Bone Marrow Transplantation, (1997) 20, 843–846 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 High-dose busulphan/melphalan with autologous stem cell rescue in Ewing’s sarcoma A Atra1, JS Whelan,2 V Calvagna1, AG Shankar1, S Ashley1, V Shepherd1, RL Souhami2 and CR Pinkerton1 1Department of Paediatric Oncology, The Royal Marsden NHS Trust, Sutton; and 2The Meyerstein Institute of Oncology, The Middlesex Hospital, London, UK Summary: Patients and methods Eighteen patients with poor risk Ewing’s sarcoma Eighteen patients were entered into the study. There were (including 11 patients with metastatic disease at nine females. The median age at diagnosis was 14.2 years presentation) received consolidation therapy of busul- (range 2.75–30 years). Primary tumours were of the central phan and melphalan with autologous stem cell rescue. skeleton in 10 cases and long bones in eight cases. Eleven There were nine females. The median age at diagnosis cases were metastatic at initial presentation, 10 with pul- was 14.2 years (range 2.75–30 years). There was one monary disease and one with bone marrow involvement. early death due to cytomegalovirus pneumonitis. One The primary tumour of the metastatic cases was central patient developed a single generalised convulsion during skeleton in six, and long bones in five cases. Six of the busulphan therapy. Severe renal toxicity was not seven non-metastatic patients had bulky primary tumours encountered. One patient developed veno-occlusive dis- (>100 ml) and the seventh patient was in second complete ease of the liver (VOD) which eventually resolved. With remission at the time of high-dose therapy. In total 12 a median follow up of 2 years, 13 patients survive patients were in first complete remission (CR1), four in including six with initial metastatic disease. We con- CR2, one in partial remission (PR) and one with progress- clude that high-dose busulphan/melphalan is well-toler- ive disease (PD) at the time of HDT. The characteristics of ated and should be evaluated for efficacy in a larger these patients including their initial chemotherapy are series of patients with high risk Ewing’s sarcoma. shown in Table 1. Keywords: busulphan/melphalan; high-risk Ewing’s Pretreatment investigations besides clinical evaluation sarcoma; autologous stem cell rescue included radiological assessment (CT scan and/or MRI) of all measurable disease, haematological and biochemical parameters, bone marrow aspirate/trephine and assessment of renal function including glomerular filtration rate. Daily The introduction of combined modality treatment has led measurement of haematological and biochemical para- to a rapid improvement in the prognosis for many patients meters were done from day 1 post-stem cell re-infusion 1–3 with Ewing’s sarcoma. However, the results from indi- until recovery. Informed verbal consent regarding the use vidual centres and cooperative groups have consistently of the drug combination and stem cell harvest procedure identified the inferior prognosis of patients with large vol- was obtained from the parents, or patients, of all cases ume primary tumours and/or metastatic disease.4,5 entered into the study. High-dose chemotherapy with autologous stem cell res- cue (bone marrow and more recently peripheral blood stem cell (PBSC)) is under evaluation in the management of Treatment 6–9 many cancers, particularly haematological malignancies. All patients were treated with busulphan 16 mg/kg (14 Ewing’s sarcoma may be a suitable disease for this strategy patients) or 600 mg/m2 (four patients), orally over 4 days because of its sensitivity to alkylating agents. Several small in 6 hourly divided doses, after 12 h prehydration, from studies have suggested that some patients with poor risk day −5to−2 prior to stem cell re-infusion. This was fol- 10–13 Ewing’s sarcoma may benefit from high-dose therapy. lowed by the intravenous infusion of melphalan at a dose The combination of busulphan/melphalan has been used in of 160 mg/m2 (11 patients) or 140 mg/m2 (six patients) on patients with acute or chronic myeloid leukaemia and other day −1. Cryopreserved autologous stem cells, bone marrow 14–16 solid tumours. This report describes the combined (BM) (seven patients), peripheral blood stem cells (PBSC) experience of two centres using a single regimen, busul- (seven patients) or both (four patients), were infused on the phan and melphalan followed by autologous stem cell following day (DO), at least 48 h after completion of the rescue in patients with Ewing’s sarcoma. busulphan course (Table 2). PBSC were harvested without the use of growth factors Correspondence: Dr A Atra, Department of Paediatric Oncology, The in 11 patients and cyclophosphamide and G-CSF priming Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT in seven patients. PBSC harvests were timed after chemo- Received 22 March 1997; accepted 26 June 1997 therapy for maximum yield (in non-primed patients) and Busulphan/melphalan in Ewing’s sarcoma A Atra et al 844 Table 1 Details of patients and prior treatment Table 2 Type and dose of stem cell rescue Sex Age Site Previous treatment Stem cell MNC 108/kg CFU-GM 104/kg Time of HDT (year) BM 3.09 8.4 CR1 F 15 L iliac bone IVAD × 4; surgery; DXT; BM 2.24 NK CR1 VP/Ifos × 2 BM 2.73 10.6 CR1 + F 16 R iliac bone IVAD × 4; surgery; VP/Ifos BM PBSC 3.06 15.43 CR1 × 2 BM 1.26 17.02 CR1 BM 4.66 36.9 CR1 × M 12 R tibia IVAD 4; surgery; VP/Ifos BM + PBSC 2.65 17.4 CR1 × × 3, IVA 2 BM + PBSC 6.05 7.54 CR1 F 8 R femur IVAD × 4; surgery; VP/Ifos BM 1.6 12.9 CR1 × 3BM+PBSC 5.49 3.08 CR1 M 12.15 L iliac bone, IVAD × 4; surgery; VP/Ifos BM 1.64 10.63 CR1 Scapula and bone × 2; DXT PBSC 4 40.5 CR1 marrow PBSC 3.8 26.9 CR2 PBSC 1.4 28.1 CR2 × × M 16.5 Second and fifth IVAD 4; VP/Ifos 2 PBSC 6.0 NK PR1 metatarsals and No surgery or DXT PBSC 5.4 59.1 PD lungs PBSC 5.6 66.7 CR2 M 9.75 R pubic bone IVAD × 4; surgery; VP/Ifos PBSC NK NK CR2 R lung × 3 M 13.6 Pubic bones IVAD × 4, IVA × 2; DXT; NK = not known; PD = progressive disease. Lungs VP/Ifos × 2, VAC × 2 F 2.75 Cervical (C3) IVAD × 6; VP/Ifos × 2 vertebra No surgery or DXT patients who remain in complete remission, including six F 17.3 Iliac bones, skull, IVAD × 4; VP/Ifos × 3; with metastatic disease (five lungs and one bone marrow) sacrum and lungs CYVAD × 3 at diagnosis (Figure 1). No surgery or DXT Five patients relapsed after high-dose therapy (two pul- M 13 L iliac bone IVAD × 4; DXT, IVA × 2; × monary, two in other bones and one in bone marrow). All VP/Ifos 2 have died except one patient who relapsed in the lung × M 30 R thigh & lungs EVAIA 8; surgery (single lesion) 7 months after busulphan/melphalan. He sur- + + + F 25 R scapula and Epi VCR Cyclo DTIC vived following lobectomy and unilateral whole lung radio- lungs × 3; DXT; EVAIA × 8 therapy and is alive in complete remission 18 months post- F 18 R femur, R lung VAIA × 4; surgery; DXT; pleura EVAIA × 3 high-dose therapy. Neutrophil .0.5 × 109/l occurred at a median of 12 days M 12 R humerus and EVAIA × 8; CbEC × 2; lungs DXT (range, 10–24 days) with a slower platelet recovery .50 × 109/l ranging from 24–52 days post-stem cell rescue. M 14 R pelvis and lung EVAIA × 8; CbEC × 2; DXT One patient experienced a single grand mal convulsion last- F 14 L femur and IVAD × 4; CbEC × 4; DXT ing 5 min during busulphan despite prophylactic phenytoin lungs measured at therapeutic levels, with no sequelae. There was F 9 R femur IVAD × 4; surgery; CbE × one toxic death, at day 51 due to pulmonary haemorrhage 4; DXT secondary to cytomegalovirus infection. Mucositis (WHO grade IV) and diarrhoea (WHO grade II–IV) requiring anal- IVAD = ifosfamide, vincristine, adriamycin; VP/Ifos = gesia were documented, and total parenteral nutrition was etoposide/ifosfamide; IVA = ifosfamide, vincristine, actinomycin; VAC = required in all patients. All patients required at least one vincristine, actinomycin, cyclophosphamide; CYVAD = cyclophospham- ide, vincristine, adriamycin; EVAIA = etoposide, vincristine, actinomycin/adriamycin, ifosfamide; DTIC = dacarbazine; CbEC = car- boplatin and etoposide, cyclophosphamide; DXT = local irradiation. 100 usually performed on two separate occasions to maximise 80 mononuclear cell counts. Phenytoin at a dose 8 mg/kg/day orally in two divided 60 doses was commenced 2 weeks prior to busulphan as prophylaxis against neurotoxicity and continued until 48 h 40 after the last dose of busulphan. No prophylactic antibiotics were used. Only one patient received G-CSF (5 mg/kg/day) + 20 post-stem cell rescue from day 10. % Probability of survival 0 Results 012345678 With a median follow-up of 2 years, (range 2 months–7 Years since bone marrow transplant years) after high-dose therapy there are 13 surviving Figure 1 Survival after bone marrow transplant. Busulphan/melphalan in Ewing’s sarcoma A Atra et al 845 course of systemic antibiotics for episodes of febrile neutro- etoposide with encouraging results as compared to histori- penia with addition of systemic antifungal agents in the cal control groups.18,19 majority of patients. One patient developed clinical and bio- Other nonrandomised studies using high-dose alkylating chemical features of VOD which resolved. Another patient agents ± TBI failed to demonstrate any benefit in poor risk developed haemorrhagic cystitis which continues to recur patients.20 The combination of busulphan/melphalan has but which required no intervention.