Case Report Voriconazole in the Management of Invasive Aspergillosis in Two Patients with Acute Myeloid Leukemia Undergoing Stem Cell Transplantation

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Bone Marrow Transplantation (2002) 30, 967–970  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Case report Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation

D Mattei1, N Mordini1, C Lo Nigro1, D Ghirardo2, MT Ferrua3, M Osenda3, A Gallamini1, A Bacigalupo4 and C Viscoli5

1Hematology Department, S Croce Hospital, Cuneo, Italy; 2Radiology Department, S Croce Hospital, Cuneo, Italy; 3Laboratory Department, S Croce Hospital, Cuneo, Italy; 4Hematology Department, S Martino Hospital, Genoa, Italy; and 5National Cancer Institute, Genoa, Italy

Summary: have also suggested the possible efficacy of oral itraconazole (ITR) and liposomal amphotericin B (L AmB) for this The management of invasive aspergillosis in patients indication.9–11 In any case, even with prophylaxis, the with hematological malignancies remains controversial. relapse rate remains very high (33%), with a mortality rate A major problem is how to manage patients who had among relapsed patients of 88%.12 Therefore, there is a invasive aspergillosis during remission induction and clear need for new strategies for patients undergoing SCT consolidation therapy and then undergo SCT. Indeed who have a history of IA. Voriconazole (VOR) is a new in these patients the mortality rate related to invasive triazole derivative with potent, broad spectrum activity aspergillosis recurrence remains unacceptably high. We against the fungi responsible for opportunistic infections in report two cases of patients who underwent remission immunocompromised patients.13 The clinical efficacy, induction for AML, developed invasive aspergillosis safety and tolerance of VOR have been recently confirmed during antifungal prophylaxis with itraconazole, failed in two large clinical trials in patients with IA.14,15 amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voricona- Patients and methods zole prophylaxis without reactivation of invasive Patient 1 aspergillosis. Bone Marrow Transplantation (2002) 30, 967–970. In July 2000, a 44-year-old male with M4 AML received doi:10.1038/sj.bmt.1703763 induction therapy with hydroxyurea, daunorubicin (DNR), Keywords: acute myeloid leukemia; invasive aspergillo- etoposide (VP16) and cytarabine (Ara-C). Throughout ther- sis; voriconazole; stem cell transplantation apy, he received antifungal prophylaxis with ITR oral sol- ution (300 mg once daily) and was monitored with twice weekly serum ELISA tests for galactomannan (GAL) (BioRad Laboratories, Marnes La Coquette, France) and Invasive aspergillosis (IA) is an important cause of mor- weekly chest computer tomographic (CT) scans for the bidity in patients with AML, being reported in a proportion early detection of IA. On 10 July 2000, since the GAL 1,2 of patients ranging from 5 to 29%. Despite the avail- test had been positive in two consecutive samples, ITR was ability of new diagnostic procedures potentially able to replaced with D AmB (1 mg/kg/day for 21 days, followed 3,4 allow early treatment, the mortality rate remains unac- by L AmB 5 mg/kg/day for renal intolerance). Pulmonary 2,5–6 ceptably high (50–70%). Patients who survive the acute CT scans were sequentially performed: the first was nega- phase are usually successfully managed, due to antifungal tive despite the positive GAL test, but the second revealed treatment and bone marrow recovery. However, the causa- a right apical subpleuric nodule, that subsequently tive agent may remain in the infected tissues and can increased in size and then cavitated. Fine needle lung 7 reactivate following further courses of chemotherapy. biopsy under CT guidance was performed and culture grew Although no large scale prospective study has ever been Aspergillus species, confirming the diagnosis. The patient performed, there is some evidence that intravenous ampho- did not achieve remission and remained on L AmB, with tericin B deoxycholate (D AmB) may be effective as sec- partial clinical response, until September 2000. At this time, 8 ondary prophylaxis in SCT recipients. Scattered reports during salvage anti-leukemic therapy with DNR, high dose Ara-C, and VP16, he had relapsing fever and a new lesion Correspondence: Dr D Mattei, Divisione di Ematologia, Ospedale S Croce, in the right pulmonary apex was detected (Figure 1). L Via Michele Coppino 26, 12100 Cuneo, Italy AmB was discontinued for clinical evidence of failure and Received 13 March 2002; accepted 10 August 2002 VOR was started, first intravenously (6 mg/kg twice daily Voriconazole in the management of invasive aspergillosis D Mattei et al 968 Patient 2 In September 2000, a 57-year-old male with M2 AML received remission induction therapy with the same regimen as described above. He was given the same antifungal prophylaxis and entered the same program of sequential GAL and CT scan monitoring of IA. On 26 September 2000 he started empirical antifungal therapy (first D AmB at 1 mg/kg/day, and then L AmB at 5 mg/kg/day) for per- sistent fever not responding to broad-spectrum antibiotics. Despite this treatment, on 27 September he suddenly presented with severe chest pain and hemoptisis. A chest CT scan showed bilateral nodular lesions (that eventually underwent cavitation) and, on the same day, the GAL ELISA turned out to be positive. A fine needle lung biopsy was attempted but failed for technical reasons. The patient showed partial response to L AmB, with defervescence but Figure 1 Patient 1: Chest CT scan before voriconazole treatment. no improvement in, and even slight enlargement of the pulmonary lesions (Figure 3). For this reason, on 24 October on day 1, then 4 mg/kg twice daily thereafter) and then L AmB was replaced with VOR (i.v. and then orally) at orally (150 mg twice daily). In October 2000, while in par- standard dosage, with clear improvement of the pulmonary tial remission, he underwent related HLA-identical BMT lesions. Following complete leukemia remission after conditioning with TBI 333 cGy once daily on days 1 (November 2000), the patient underwent consolidation to 3 (total dose 999 cGy) and cyclophosphamide (CTX) 60 therapy with ARA-C, DNR and filgrastim, with successful mg/kg once daily i.v. on days 6 and 7 (total dose 120 harvest of PBSC. He was then autografted in January 2001 mg/kg). GVHD prophylaxis consisted of cyclosporin A and after conditioning with busulfan (4 mg/kg p.o. in divided methotrexate. The overall clinical course was uneventful doses daily for 4 days to a total dose 16 mg/kg) and CTX with regard to infectious complications. VOR was adminis- (60 mg/kg once daily i.v. on days 5 and 6 for a total dose tered for a total of 45 days and discontinued at the begin- of 120 mg/kg). Since the CT scan still revealed bilateral ning of November 2000. At this point, the pulmonary CT cavitating lesions, VOR was continued until 13 February, scan was negative for any new lesions, with only one first intravenously and then orally. Throughout prophylaxis, residual micronodule at the right apex (Figure 2). Unfortu- the patient did not experience any major infectious compli- nately, in February 2001 the patient experienced AML cation, the GAL ELISA assays remained negative and the relapse. After additional chemotherapy (two courses of chest CT scan did not reveal any new lesions (Figure 4). fludarabine, Ara-C and mitoxantrone), in April 2001 he The patient is alive and free of both leukemia and IA 1 underwent a second related HLA-identical PBSCT without year after PBSCT. conditioning. New pulmonary lesions were detected on CT scanning, with borderline positive GAL antigenemia. For this reason, on 25 April VOR was restarted and continued Discussion until 28 June 2001. The patient died of refractory leukemia on 20 July 2001, without laboratory, clinical or radiological Patients with a history of IA appear to be at high risk of evidence of relapsed IA. reactivation when undergoing further chemotherapy. This is probably due to the fact that fungal organisms remain

Figure 2 Patient 1: Chest CT scan after voriconazole treatment. Figure 3 Patient 2: Chest CT scan before voriconazole treatment.

Bone Marrow Transplantation Voriconazole in the management of invasive aspergillosis D Mattei et al 969 Indeed, in both cases VOR was well tolerated, with no vis- ual hallucinations and only mild and transient WHO grade II hepatotoxicity in patient 1. This report conﬁrms that IA occurring during the management of AML is not a contraindication to intensive chemotherapy and allogeneic or autologous SCT. If strict diagnostic monitoring is applied and antifungal treatment is promptly initiated, patients can survive the acute phase. Then, if an effective and well-tolerated antifungal treatment is administered pre-emptively for a prolonged period of time, relapse can be successfully pre- vented.

Acknowledgements

Voriconazole was supplied as compassionate treatment by Pfizer Central Research, Sandwich, UK. Figure 4 Patient 2: Chest CT scan after voriconazole treatment. viable in these lesions.16 Whether or not the risk of relapse References depends on the persistence of lesions is a matter of contro- versy. According to Martino et al,16 the risk is lower in 1 Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26: the presence of a complete radiological response, while for 781–805. Offner et al,12 patients may relapse even in the absence of 2 Bow EJ, Loewen R, Cheang MS, Schacter B. Invasive fungal residual lesions. What is universally agreed is that a history disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileu- of IA is not an absolute contraindication to further chemo- 10,17–18 kemic regimen. Clin Infect Dis 1995; 21: 361–369. therapy and SCT. Ideally, patients needing further 3 Maertens J, Verhaegen J, Lagrou K et al. Screening for circul- treatment for leukemia should undergo surgical excision of ating galactomannan as a noninvasive diagnostic tool for the pulmonary lesions, but this is often impossible due to invasive aspergillosis in prolonged neutropenic patients and the impending risk of leukemia relapse or the presence of stem cell transplantation recipients: a prospective validation. multiple, bilateral lesions. In any case, even surgical exci- Blood 2001; 97: 1604–1610. sion does not guarantee complete cure, since aspergillosis is 4 Caillot D, Casanovas O, Bernard A et al. Improved manage- usually a multifocal disease, at least at microscopic level.12 ment of invasive pulmonary aspergillosis in neutropenic Therefore, even if this indication has never been proven in patients using early thoracic computer tomographic scan and large-scale clinical trials, secondary antifungal prophylaxis surgery. J Clin Oncol 1997; 15: 139–147. 5 Pagano L, Girmenia C, Mele L et al. Infections caused by (or pre-emptive therapy) remains the only possible option filamentous fungi in patients with hematological malignancies. in these patients. The drug of choice seems to be AmB (in A report of 391 cases by GIMEMA Infection Program. any formulation), but ITR (alone or in combination) has Haematologica 2001; 86: 862–870. also been used.8–11,17,19–21 The efficacy and safety of VOR 6 Denning DW. Therapeutic outcome in invasive aspergillosis. in acute IA had been recently assessed in two large prospec- Clin Infect Dis 1996; 23: 608–615. tive studies. In a non-comparative, phase II, multicenter 7 Robertson MJ, Larson RA. Recurrent fungal pneumonias in study of 116 patients with IA, Denning et al14 found a patients with acute nonlymphocytic leukemia undergoing mul- response rate of 58% in patients with hematologic disorders tiple courses of intensive chemotherapy. Am J Med 1988; 84: and 26% in allogeneic SCT recipients. In a phase III, ran- 233–239. domized clinical trial of VOR vs D AmB (both followed 8 Karp JE, Burch PA, Merz WG. An approach to intensive anti- leukemia therapy in patients with previous invasive aspergillo- other licensed antifungal therapies) the EORTC and MSG sis. Am J Med 1988; 85: 203–206. study groups found a better 12-week response rate (53% vs 9 Nosari A, Cantoni S, Muti G et al. Itraconazole in leukemic 32%) and a better survival (71% vs 58%) in patients treated patients with invasive aspergillosis: impact on intensive with VOR.15 chemotherapy completion. Eur J Haematol 1994; 53: 183– The present report suggests that VOR may be effective 185. not only as therapy for IA, but also as secondary prophy- 10 Nosari A, Oreste P, Cairoli R et al. Invasive aspergillosis in laxis or pre-emptive therapy and provides the rationale for haematological malignancies: clinical findings and manage- implementing randomized clinical trials for this indication. ment for intensive chemotherapy completion. Am J Hematol Both our patients had proven or probable IA22 and were at 2001; 68: 231–236. high risk of relapse. In light of the long duration of VOR 11 Mele L, Pagano L, Equitani F, Leone G. Case reports. Second- ary prophylaxis with liposomal amphotericin B after invasive administration and the investigational nature of the indi- aspergillosis following treatment for haematological malig- cation, both patients were genotyped for defects in nancy. Mycoses 2001; 44: 201–203. CYP2C19 on the basis of the polymerase chain reaction- 12 Offner F, Cordonnier C, Ljungman P et al. Impact of previous based restriction endonuclease cleavage analysis.23 Both aspergillosis on outcome of bone marrow transplantation. Clin patients were shown to be extensive VOR metabolizers. Infect Dis 1998; 26: 1098–1103.

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