Case Report Use of Amifostine As a Chemoprotectant During High-Dose Chemotherapy in Autologous Peripheral Blood Stem Cell Transplantation

Home , Amifostine, Chemoprotective agent

Bone Marrow Transplantation (2000) 26, 1247–1249  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Use of amifostine as a chemoprotectant during high-dose chemotherapy in autologous peripheral blood stem cell transplantation

S Cronin1, JP Uberti2, LJ Ayash2, C Raith1 and V Ratanatharathorn2

1Blood and Marrow Stem Cell Transplantation Program, College of Pharmacy and 2Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

Summary: num-induced nephrotoxicity. Chemically it is ethanethiol,2- [(3-aminopropyl)amino]dihydrogen phosphate ester or This report describes two patients with germ cell WR2721. Developed at the Walter Reed Army Institute of tumors who underwent tandem autologous peripheral Research, amifostine was selected as the best candidate to stem cell transplants. The chemotherapy consisted of protect troops from the myelosuppressive effects of radi- high-dose carboplatin and etoposide. Both patients ation.3 Amifostine is rapidly dephosphorylated by alkaline developed chemotherapy-related toxicities, which phosphatase present on the plasma membrane of the arteri- included nephrotoxicity in one case and febrile neutro- olar endothelium of normal tissues and on the plasma mem- penia, thrombocytopenia, ototoxicity and mucositis in brane of renal proximal tubular epithelium, to form the both. During the second transplant, both patients active metabolite ‘WR-1065’ (containing free thiol).4 Once received amifostine 15 min before and 2 h after each inside the cell, the free thiol moiety can bind and neutralize dose of carboplatin. The patients had less mucositis and reactive species of cisplatin. nephrotoxicity. The duration of neutropenia and throm- In this report, we studied the efficacy of amifostine given bocytopenia was less in both cases resulting in a as a chemoprotectant during conditioning for a second stem decreased use of antibiotics and platelet transfusions. cell graft. Both patients experienced substantial toxicity due These cases suggest that the use of amifostine may be to high-dose carboplatin during the first of two planned of benefit in minimizing toxicities associated with high- consecutive transplants. Sensorineural hearing loss and sev- dose chemotherapy. Bone Marrow Transplantation (2000) ere mucositis were seen in both patients and nephrotoxicity 26, 1247–1249. was seen in one. The preparative regimen for both trans- Keywords: amifostine; WR2721; ethyol; chemoprotect- plants in each patient was identical and consisted of etopo- ant; autologous peripheral blood stem cell transplantation; side 750 mg/m2 and carboplatin 700 mg/m2 administered germ cell tumor intravenously daily over 15 min for 3 consecutive days (day −6 to day −4). Patients received G-CSF-mobilized autologous peripheral blood stem cell transplantation on day 0. G- CSF (Filgrastim; Amgen, Thousand Oaks, CA, USA) 5 The treatment of refractory nonseminomatous germ cell ␮g/kg was given by subcutaneous injection daily starting tumors (NSGCT) involves the administration of high-dose day 6 post transplant until ANC Ͼ1 × 109 cells/l. We chemotherapy with stem cell support. In addition, tandem attempted to minimize the toxicity of the second transplant stem cell transplants have also been used to further dose- by pre-treating with amifostine, an agent known to reduce 1 intensify the chemotherapy. One of the more common pre- cisplatin-associated nephrotoxicity.5 It was reasoned that parative regimens in these tandem transplants involves eto- amifostine may have similar protective effects on carbo- poside and carboplatin. The expected toxicities of this regi- platin-associated neurotoxicity.6 men include myelosuppression, mucositis, neurotoxicity, sensorineural hearing loss, and nephrotoxicity. Although mucositis and myelosuppression are often severe, they are Case 1 usually reversible without significant long-term sequelae.2 However, nephrotoxicity and neurotoxicity from carbo- A 25-year-old male with NSGCT received four cycles of platin are often cumulative and may not be completely cisplatin, etoposide and bleomycin. The patient underwent reversible. surgical resection for residual tumor and was given two Amifostine (Ethyol; Alza, Palo Alto, CA, USA) is a additional cycles of cisplatin and etoposide. Four months chemoprotective agent available for preventing cis-plati- later, a CT scan showed new retroperitoneal disease causing bilateral ureteral obstruction and renal failure (serum creati- Correspondence: Dr V Ratanatharathorn, B1–207 Cancer Center, 1500 E nine of 5.0 mg/dl). Bilateral ureteral stents were placed and Medical Center Drive, Ann Arbor, Michigan 48109, USA the serum creatinine slowly normalized. The patient Received 10 May 2000; accepted 19 July 2000 received the first preparative regimen with stem cell sup- Amifostine use during high-dose chemotherapy S Cronin et al 1248 port. The clinical course was complicated by febrile neutro- Discussion penia, grade IV mucositis, renal failure, and hearing loss. Tumor response was documented by CT scan and normaliz- Persons with testicular germ cell tumor, either refractory ation of tumor markers. Audiometry showed a 20% or in relapse after primary chemotherapy, have a 5-year reduction in the right ear and 16% in the left ear from the progression-free survival of less than 25% after salvage baseline. For the second transplant, amifostine was admin- therapy.7,8 To improve prognosis, patients often receive istered (500 mg in 50 ml of normal saline over 15 min) 15 high-dose platinum-based chemotherapy with autologous min before each dose of carboplatin and 2 h after com- stem cell support. Investigators at Indiana University have pletion of each daily infusion of carboplatin. This transplant pioneered the use of tandem high-dose chemotherapy was associated with febrile neutropenia and grade III muco- cycles with etoposide and carboplatin, followed by autolog- sitis but no significant nephrotoxicity. The severity of ous stem cell support after each cycle.1 While many mucositis was significantly reduced in the second transplant patients have been cured with this approach, substantial and required 5 days of a morphine drip (at a dose of 0.75 morbidities including peripheral neuropathy, sensorineural mg/h) compared with 11 days in the first transplant at a hearing loss, mucositis, sepsis, renal and hepatic insuf- higher dose (4 mg/h). There was no further impairment of ficiency have been observed. hearing after the second transplant. There was no hypoten- For these two patients treated with high-dose carboplatin sion, nausea or emesis associated with the administration and tandem transplants, amifostine appeared to attenuate of the amifostine. toxicities seen during the first transplant. There was less- ened nephrotoxicity when amifostine was used as a chemoprotectant in one patient. In both cases, there was a decrease Case 2 in the severity and duration of mucositis, a shorter duration of platelet transfusion dependency, and a decrease in the A 33-year-old male with NSGCT tumor originally number of days on antibiotics (Table 1). It is less clear presented with an enlarged testicle, an ␣-fetoprotein of whether amifostine protected against neurotoxicity, 19409 ng/ml (normal, Ͻ10 ng/ml) and a ␤-HCG of 677 although the lack of progressive hearing loss may be mIU/ml (normal, 0–5 mIU/ml). CT scan revealed pulmon- indicative of its protective effect. ary, hepatic and retroperitoneal metastases. The patient was Several investigators suggest that amifostine has a broad initially treated with cisplatin, etoposide and bleomycin for spectrum of chemoprotective activity with amelioration of four cycles with a partial response. A left orchiectomy was myelotoxicity, nephrotoxicity, esophagitis, xerostomia, and performed followed by one course of vinblastine, ifosfam- oral mucositis.6 The largest published study involved 242 ide and cisplatin. His disease progressed despite salvage women with advanced ovarian cancer, randomized to therapy. The patient then underwent tandem transplants. receive six cycles of cyclophosphamide 1000 mg/m2 and The first transplant was complicated by fever with neutro- cisplatin 100 mg/m2 with or without amifostine dose of penia, grade IV mucositis, peripheral neuropathy, tinnitus, 910 mg/m2.9 The authors concluded that pretreatment with and hearing loss. The second transplant which included pre- amifostine reduces the cumulative hematological, renal, and treatment with amifostine was complicated by a spon- neurological toxicities without reduction in antitumor taneous pneumothorax, presumably from tumor necrosis. efficacy. Despite the pain associated with the thoracostomy tube, the We elected to treat each patient with a fixed dose of 1000 patient required 1 day less of parenteral analgesia than for mg of amifostine for each of the 3 days of chemotherapy the first transplant. Both the severity and duration of muco- treatment. Amifostine was administered in two divided sitis was reduced with the use of amifostine. Sensorineural doses of 500 mg each given 15 min before and 2 h after hearing decreased 33% in the right ear and 50% in the left carboplatin infusion. We reasoned that amifostine blood after the first transplant but remained unchanged after the levels might not be maintained long enough on a once daily second transplant. There were no side-effects associated schedule to cover the long half-life of high-dose carbopla- with the administration of the amifostine. tin, which might be further prolonged with concomitant

Table 1 Clinical and laboratory parameters

Case 1 Case 2

1st APBSCT 2nd APBSCT 1st APBSCT 2nd APBSCT

CD34 cell dose (× 106 cells/kg) 2.65 2.65 2.0 2.0 Days to ANC Ͼ0.5 × 109/l 10 8 9 10 Days to platelets Ͼ20 × 109/l 23 16 13 10 Days with fever and neutropenia 8 2 1 2 Days receiving antibiotics 10 5 10 4 Days with mucositis 17 10 15 11 Serum creatinine (mg/dl) baseline, peak and at discharge 1.4, 2.6, 1.4 1.0, 1.2, 0.8 0.8, 0.8, 0.6 0.8, 0.8, 0.7

APBSCT = autologous peripheral blood stem cell transplantation.

Bone Marrow Transplantation Amifostine use during high-dose chemotherapy S Cronin et al 1249 administration of amifostine.10 The dose schedule of ami- study of high-dose carboplatin and etoposide with autologous fostine described in our patients appeared to be efﬁcacious marrow support in patients with recurrent and refractory germ in attenuating the toxicities of carboplatin. Furthermore, cell tumors. Bone Marrow Transplant 1995; 16: 353–358. there were no toxicities attributed to amifostine. 3 Capizzi RL. Clinical status and optimal use of amifostine. A theoretical concern about the use of amifostine is the Oncology 1999; 13: 47–59. 4 Markman M. Amifostine in reducing cisplatin toxicity. Semin possibility of tumor protection. In the previously mentioned Oncol 1998; 25: 522–524. study in advanced ovarian cancer, there was no difference 5 Capizzi RL. Amifostine reduces the incidence of cumulative 11 in survival in the patients treated with amifostine. nephrotoxicity from cisplatin: laboratory and clinical aspects. We report the use of amifostine as pretreatment prior to Semin Oncol 1999; 26: 72–81. high-dose carboplatin in two patients with NSGCT 6 Alberts DS, Bleyer WA. Future development of amifostine in undergoing peripheral stem cell transplant, and conclude cancer treatment. Semin Oncol 1996; 23 (Suppl. 8): 90–99. that this agent may protect against chemotherapy-induced 7 Loehrer PJ Sr, Gonin R, Nichols CR et al. Vinblastine plus toxicity. Further study of amifostine in patients receiving ifosfamide plus cisplatin as initial salvage therapy in recurrent high-dose carboplatin in autologous stem cell transplant germ cell tumor. J Clin Oncol 1998; 16: 2500–2504. setting is warranted. 8 Motzer RJ, Cooper K, Geller NL et al. The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors. Cancer 1990; 66: 2476–2481. References 9 Kemp G, Rose P, Lurain J et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin- induced toxicities: results of a randomized control trial in 1 Broun ER, Nichols CR, Gize G et al. Tandem high dose patients with advanced ovarian cancer. J Clin Oncol 1996; 14: chemotherapy with autologous bone marrow transplantation 2101–2112. for initial relapse of testicular germ cell cancer. Cancer 1997; 10 Korst AE, van der Sterre ML, Eeltink CM et al. Pharmacoki- 79: 1605–1610. netics of carboplatin with and without amifostine in patients 2 Broun ER, Nichols CR, Mandanas R et al. Dose escalation with solid tumors. Clin Cancer Res 1997; 3: 697–703.

Bone Marrow Transplantation