Consolidation with a Busulfan-Containing Regimen Followed by Stem Cell Transplantation in Infants with Poor Prognosis Stage 4 Neuroblastoma

Home , Busulfan

Bone Marrow Transplantation (2000) 25, 937–942  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Consolidation with a busulfan-containing regimen followed by stem cell transplantation in infants with poor prognosis stage 4 neuroblastoma

D Valteau-Couanet1, E Benhamou2, G Vassal1, F Stambouli1, V Lapierre3, D Couanet4, J Lumbroso5 and O Hartmann2

1Pediatrics Department, 2Biostatistics Department, 3Hematology Unit, 4Radiology Department, and 5Nuclear Medicine Department Institut Gustave Roussy, Villejuif, France

Summary: usually have a good prognosis2,4,5 although they receive less aggressive treatment than older patients. However, not all Although infants with stage 4 neuroblastoma (NB) usu- of these good prognosis cases fare well. For a long time, ally have a good prognosis, metastatic relapses after 1 the subgroup of children with a poor prognosis could only year of age and amplification of the N-myc oncogene be identified once relapses had occurred. As N-myc ampli- are established poor prognostic factors. In order to fication (NMA) has recently been demonstrated to be a sig- improve the survival of patients with such high-risk fac- nificant indicator of a poor outcome, these less favorable tors, we performed consolidation with a busulfan cases may now be detected and treated more rapidly.6–10 (600 mg/m2)-melphalan (140 mg/m2)-containing regi- Since the mid-1980s we have been developing an intensi- men followed by autologous stem cell transplantation fication strategy in infants with metastatic NB. Adminis- (SCT). From 1986 to 1998, 12 patients were treated tered either after recurrent disease or when N-myc amplifi- according to this strategy. Their median age at diagnosis cation is demonstrated in their tumor, this intensive was 9 months (1–11). Consolidation was performed consolidation therapy consists of a busulfan (Bu)-mel- after a metastatic relapse in five children, because of phalan (Mel)-containing regimen followed by autologous persistent bone metastases in one and as first-line con- stem cell transplantation (SCT) and is similar to the consolidation in six patients whose tumor exhibited N-myc ditioning regimens used in older patients with stage 4 NB. amplification. The 5-year EFS rate is 64.5% (36–85%) Here we present the results of this aggressive consoli- with a median follow-up of 92 months (20–126). One dation strategy applied to very young children. toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. Patients and methods This busulfan-melphalan combination appears to dra- matically improve the prognosis of these high-risk Patients infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high- From 1986 to 1998, 73 children with metastatic NB diag- risk infants and a lower dose of busulfan (480 mg/m2) nosed before 1 year of age were treated in the Pediatrics is recommended in children weighing less than 10 kg. Department of the Institut Gustave Roussy. Among them, Bone Marrow Transplantation (2000) 25, 937–942. 12 received consolidation with a busulfan-melphalan (Bu- Keywords: neuroblastoma; infant; SCT; busulfan Mel)-containing high-dose chemotherapy (HDC) regimen followed by SCT either as a consolidation after treatment of a metastatic relapse or as a first-line consolidation in patients with an NMA tumor. Their median age at the time Neuroblastoma (NB) is the most common solid tumor of the diagnosis and HDC was 9 months (1–11) and 17.5 affecting children under 1 year of age. Twenty percent of (12–35) respectively. There were six boys and six girls. these children have stage 4s disease according to the defi- Their clinical status at diagnosis is detailed in Table 1. Uri- 1 nition proposed by Evans et al in 1971 and 10% have stage nary catecholamines were elevated in all patients. They all 4 disease with, as stipulated in the revised International received conventional chemotherapy either at diagnosis or 2 Neuroblastoma Staging System, either bone marrow at relapse or both, according to the on-going French Society involvement exceeding 10% or radiological evidence of of Paediatric Oncology (SFOP) protocols.5,11,12 Combi- 3 bone metastases. nations of the following drugs were administered: cyclo- Patients with stage 4 NB diagnosed under 1 year of age phosphamide, doxorubicin, vincristine, cisplatinum, etoposide and carboplatin (Table 2). One patient (No. 10) 2 Correspondence: Dr D Valteau-Couanet, Pediatrics Department, Institut received two courses of high-dose thiotepa (600 mg/m ) Gustave Roussy, Rue Camille Desmoulins, 94800 Villejuif, France followed by peripheral blood stem transplantation (PBSCT) Received 16 August 1999; accepted 16 January 2000 before Bu-Mel. In another patient (No. 2), initial treatment Busulfan-consolidation in infants with stage 4 neuroblastoma D Valteau-Couanet et al 938 Table 1 Tumor status at diagnosis

No. Age Stage Primary Liver Bone MIBG Skeletal N-myc (months) tumor metastases marrow skeletal lesions Status (max length) involvement metastases on X-ray

15. 4S suprarenal 7 cm ϩϩϪϪND 2 1 4S suprarenal 6 cm ϩϩND Ϫ ND 3 8 4 suprarenal ϩϪϩϩϩND median 7cm 4 7 4 suprarenal 8 cm ϩϩϩND ND 5 4 4S suprarenal 5 cm ϩϩϩϪNMNA (ϩ ascites) 6 11 4 suprarenal 9 cm ϪϪϩND NMA ϩ median 7 11 4 suprarenal 8 cm ϪϩϪϩNMA 8 10 4 suprarenal 8 cm ϪϩϪϪNMA ϩ median 9 3 4S suprarenal ϩϪϪϪNMA 7.5 cm 10 10 4 suprarenal 8 cm ϪϩϪϪNMA ϩ median 11 11 4 suprarenal 2 cm ϪϪϩϩNMA ϩ median 12 9 4 suprarenal 6 cm ϩϩϩϪNMA

NMA ϭ ampliﬁed; NMNA ϭ nonampliﬁed.

Table 2 Treatment before Bu-Mel-containing high-dose chemo- planned for all tumors. Results were considered reliable therapy only if tumor material contained over 10% of neuroblasts. N-myc genomic content was determined using Southern Initial therapy Chemotherapy at time of blotting with second exon probes. N-myc amplification relapse (NMA) was defined as Ͼ10 copies per haploid genome. 1 10 CO 6 CADO HDC was administered as consolidation therapy, after 2 Liver radiation therapy: 2 CADO treatment of a relapse in five patients whose N-myc status 4.5 gy 2 VP-CP was either unknown (4) or not amplified (1). The bone was 3 8 CADO 3 VP-CP the site of recurrent disease in all of these patients and 4 6 CADO 2 VP-CP lesions were associated with bone marrow involvement in 5 6 CO 2 CADO four. Their median age at the time of relapse was 22 months 2 VP-CP (range 21–30). For the seven remaining patients, HDC was 6 5 CADO given as consolidation therapy immediately after first-line 7 2 CADO (PD) 1 VP-CP, 2 VP CARBO chemotherapy to six patients with an NMA tumor and to 8 2 VP-CARBO one patient with persistent bone metastases in spite of eight 2 CADO courses of conventional chemotherapy. 9 3 VP CARBO 3 CADO 10 4 CADO 2 VP-CP 2 VP-CARBO 2 HD-Thiotepa Treatment regimens 11 2 CADO, 2 VP-CP, 2 VP Carbo 12 2 CADO, 2 VP-CP, 2 The HDC regimen consisted of either a combination of bus- VP Carbo ulfan, cyclophosphamide and melphalan or of busulfan and melphalan. Busulfan was administered orally (37.5 mg/m2 every 6 h) over 4 days. Then cyclophosphamide (2.2 g/m2/day) was infused intravenously over 2 consecutive consisted of radiation therapy to the liver with 1.5 Gy being days. On the last day of the HDC regimen, melphalan (140 delivered in three consecutive sessions. One patient (No. mg/m2) was administered as an i.v. bolus through a central 7) received radiotherapy to the orbit after two courses of venous line. CADO because of disease progression with sight-threaten- In five patients (Nos 5, 6, 7, 11 and 12) who weighed ing lesions. less than 10 kg, the dose of busulfan was reduced to 120 All patients underwent surgical excision of their primary mg/m2/day (total dose: 480 mg/m2) and cyclophosphamide tumor. Response to therapy was assessed according to 1 was administered at a maximum dose of 200 mg/kg in INSS criteria. patients 5 to 7. Since 1990 N-myc oncogene evaluation has been

Bone Marrow Transplantation Busulfan-consolidation in infants with stage 4 neuroblastoma D Valteau-Couanet et al 939 Table 3 Conditioning regimen/tumor status before and after transplantation and current status

No. Conditioning regimen Tumor status at time of HDC Post SCT treatment Current tumor status (months after SCT/diagnosis)

1 BU-CY-MEL 2nd PR Radiotherapy to local relapse DOD 11 m 2 BU-CY-MEL 2nd CR IL-2 Alive in CR 112 mϩ (146 mϩ) 3 BU-CY-MEL 2nd CR 0 Alive in CR 126 mϩ (146 mϩ) 4 BU-CY-MEL 1st PR Surgical excision of residual Alive in CR 124 mϩ (136 mϩ) primary tumor 5 BU-CY-MELa 2nd CR 0 Alive in CR 92 mϩ (108 mϩ) 6 BU-CY-MELa 1st CR 0 DOD 10 m 7 BU-CY-MELa 1st CR 0 DOD 28 m 8 BU-MEL 1st CR Radiotherapy to primary tumor Alive in CR 65 mϩ (71 mϩ) site 9 BU-MEL 1st CR Radiotherapy to primary tumor Alive in CR 59 mϩ (67 mϩ) site 10 BU-MEL 2nd PR / Toxicity-related death 1 m 11 BU-MELa 1st CR Radiotherapy to primary tumor Alive in CR 20 mϩ (26 mϩ) site 12 BU-MELa 1st PR Radiotherapy to primary tumor Alive in CR 14 mϩ (20 mϩ) site aDoses adapted to body weight Ͻ10 kg.

Transplantation procedures intervals.19 Survival curves were compared by the log rank test.20 Hematopoietic stem cell transplantation was performed within 48 h after the end of the melphalan infusion. Auto- logous bone marrow was grafted in nine patients and per- Results ipheral stem cells obtained by leukapheresis in three. Five of the 12 patients received G-CSF after SCT. Survival

Supportive care In May 1999, eight patients were alive in continuous CR. Their median follow-up post diagnosis was 108 months All children were isolated in single laminar air-flow rooms. (20–144) and post HDC and SCT was 92 months (14–126). Standard supportive care was provided, as previously Four patients died in total. Three of them relapsed 7, 11 described.13 During HDC, patients were hydrated with 5% and 13 months post SCT. Two had a metastatic relapse and dextrose and the usual concentrations of electrolytes (3 one, a recurrent primary and metastatic lesions. Of the three l/m2/day). patients, one initially had stage 4S disease and an unknown Prophylaxis against busulfan-related seizures was N-myc status and HDC was administered as consolidation provided with continuous intravenous clonazepam from therapy after a metastatic relapse. The other two had stage the first day of HDC to the day on which the SCT was 4 disease and HDC was administered as consolidation ther- performed.14 apy while they were in first CR because of NMA. One toxicity-related death occurred. Overall, event-free survival Evaluation of toxicity at 5 years is 64% (36–85%) (Figure1). Neutrophil recovery was defined as a blood neutrophil 1.00 count above 0.5 ϫ 109/l and platelet recovery as a blood platelet count above 50 ϫ 109/l without transfusion. Vis- 0.90 ceral toxicity was evaluated according to the criteria 0.80 defined by Bearman et al.15 Hepatic veno-occlusive disease 0.70 16 was defined clinically according to McDonald’s criteria. 0.60 0.50 Post HDC treatment 0.40 Radiation therapy was delivered to the primary tumor in 0.30 five patients (1, 8, 9, 11, 12) and also to residual metastatic 0.20 disease in patient No. 1. Patient No. 2 received interleukin- 0.10 2 after HDC according to a schedule described elsewhere.17 0.00 012345678910 Years Statistical methods At risk 12 866663322

Survival probabilities were estimated by the Kaplan–Meier Figure 1 Post transplantation EFS of the 12 patients consolidated with method.18 Survival curves carry Rothman’s 95% conﬁdence a busulfan-containing regimen.

Bone Marrow Transplantation Busulfan-consolidation in infants with stage 4 neuroblastoma D Valteau-Couanet et al 940 Toxicity presence of bone lesions and of NMA were the two major poor prognostic factors. Sixteen of the 17 patients with All patients experienced profound myelosuppression. The NMA in Lampert’s series died during the study period.7 Ͻ ϫ 9 median duration of neutropenia ( 0.5 10 /l) and throm- These three authors concluded that as NMA appeared to be Ͻ ϫ 9 bocytopenia ( 50 10 /l) was 26 days (range 7–42) and a major indicator of a poor outcome, alternative therapies 46 days (range 36–657), respectively. Patients were given were warranted. In Katzenstein’s series, the 3-year survival a median of five RBC transfusions (range 2–50) and a rate of patients with NMA was 33% (ϩ/Ϫ 27%) vs 91% ( median of 21 platelet transfusions (range 6–99) to counter- ϩ/Ϫ 9%) in patients without NMA (P ϭ 0.005).10 The act anemia and thrombocytopenia. authors concluded that these patients ought to receive mye- All but one patient experienced fever for a median dur- loablative therapy with stem cell rescue as consolidation ation of 8 days (range 1–146). Three patients developed therapy after intensive induction chemotherapy. In Paul’s septicemia related to Staphylococcus epidermidis in two series22 only one out of the seven tumors tested showed cases and to Candida tropicalis in one case. Infection NMA, and it was the patient with this tumor who relapsed resolved easily in the former two cases and completely and died. under amphotericin B therapy in the latter case. Of the 12 patients in the present study, five were treated Two patients experienced a viral infection: pneumonia with HDC after a metastatic relapse that occurred after 1 due to respiratory syncithial virus during aplasia (1) and year of age, and six, with an NMA tumor, were consoli- varicella (1) within the 6 months post-BMT. Both cases dated while in first CR. The last patient had persistent bone resolved under antiviral therapy. metastases after eight courses of conventional chemo- Three cases of severe hemorrhagic cystitis were observed therapy. All these patients had a poor prognosis either among the first patients treated. Although severe and requir- because of their clinical outcome or because of their bio- ing multiple blood transfusions, all recovered without late logical status (NMA). They all received a busulfan–mel- effects. As soon as effective prophylaxis was prescribed phalan–containing regimen followed by SCT. Their 5-year (hourly voiding of the bladder under forced diuresis with EFS rate is 64% (36–85%) and compares favorably with furosemide) during cyclophosphamide administration, this all published data. In Bowman’s study, the 3-year DFS of complication ceased to occur in consecutive patients. patients with an NMA tumor was 20% (0–44.8%); all Gastro-intestinal toxicity was frequent and often severe. but one of the patients with an NMA tumor died in Half of the patients had moderate or severe vomiting. Lampert’s series. Mucositis requiring narcotics (у grade 2) occurred in seven у The benefits of consolidation with HDC appear greater patients (four grade 3) and grade 2 diarrhea in seven (one in these young children than in older patients18 even though grade 3). Two cases of gastro-intestinal hemorrhage were the conditioning regimens were similar.27 That busulfan observed that resolved rapidly without sequelae. Liver tox- plays a major role in the treatment of NB has been demon- icity was a major concern since nine of 12 experienced strated in xenograft models28 as well as in clinical stud- hepatic veno-occlusive disease (HVOD). It was mild in ies.27,29,30 Hartmann et al30 showed that a combination of intensity in three, moderate in three and severe in three. three alkylating agents including busulfan improved the All cases resolved completely except for one in whom it prognosis of poorly responding stage 4 NB in patients over was associated with multi-organ failure. That patient, who 1 year of age. In addition, a multivariate analysis of 218 had previously received two courses of high-dose thiotepa patients with stage 4 NB over 1 year of age demonstrated followed by SCT, died of multi-organ failure. that being younger than 2 years at diagnosis and the presence of a busulfan–melphalan combination in the high-dose conditioning regimen were the two main independent sig- Discussion nificant prognostic factors. The present study shows that such conditioning regimens can indeed improve the sur- During the last decade, HDC followed by autologous bone vival of infants with poor prognosis NB. That NB carries marrow transplantation has been used extensively as con- a better prognosis in children under 2 years of age has solidation therapy in stage 4 NB. A randomized study already been demonstrated by the analysis of the EBMT recently demonstrated that it significantly improved the registry,31 the CCG studies32 and by the series reported by prognosis of NB patients over 1 year of age.21 In contrast, Hartmann et al.27 Although the number of patients in this most patients with stage 4 NB under 1 year of age and latter series is low, the very high DFS emphasizes the prog- stage 4S NB are usually cured with minimal treatment. The nostic significance of a young age at diagnosis. In poor risk 5-year EFS of infants with stage 4 or 4S neuroblastoma patients, consolidation appears to improve the survival rate treated with conventional chemotherapy varies between 60 all the more when patients are young. No relapses have and 85% according to published series.6,8,10,22 Paul et al,22 been observed after 2 years post SCT, which is not usually who obtained a 75% 5-year EFS rate in 24 patients did not the case in children over 1 year of age at diagnosis, since advocate using HDC in these patients. N-myc amplification survivors at 5 years have a DFS rate of only 80%.33 has however been found to be correlated with a poor prog- The toxicity of the regimen used in these young children nosis in NB23–25 and was demonstrated to be the most rel- was very high. Myelotoxicity can now be attenuated by evant adverse prognostic indicator in localized NB.26 In using peripheral stem cell transplantation.34 Liver toxicity Bowman’s series,6 patients with diploid tumors charac- and especially HVOD was the major side-effect. We have terized by an amplified N-myc locus represented a parti- shown that high doses of busulfan and the combination of cularly unfavorable risk group. In Hartmann’s series,8 the three alkylating agents were the major risk factors in the

Bone Marrow Transplantation Busulfan-consolidation in infants with stage 4 neuroblastoma D Valteau-Couanet et al 941 occurrence of HVOD.35 No patient died of this toxicity and 2 Brodeur GM, Pritchard J, Berthold F et al. Revisions of the all recovered completely. The incidence and the severity of International Criteria for Neuroblastoma Diagnosis, Staging this complication could probably be decreased by prophy- and Response to Treatment. J Clin Oncol 1993; 11: 1466– laxis with ursodiol.36 1477. After a busulfan–cyclophosphamide regimen, the inci- 3 Castel Sanchez V, Melero Moreno C, Garcia-Miguel Garcia- Rosados A et al. Stage 4 neuroblastoma en ninos menores de dence of severe HVOD has been related to a high systemic 37 1 ano. Ann Esp Pediatr 1997; 47: 584–590. exposure to busulfan and dose adjustment is currently 4 Evans AE, Chatten GJ, D’Angio GJ et al. A review of 17 IV- investigated by several teams, mainly in the hematological S neuroblastoma patients at the Children’s hospital of Philad- setting, in order to reduce drug-related toxicity. In our insti- elphia. Cancer 1980; 45: 833–839. tution, we did not embark on such a prospective evaluation 5 Labreveux de Cervens C, Hartmann O, Bonnin F et al. What of pharmacokinetically guided dose adjustment of high- is the prognostic value of osteomedullary uptake on MIBG dose busulfan for two major reasons. First, we did not find scan in neuroblastoma patients under 1 year of age? Med Ped a significant correlation between a high systemic exposure Oncol 1994; 22: 107–114. to busulfan and severe liver toxicity in the high-dose 6 Bowman LC, Castelberry RP, Cantor A et al. Genetic staging chemotherapy regimens we have developed for children of unresectable or metastatic neuroblastoma in infants: a Pedi- 38 atric Oncology Group study. J Natl Cancer Inst 1997; 89: with solid tumors. Second, the wide inter- and intra- 373–380. patient variability of busulfan disposition following oral 7 Lampert F, Christiansen H, Terpe HJ et al. Disseminated dosing may be responsible, in part, for the absence of neuroblastomas under 1 year of age: cell biology and prog- pharmacokinetic/pharmacodynamic correlation and will nosis. J Neuro-Oncol 1997; 31: 181–184. greatly jeopardize the accuracy and effectiveness of dose 8 Hartmann O, Rubie H, Coze C et al. Stage 4 neuroblastoma in adjustment.39 We strongly believe that the use of i.v. busul- infants: N-myc amplification (NMA) correlates with adverse fan40,41 will avoid the consequences of oral absorption and outcome. SIOP XXX meeting. Med Ped Oncol 1998; 31: 267 may allow accurate targetting of a maximum tolerated sys- (Abstr. P-41). temic exposure. Appropriate randomized studies will then 9 Matthay KK. Stage 4s neuroblastoma: what makes it special? evaluate the benefit of individual dose adjustment vs the J Clin Oncol 1998; 16: 2003–2006. 10 Katzenstein HM, Bowman L, Brodeur GM et al. Prognostic administration of a fixed dose (corrected for body surface significance of age, MYCN oncogene amplification, tumor cell area) of i.v. busulfan, especially in infants with stage 4 ploidy, and histology in 110 infants with stage D(S) neuroblas- neuroblastoma. toma: the Pediatric Oncology Group experience. A Pediatric The only toxicity-related death occurred in a very heavily Oncology Group study. J Clin Oncol 1998; 16: 2007–2017. pretreated patient who had received two courses of high- 11 Coze C, Hartmann O, Michon J et al. NB 87 induction proto- dose thiotepa before busulfan and melphalan consolidation. col for Stage 4 neuroblastoma in children over 1 year of age: We have recently observed that although rapidly sequenced a report from the French Society of Pediatrics Oncology. 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