence with combinations of treosulfan with melphalan and The secondary endpoints were overall survival (OS), de ned as the time from transplantation to death or the last report from patients with no event, thiotepa (TMT) is virtually nonexistent; only an Israeli pilot and EFS, defined as the time from transplantation to progression, relapse, sec- study from 2005 reported the use of a TMT protocol in 3 ond malignancy or death. Survival curves were estimated using the Kaplan- patients with hematologic malignancies [12]. To date, the TMT Meier method. Statistical analysis and data presentation were performed combination has not been studied in any trials. The purpose of with the computer software GraphPad Prism (GraphPad Software, La Jolla, CA) and Statistica 13.0 (StatSoft, Tulsa, OK). this analysis was to determine the feasibility and tolerability of TMT with SCT and the tumor response in children with recur- rent or refractory neuroblastoma. RESULTS Evaluation of Toxicity The median duration of hospitalization 31 days (range, 21 METHODS to 51 days) and was shorter in the auto-SCT group compared Between 2010 and 2018, 17 children with neuroblastoma underwent megachemotherapy with auto-SCT or allo-SCT at our institution. Patient char- with the allo-SCT group (median, 25 days versus 40 days; acteristics and clinical data are presented in Table 1. The cohort for analysis range, 21 to 45 days versus 28 to 51 days; P = .014). All 17 consisted of children who relapsed after auto-SCT (n = 12) or had primary patients had grade 4 leukopenia and neutropenia, and 13 therapy-resistant neuroblastoma (n = 5) and had received prolonged chemo- (76%) had fever. Two patients were transferred to the intensive therapy and previous local irradiation, which made them ineligible for busul- fan owing to the risk of VOD. The interval from the previous busulfan- care unit for treatment of septic shock, but both recovered and melphalan megatherapy and auto-SCT was 19.1 months (range, 8.9 to 48.74 continued hospitalization in the transplantation unit. Revers- months). MYCN amplification was identified in 6 of the 17 patients. The ible grade 3 nonhematologic toxicities included mucositis parents of all 17 children provided written informed consent for the treat- (n = 15; 88%) with total parenteral nutrition (n = 15; 88%) and ment and analysis of clinical data. diarrhea (n = 5; 29%). One patient exhibited elevated alkaline Megatherapy phosphatase activity, and 6 patients (35%) had elevated amino- For all patients, the conditioning regimen consisted of treosulfan (10 g/m2/day transferase activity. Grade 1 hypertransaminasemia was found 2 for 3 days), melphalan (70 mg/m /day for 2 days), and thiotepa (2 £ 5mg/kgbody
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