Busulfan–Melphalan Followed by Autologous Stem Cell

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LETTER TO THE EDITOR Busulfan–Melphalan followed by autologous stem cell transplantation in patients with high-risk neuroblastoma or Ewing sarcoma: an exposed–unexposed study evaluating the clinical impact of the order of drug administration

Bone Marrow Transplantation (2016) 51, 1265–1267; doi:10.1038/ survival (OS) was the time from study entry (that is, the first day bmt.2016.109; published online 25 April 2016 of HDC) to death or the last follow-up, whichever occurred first. EFS was the time from study entry to disease progression, a second malignancy, death or the last follow-up, whichever High-dose chemotherapy (HDC) and autologous stem cell occurred first. OS and EFS were estimated using the Kaplan–Meier transplantation (ASCT) have improved the prognosis of high-risk method. Patients from the two treatment groups (Bu–Mel neuroblastoma and metastatic Ewing sarcoma.1,2 The impact of and Mel–Bu) of the same age at diagnosis were matched. the drugs in the HDC regimen was first demonstrated in a The association of the treatment group with toxicity and study performed in the Gustave Roussy Pediatrics Department. efficacy outcomes was assessed using Cox regression models It showed improved survival for patients with stage 4 stratified on matched pairs and adjusted for other confounding neuroblastoma who received a combination of busulfan (Bu) factors, such as the year of diagnosis, VOD prophylaxis and age at and melphalan (Mel).3 These results were confirmed in a diagnosis. European randomized study (HR-NBL1/SIOPEN), and this From 2002 to 2012, 81 patients were included in this study: 46 combination is now administered worldwide to patients with patients treated with Mel–Bu (median year of diagnosis: 2008) and high-risk neuroblastoma.4,5 This HDC was used as a consolidation 35 patients with Bu–Mel (median year of diagnosis: 2004), regimen in metastatic Ewing sarcoma and proved beneficial for followed by ASCT. The characteristics of the two populations event-free survival (EFS).6 are described in Table 1. The median age at diagnosis was However, the toxicity of Bu–Mel is severe with specific 4 years in both groups (range: 0–20). Patients were diagnosed endothelial toxicity and a high rate of hepatic veno-occlusive with either a high-risk neuroblastoma (65), mainly metastatic disease (VOD), non-infectious interstitial pneumonitis or disease at diagnosis (54) or a localized tumor with N-MYC pulmonary hypertension. Reducing the incidence of these amplification (9), or a Ewing sarcoma (16), mainly metastatic complications remains a major issue for the future strategy for disease at diagnosis (13). Most of the tumors were located in the administering this regimen. Preclinical and clinical studies adrenal glands (47) or limbs (8), and were stage 4 (70:66 at suggest that the order of administering alkylating agents can diagnosis and 4 at relapse between the diagnosis and ASCT). influence the toxicity of HDC. When Bu is given first in Metastatic tumors had mainly spread to the bone (47) and combination with another alkylating agent, it can increase the bone marrow (45). No significant difference was observed in toxicity of the second drug by inducing glutathione depletion the conventional chemotherapy received before HDC (type and and/or lower the metabolism of the second chemotherapeutic number of courses, number of drugs) between the two agent.7,8 groups. Prophylactic therapy against VOD was administered to Based on these pharmacological data, patients o20 years old 57 patients: either oral ursodeoxycholic acid (26 patients: at diagnosis of a high-risk neuroblastoma or Ewing sarcoma, not 9 Mel–Bu and 17 Bu–Mel treated between 2002 and 2008) included in ongoing protocols, have been treated with the Mel–Bu or IV defibrotide (31 patients: 18 Mel–Bu and 13 Bu–Mel treated combination with Mel administered before Bu since 2002 in the between 2006 and 2012). Gustave Roussy Pediatrics Department. The primary aim of the VOD occurred in 16 Mel–Bu and 10 Bu–Mel patients, mostly present study was to perform an exposed (Mel–Bu order, that is, grade II disease (11 and 6 patients, respectively). The new order) - unexposed (Bu–Mel order, that is, classic order) study 4-week incidence of grade II/III VOD was 31% (95% in order to evaluate and compare toxicity VOD in two groups of confidence interval (CI): 19–45%) and 17% (95% CI: 8–33%) for patients. We also evaluated and compared the efficacy (EFS), a Mel–Bu and Bu–Mel patients, respectively (Figure 1a). Before secondary aim, to determine the potential benefit of changing the 3 months after ASCT, one patient in the Mel–Bu group order of administration of the two alkylating agents in future experienced non-infectious interstitial pneumonitis and one protocols. patient in the Bu–Mel group developed infrasystemic pulmonary Bu–Mel patients received either oral (before 2003) or IV hypertension with a favorable outcome. One patient in the (after 2003) Bu for 4 days followed by one dose of IV Mel 24 h Mel–Bu group died of acute respiratory distress syndrome after after the last dose of Bu, whereas Mel–Bu patients received Mel surgical resection of the tumor, 34 days after ASCT. In the followed by Bu. ASCT was performed 24–48 h after the last dose multivariate analysis, no significant difference in the risk of of chemotherapy. Supportive care was comparable to IV grade II/III VOD was observed between the two groups granulocyte colony stimulating factor (5 μg/kg per day) (hazards ratio = 2.1 (95% CI: 0.8–5.9), P-value = 0.14). No significant administered from day 5 after ASCT to the end of neutropenia. difference was found between the two groups in other toxicities The definition of VOD fulfilled the Seattle criteria and its severity such as digestive or hematological toxicity or even infectious was graded according to the Bearman toxicity score. Overall complications (data not shown). Two toxic deaths occurred only in Letter to the Editor 1266 respectively. Regarding the two efficacy outcomes, 3-year EFS Table 1. Patient characteristics (Figure 1b) and 3-year OS (Figure 1c) were, respectively, 61% – – – Characteristics Melphalan-Busulfan Busulfan-Melphalan (95% CI: 44 76%) and 69% (95% CI: 52 83%) for the Mel Bu combination (Mel-Bu) combination (Bu-Mel) patients, and 55% (95% CI: 37–72%) and 65% (95% CI: 46–81%) for the Bu–Mel patients. In the multivariate analysis, no significant Overall 46 35 difference in the two efficacy outcomes was observed between Sex the two groups: EFS (hazards ratio = 1.1 (95% CI: 0.4–3.1), Male 30 (65%) 17 (49%) P-value = 0.9) and OS (hazards ratio = 1.2 (95% CI: 0.3–4.0), Age at diagnosis (years) P-value = 0.8). In addition, no difference in EFS was observed Median, range 4 (0–19) 4 (0–20) between neuroblastoma and Ewing sarcoma (hazards ratio = 1.5 (95% CI: 0.5–5.2), P-value = 0.5). Years of diagnosis The morbidity of the Bu–Mel combination, mainly related to the Median, range 2008 (2003–2011) 2004 (2002–2011) high incidence of diffuse endothelial injury and especially hepatic VOD, remains a major concern.9 Diagnosis The impact on toxicity of the order of administering alkylating Neuroblastoma 37 (80%) 28 (80%) agents was demonstrated with the Bu–Cy regimen commonly Ewing sarcoma 9 (20%) 7 (20%) administered before allogeneic transplantation. Cyclophospha- – Primary tumor site mide pharmacokinetics were compared in the Bu Cy and Cy-TBI Adrenal 28 (60%) 19 (55%) combinations. Higher exposure to cyclophosphamide and its toxic Limbs 4 (9%) 4 (11%) metabolite, 4-hydroxy cyclophosphamide (4OHCY) was demon- Thorax 4 (9%) 1 (3%) strated in the Bu–Cy combination than in its Cy-TBI counterpart. Abdomen 0 5 (14%) – a The incidence of VOD with the Bu Cy regimen could be explained Other 10 (22%) 6 (17%) by enhanced exposure to 4OHCY.7 An interval of o24 h between Bu and cyclophosphamide administration caused lower cyclopho- Stage of tumorb II 2 (5%) 0 sphamide clearance and a higher incidence of VOD. The III 3 (6%) 2 (6%) administration of Bu induces glutathione depletion and inhibition IV 38 (83%) 32 (91%) of hepatic cytochrome activity leading to an increase in Not precised 3 (6%) 1 (3%) 4OHCY.10,11 Preclinical studies compared the myeloablative and c Extension of tumor immunosuppressive effects of Bu–Cy and Cy–Bu in mice. Bone 27 (71%) 20 (63%) Hepatic toxicity was significantly lower in the Cy–Bu group with Bone marrow 26 (68%) 19 (59%) faster bone marrow engraftment.12 The lower liver toxicity of Ganglionic 7 (18%) 10 (31%) Cy–Bu was confirmed, with no impact on long-term engraftment Pulmonary 1 (3%) 5 (16%) 13 Othera 42in the same mouse model. In two clinical studies comparing patients receiving Bu–Cy or Cy–Bu before allogeneic or Initial chemotherapy autologous transplantation for hematological malignancies, Rapid COJEC 17 (37%) 17 (49%) hepatic toxicity was lower in the Cy–Bu group with no impact on engraftment, survival or relapse.8,14 A pharmacodynamic study Follow-up (months) of Bu was conducted in pediatric patients with a solid Median, 95% CI 40.6 (23.0–47.1) 52.6 (24.2–60.6) tumor receiving Bu-containing HDC. The incidence of VOD in – Duration of hospitalization (days) the Bu Mel group was not correlated with systemic exposure to Median, range 27 (21–57) 28 (12–50) Bu unlike that observed in the Bu-Thiotepa group. This finding supported the impact of Mel on the incidence of VOD observed. Veno-occlusive disease (VOD)d The hypothesis was that the glutathione depletion induced when None 30 (65%) 25 (71%) Bu is metabolized by glutathione-S-transferase could sensitize the Grade I 2 (4%) 3 (9%) liver to Mel.15 Grade II 11 (24%) 6 (17%) Contrary to the results expected and previous data with the Grade III 3 (7%) 1 (3%) Bu–Cy combination, no significant difference was observed in VOD prophylaxis terms of liver toxicity, hepatic VOD, hematological toxicity, None 19 (41%) 5 (14%) digestive and mucosal toxicity, infectious complications and EFS. Ursodeoxycholic acid 9 (20%) 17 (48%) Changing the order of drug administration in the Bu–Mel Defibrotide 18 (39%) 13 (37%) combination (Mel–Bu) did not reduce toxicity. Conversely, a slight increase in the incidence of grade II/III VOD was observed by Abbreviations: CI = confidence interval; COJEC = cisplatin, vincristine, car- boplatin, etoposide and cyclophosphamide; INSS = International Neuro- changing the order of drug administration (4-week incidence: 31% blastoma Staging System. aCategories with fewer than five patients. bINSS and 17% for the Mel–Bu and Bu–Mel patients, respectively). and TNM classification for neuroblastoma and Ewing sarcoma, respectively. However, no clear conclusion can be drawn due to the small cMetastatic patients only. dAccording to Bearman criterion. number of patients. These considerations need to be explored through pharmacokinetic studies in Bu–Mel and Mel–Bu patients. Pharmacokinetic studies of both Bu and Mel are required to elucidate the mechanisms of interaction between these two alkylating agents. – the Mel Bu group after resection of an abdominal neuroblastoma. In conclusion, we failed to identify any benefit in changing the In addition, no difference in toxicity was observed between order of administration of Bu and Mel to decrease the toxicity of neuroblastoma and Ewing sarcoma (hazards ratio = 1.2 (95% CI: this effective high-dose regimen. However, a better understanding 0.4–3.5), P-value = 0.8). of the interactions of these two drugs will help to define The median follow-up was 40.6 (95% CI: 23.0–47.1) and preventive strategies enabling the safe use of this HDC in a larger 52.6 months (95% CI: 24.2–60.6) for Mel–Bu and Bu–Mel patients, number of patients.

Bone Marrow Transplantation (2016) 1265 – 1267 © 2016 Macmillan Publishers Limited, part of Springer Nature. Letter to the Editor 1267 acb 100% 100% 100% 90% 90% 90% Bu-Mel 80% 80% 80% 70% Mel-Bu 70% 70% 60% 60% 60% 50% 50% 50% 40% 40% 40% 30% 30% Bu-Mel 30% Bu-Mel 20% 20% 20% Mel-Bu Mel-Bu 10% Days 10% Months 10% Months 0% 0% 0% 0 7 14 21 28 35 42 49 56 63 70 0 6 12 1824 30 36 42 48 54 60 0 6 12 1824 30 36 42 48 54 60 At risk At risk At risk 35 35 35 31 27 25 25 25 25 25 25 35 31 25 19 16 15 14 12 11 7 6 35 31 27 23 20 19 15 14 13 8 7 46 46 44 38 30 29 28 27 26 25 25 46 34 27 26 21 19 15 13 10 9 8 46 34 28 28 23 21 16 13 10 9 8 Figure 1. Incidence of grade II/III VOD (a), EFS (b) and OS (c) for the two HDC combinations. Bu-Mel = busulfan followed by melphalan combination; Mel-Bu = melphalan followed by busulfan combination.

CONFLICT OF INTEREST 5 Ladenstein RL, Poetschger U, Luksch R, Brock P, Castel V, Yaniv I. Final results The authors declare no conflict of interest. from the HR-NBL1/SIOPEN Trial favour Busulphan-Melphalan as Superior Myeloablative Therapy (MAT) for high risk neuroblastoma. Abstract ANR 2012: Advances in Neuroblastoma Research; Toronto, Ontario, Canada, 2012. ACKNOWLEDGEMENTS 6 Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O et al. Primary disseminated multifocal ewing sarcoma: results of the Euro-EWING We are grateful to Lorna Saint Ange for editing. We thank Pierre Fabre Medicament 99 trial. J Clin Oncol 2010; 28: 3284–3291. who provided financial research support for the current study but did not participate 7 Slattery JT, Kalhorn TF, McDonald GB, Lambert K, Buckner CD, Bensinger WI et al. in the conduct of the study or data analyses. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. ME Dourthe1, N Ternès2, D Gajda2, A Paci3, C Dufour1, J Clin Oncol 1996; 14: 1484–1494. E Benhamou2 and D Valteau-Couanet1 8 Cantoni N, Gerull S, Heim D, Halter J, Bucher C, Buser A et al. Order of application 1Gustave Roussy, Université Paris-Saclay, Département de and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT. Bone Marrow Transplant 2011; 46: Cancérologie de l’Enfant et de l’Adolescent, Villejuif, France; – 2 344 349. Gustave Roussy, Université Paris-Saclay, Service de Biostatistique 9 Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A et al. Hepatic et d’Epidémiologie, Villejuif, France and veno-occlusive disease following stem cell transplantation: incidence, clinical 3 Gustave Roussy, Université Paris-Saclay, Service de course, and outcome. Biol Blood Marrow Transplant 2010; 16:157–168. Pharmacologie et d’analyse, Villejuif, France 10 Hassan Z, Hellström-Lindberg E, Alsadi S, Edgren M, Hägglund H, Hassan M. The E-mail: [email protected] effect of modulation of glutathione cellular content on busulphan-induced cytotoxicity on hematopoietic cells in vitro and in vivo. Bone Marrow Transplant 2002; 30:141–147. REFERENCES 11 Hassan M, Ljungman P, Ringdén O, Hassan Z, Oberg G, Nilsson C et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy 1 Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK et al. metabolite: time interval influence on therapeutic efficacy and therapy-related Treatment of high-risk neuroblastoma with intensive chemotherapy, toxicity. Bone Marrow Transplant 2000; 25:915–924. radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. 12 Nilsson C, Forsman J, Hassan Z, Abedi-Valugerdi M, O’Connor C, Concha H et al. Children’s Cancer Group. N Engl J Med 1999; 341: 1165–1173. Effect of altering administration order of busulphan and cyclophosphamide on 2 Oberlin O, Rey A, Desfachelles AS, Philip T, Plantaz D, Schmitt C et al. Impact of the myeloablative and immunosuppressive properties of the conditioning high-dose busulfan plus melphalan as consolidation in metastatic ewing tumors: regimen in mice. Exp Hematol 2005; 33: 380–387. a study by the Société Française des Cancers de l’Enfant. J Clin Oncol 2006; 24: 13 Sadeghi B, Jansson M, Hassan Z, Mints M, Hägglund H, Abedi-Valugerdi M et al. 3997–4002. The effect of administration order of BU and CY on engraftment and toxicity in 3 Hartmann O, Valteau-Couanet D, Vassal G, Lapierre V, Brugières L, Delgado R et al. HSCT mouse model. Bone Marrow Transplant 2008; 41:895–904. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age 14 Kerbauy FR, Tirapelli B, Akabane H, Oliveira JSR. The effect of administration order treated with high-dose chemotherapy and stem cell transplantation: a of BU and CY on toxicity in hematopoietic SCT in humans. Bone Marrow multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 2009; 43:883–885. Transplant 1999; 23: 789–795. 15 Bouligand J, Boland I, Valteau-Couanet D, Deroussent A, Kalifa C, Hartmann O 4 Ladenstein RL, Poetschger U, Luksch R, Brock P, Castel V, Yaniv I et al. Busulphan- et al. In children and adolescents, the pharmacodynamics of high-dose busulfan is melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: results dependent on the second alkylating agent used in the combined regimen from the HR-NBL1/SIOPEN trial. J Clin Oncol 2011; 29: 2011 (suppl; abstract 2). (melphalan or thiotepa). Bone Marrow Transplant 2003; 32:979–986.