Foscarnet Prophylaxis of Cytomegalovirus Infections in Patients Undergoing Allogeneic Bone Marrow Transplantation (BMT): a Dose-ﬁnding Study

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Bone Marrow Transplantation (2000) 26, 23–29  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-ﬁnding study

S Bregante, S Bertilson, E Tedone, MT Van Lint, G Trespi, N Mordini, G Berisso, F Gualandi, T Lamparelli, O Figari, F Benvenuto, AM Raiola and A Bacigalupo

Dipartimento di Ematologia, Ospedale San Martino, Genova, Italy

Summary: Keywords: cytomegalovirus; foscarnet; bone marrow transplantation This is a dose-finding study using foscarnet for CMV prophylaxis after allogeneic bone marrow transplantation (BMT) in 20 high risk patients (unrelated donors, or T cell depleted, and/or advanced disease). Foscarnet Cytomegalovirus (CMV) infection is a major cause of mor- was started on day ؉1 after BMT and continued until bidity and mortality in allogeneic bone marrow transplant day ؉100. We explored four different dose levels, recipients (BMT).1 Major risk factors for CMV pneumonia patients being entered at the lowest dose level until one include: acute graft-versus-host disease (GVHD), allo- patient experiences CMV-reactivation, identified as two geneic vs syngeneic or autologous transplantation, increas- consecutive positive CMV antigenemias (CMVAg- ing patient age, use of total body irradiation and multiple emia). The four dose levels expressed as mg/kg/day agents in the pretransplant conditioning regimen.2–4 There between days 1 and 30 (induction) and between days 31 are two approaches for the prevention of CMV disease: the first is pre-emptive treatment of CMV infection, on the ؍ and 100 (maintenance) were respectively: dose level I dose level basis of CMVAg-emia5–8 positive blood CMV-PCR9–12 or ;(4 ؍ n) 60/120 ؍ dose level II ;(5 ؍ n) 60/30 positive broncho-alveolar lavage.13–15 The second option is ؍ n) 120/120 ؍ and dose level IV (5 ؍ n) 90/120 ؍ III All patients showed engraftment: PMN Ն0.5 ؋ 109/l CMV prophylaxis with agents such as gancyclovir16,17 or .(6 at a median interval of 16, 21, 17, 15 days after BMT, foscarnet.18–20 and Plt у30 ؋ 109/l on days 19, 16, 17, 17 respectively. Prophylaxis is probably necessary in patients at high risk CMVAg-emia was seen in 10 patients at a median inter- of developing CMV infections: namely those receiving T val of 53 days post-BMT (range 33–89) with a median cell-depleted grafts, and transplants from unrelated or of 10 CMV antigen؉ cells (range 1–16). There was a mismatched donors.18,19 dose effect of foscarnet on CMVAg-emia: respectively Prophylactic ganciclovir has been shown to be effective 4/5 patients (80%), 2/4 (50%), 3/5 (60%) and 1/6 (18%) in preventing CMV disease in two randomized studies.16,17 ,CMV disease was However, it did not improve the outcome of the transplant .(0.1 ؍ at dose levels I, II, III, IV (P seen in 3/9 (33%) at dose levels I, II and 0/11 at dose and survival was comparable in patients receiving placebo. -The median number of CMV This is due to the myelotoxicity and neutropenia in gan .(0.07 ؍ levels III, IV (P antigen-positive cells at diagnosis of CMV infection was ciclovir-treated patients. Foscarnet (trisodium phosphono- different: 13 in dose levels I–II and two in dose levels formate) is a synthetic antiviral drug with activity against Increased creatininine was seen in 15 all known human herpes viruses, including CMV.20 It is .(0.01 ؍ III–IV (P patients with a mean of 1.8 mg% (range 1.5–5.7) and registered in a number of countries for the treatment of was the cause of discontinuation in nine patients (45%). CMV retinitis in AIDS patients. There is some experience Renal toxicity was reversible in all nine patients. Overall of foscarnet treatment in CMV gastrointestinal disease in actuarial TRM at 2 years was 31%: 47% for patients AIDS patients and it has also been used to treat CMV dis- at dose levels I–II and 19% for patients at dose levels ease in transplant recipients.21–23 An advantage of foscarnet III–IV. In conclusion, foscarnet exhibits a dose-depen- is the lack of myelotoxicity and its activity against gan- dent prophylactic effect on CMVAg-emia, CMV disease ciclovir-resistant CMV. The most frequently reported and transplant-related mortality with acceptable and adverse events in connection with foscarnet are changes reversible renal toxicity. Bone Marrow Transplantation in serum levels of calcium, magnesium and phosphate and (2000) 26, 23–29. decreased renal function. Prehydration with intravenous saline reduces the risk of nephrotoxicity.24 In a previous study we have shown that foscarnet can prevent CMV infections in patients receiving T cell- 18 Correspondence: Dr A Bacigalupo, Divisione Ematologia 2, Ospedale San depleted grafts. We are now reporting a dose-finding Martino, 16132 Genova, Italy study for CMV prophylaxis, designed to test: (a) safety and Received 21 July 1999; accepted 2 March 2000 tolerability of foscarnet; (b) efficacy in preventing CMV Foscarnet prophylaxis of CMV infection S Bregante et al 24 disease; and (c) influence of foscarnet prophylaxis on Patient description engraftment kinetics. Patients clinical data are outlined in Table 1.

Therapy and drug handling Patients and methods Foscarnet: Solution for infusion 2.4% (24 mg/ml) from Objectives and study design Astra Arcus AB, Sodertalje, Sweden. This was a prospective, open, single center study. The pri- Hydration: Before the first infusion of foscarnet, and con- mary objective was to find a dose of foscarnet which was current with each subsequent foscarnet infusion, normal safe and tolerable as CMV prophylaxis for BMT patients. saline (0.9% NaCl) was infused. The secondary objectives were to study the efficacy of foscarnet prophylaxis in preventing CMV disease and the Treatment plan influence on engraftment kinetics. Four different dose levels were studied. Patients were Initially patients received one infusion at a constant rate entered at the lowest dose level until one patient experi- (over 1 h) of 30 mg foscarnet/kg every 12 h. If 10 patients enced CMV-reactivation, as identified by two consecutive tolerated foscarnet at 30 mg/kg twice a day and did not positive CMV-antigenemia tests. If none of the patients on develop CMV antigenemia within day 100, the study would the low-dose experienced severe toxicity, the subsequent close. If one patient experienced CMVAgemia, he would patient was then entered on a higher dose level. At termin- complete the course, but the next patient would receive fos- ation of the study none of 10 patients had developed CMV carnet at the high dose level. We explored four different antigenemia, at a given dose. dose levels (Table 2). The 30 mg/kg and the 60 mg/kg infusions were given over 1 h and the 90 mg/kg dose over 2 h. Starting 1 h before the first administration and concur- Induction and maintenance treatment rent with each infusion, a normovolemic patient received Daily intravenous (i.v.) treatment from day ϩ1 until day 750 ml of normal saline. Dehydrated patients received ϩ30 was considered induction, whereas 5 days/week from additional fluid until fully rehydrated. If a peripheral vein day 31 until day ϩ100, was considered maintenance. The was used for infusion, the foscarnet solution was diluted to patients were followed daily for adverse events and clinical 1.2% (12 mg/ml) by adding an equal volume of normal symptoms (Tables 1 and 2). Venous blood samples were saline or 5% glucose. obtained twice weekly from study start to day 30 and there- If renal function deteriorated during treatment with fos- after weekly up to day 100. Hematology and clinical chem- carnet, dose adjustments were made as in Table 3. istry were assessed in these samples for evidence of engraftment and safety of the prophylaxis. Weekly assess- Toxicity ments of CMV IgG, IgM and pp65-antigenemia were per- formed. Samples for assessment of foscarnet peak and If one of three patients at a particular dose level experi- trough levels were obtained on three occasions during treat- enced toxicity of grade 3 or above, believed to be due to ment in patients receiving the lowest dose of foscarnet, and foscarnet, three additional patients would be entered at this saved frozen for later analysis. Samples for assessment of dose level. If two of six patients experienced severe tox- foscarnet levels were also obtained if drug toxicity was icity, no further patients would be enrolled until data had suspected. been reviewed and there was a mutual agreement between the investigator and Astra that it was safe to continue the study. Inclusion criteria for the study These were (1) recipients of an allogeneic BMT; (2) CMV seropositivity (seropositivity being defined as Ͼ23 units by Table 1 Clinical data of patients who entered the trial according to the dose level of foscarnet prophylaxis EIA); (3) high risk of CMV infection post transplant (patients receiving T cell-depleted grafts, and/or unrelated Dose level I II III IV donor transplants and/or patients with advanced disease); (4) total/ionized calcium, magnesium and phosphorus con- Induction period mg/kg/day 60 120 120 120 centrations within normal reference range; (5) age range 18 Maintenance period mg/kg/day 30 60 90 120 to 55 years; and (6) signed informed consent. Number of patients 5 4 5 6 Patient’s age (median) 42 37.5 42 36 No. patients with disease Ͼ1CR2323 Interval diagnosis–transplant in 396 268 298 939 Exclusion criteria for the study days (median) Donor age (median) 46 35 40 39 Exclusion criteria were (a) baseline estimated creatinine HLA ϭ sibling, unmanipulated 3 2 3 2 clearance Ͻ60 ml/min; (b) known hypersensitivity to fos- HLA ϭ sibling T cell-depleted 1 1 0 0 carnet; (c) pregnant or nursing women; and (d) previous Unrelated donor 1 1 2 4 inclusion in this study.

Bone Marrow Transplantation Foscarnet prophylaxis of CMV infection S Bregante et al 25 Table 2 Dose levels

Treatment group Dose level Dose level Dose level Dose level I II III IV

Induction therapy 30 mg/kg 60 mg/kg 60 mg/kg 60 mg/kg Days 1–30 bid bid bid bid Maintenance 30 mg/kg 60 mg/kg 90 mg/kg 120 mg/kg Days 31–100 5 days/week 5 days/week 5 days/week 5 days/week bid ϭ twice a day.

Table 3 Dose adjustments in the event of renal function deterioration tion dose (day 1–30), the median percentage of the planned dose for the induction period was 94% (79–103%) for dose Estimated creatinine Foscarnet dose mg/kg level I (30 mg/kg ϫ 2/day), and 84.9% (64–96%) for dose clearance level II, III, IV (60 mg/kg ϫ 2/day) (Figure 1). Mainte- Low Medium High nance dose (day 31–100), the median percentage of foscarnet administered was as follows: 88% (65–103%), 84% Ͼ90 30 60 90 (64–97%), 71% (61–79%), 60% (31–84%) for dose I, II, 70–90 23 47 70 50–70 17 33 50 III and IV respectively (Figure 1). 30–50 10 20 30 Concomitant treatment Potential nephrotoxic drugs administered during the study Concomitant treatment period were as follows: amikacin and/or gentamycin, and/or Treatment with ganciclovir was prohibited during the study nethilmicin and/or tobramycin in 17/20 patients, vancomy- period. Patients received prophylactic i.v. immunoglobulin cin and/or teicoplanin in 16/20 patients, amphotericin B in 400 mg/kg once a week during the study period. Patients 12/20 patients, ceftazidime in 17/20 patients, cyclosporin also received prophylactic pefloxacin and fluconazole p.o. in 14/20 patients. Patients received conditioning therapy before transplantation, including total body irradiation (750–990 rads) and cyclophosphamide 60 mg/kg ϫ 2. Safety The 20 patients enrolled in this study were all eligible for Statistical analysis analysis of safety. Baseline characteristics of the patients ϫ are described on Table 1. Other parameters of safety The Fisher test was used for 2 2 tables; the rank sum included. Mann–Whitney test was used for differences between con- tinuous variables. Kaplan–Meier plots were used to calcu- late the actuarial transplant-related mortality (TRM). Clinical examinations Blood pressure and pulse rate: The following definitions Results are valid: hypotension ϭ systolic blood pressure р90 mm Hg; hypertension ϭ diastolic blood pressure Ͼ90 mm Hg Compliance, duration of treatment, treatment on two consecutive occasions; tachycardia ϭ pulse Ͼ100 discontinuation bpm on more than two occasions. There were two patients with treatment-dependent hypotension and one patient with Thirteen of 20 patients stopped study medication prema- hypertension; tachycardia was recorded in one patient with turely: (Table 4) two cases stopped foscarnet because of hypotension and in an additional nine patients. deterioration of their underlying disease (both patients were in group IV); six patients stopped foscarnet because of CMV reactivation, (three in group I, one in group II, two Body weight: Eighteen of 20 patients experienced weight in group III). Five patients stopped the drug because of reduction, ranging from 1.5% to 20% of initial body renal impairment: of these, two discontinued the drug tem- weight, and in one patient this did not change during the porarily and then recommenced, whereas three did not start study period; in one patient it increased to 10% at treatment foscarnet again owing to early death (n ϭ 1) or medical termination in association with abnormal renal function. decision (n ϭ 2) (one because of renal impairment due to myeloma, and one restarted the protocol, but only 3 Body temperature: Seven of 20 patients had у38°C on two days/week, due to persisting renal problems). occasions or more. In one of these fever was also reported We calculated the actual dose of foscarnet which could as an adverse event, in two patients it occurred in associ- be administered, compared with the planned dose and ation with bacterial infection and in one patient fever expressed it as a percentage (%) of the planned dose: Induc- appeared closely associated with graft-versus-host disease.

Bone Marrow Transplantation Foscarnet prophylaxis of CMV infection S Bregante et al 26 Table 4 CMV antigenemia, foscarnet treatment duration and transplant-related mortality (TRM)

Dose level No. Last day of First day of Last day of CMV TRM group patients CMV negative CMV positivity foscarnet disease Y/N treatment During After foscarnet foscarnet

I 1 48 53 53 IP N induction 2 96 98 Y 60 mg/kg 3 28 39 7 N maintenance 4 27 33 35 IP Y 30 mg/kg 5 61 69 96 Y II induction 6 66 70 70 N 120 mg/kg 7 93 100 N maintenance 8 21 33 18 IP Y 60 mg/kg 9 97 100 N III 10 53 46 N induction 11 33 38 53 N 120 mg/kg 12 57 68 99 N maintenance 13 95 98 N 90 mg/kg 14 46 53 80 N IV 15 104 100 N induction 16 53 49 N 120 mg/kg 17 80 73 Y maintenance 18 38 55 33 N 120 mg/kg 19 104 100 N 20 12 11 Y

Table 5 Treatment-related adverse events reported in more than one patient

System organ class Adverse event (preferred term) Intensity Number of patients (%) n ϭ 20 Mild Moderate Severe

Liver and biliary disorders Bilirubinemia 2 2 (10.0) Metabolic and nutritional disorders Nonprotein nitrogen increaseda 1 7 3 11 (55.0) Urinary tract disorders Hematuria 1 3 4 (20.0) Renal failure NOS 2 2 (10.0) Renal function abnormal 1 1 2 (10.0) General Fever 4 4 (20.0) Reduced physical ﬁtness 1 1 2 (10.0) Disorders of immune resistance Infection bacterial 3 1 4 (20.0) Graft-versus-host reaction 3 1 4 (20.0)

aCreatinine serum increased.

Laboratory tests Renal function tests: Treatment-related increases in serum levels of creatinine and BUN were recorded in 15 patients Liver and renal function, electrolytes, albumin, creatinine, (75%). Increased BUN was also recorded in another three hematology variables and urinalyses were continuously fol- patients. In only two patients was there no treatment-related lowed in all patients. deterioration in renal function. An increased serum creatinine was reported as an adverse event in 10 of the 15 patients Liver function tests: Treatment-related abnormalities in where creatinine levels were raised above the upper refer- one or more liver function tests including alanine amino- ence limit. There was one additional report of a raised transferase (ALAT), aspartate aminotransferase (ASAT), serum creatinine, but in this patient the creatinine level was alkaline phosphatase (ALP) and bilirubin were recorded in not increased above the upper reference limit. 19 (95%) of patients. Increases in ALAT and AST and decreases in ALP were the most frequently recorded abnormalities; the only reported adverse events were increased Electrolytes: All patients experienced treatment-related bilirubins in two patients (Table 5). One of these died abnormalities in one or more of the electrolytes. Most fre- before the bilirubin value was followed up, and in the other quently seen were hyperphosphatemia, hypomagnesemia, patients the value had not normalized at follow-up. hyponatremia and hypokalemia. Hyperkalemia and hypo-

Bone Marrow Transplantation Foscarnet prophylaxis of CMV infection S Bregante et al 27 100 93.9 Treatment discontinuation: Thirteen of 20 patients stopped 87.9 90 84.9 84.1 84.9 84.9 the study medication prematurely, two because of deterio- 80 71.2 ration in the underlying disease and six because of CMV 70 60.8 reactivation. Five patients had renal impairment: four reco- 60 vered their renal function, and one died of acute GVHD 50 within 15 days of discontinuation of foscarnet. Seven 40 patients completed the planned prophylaxis up to day 100

% of planned 30 post BMT without reactivation of CMV. 20 10

Administered dose of Foscarnet Efficacy 0 Dose level I Dose level II Dose level III Dose level IV CMV antigenemia: There were no patients with CMV antigenemia during the induction period (0–30) and 10 with induction maintenance CMV antigenemia in the maintenance period (days 31– Figure 1 Administered dose of foscarnet expressed in percentage (%) 100), at a median interval of 53 days (range 33–89) (Table planned/administered on days 1–30 (induction) and on 31–100 4), with a median of 10 CMV antigen positive cells (range (maintenance). The four dose levels expressed as mg/kg/day between days 1–16). We saw CMV antigenemia in 4/5 patients at dose 1–30 (induction) and between days 31–100 (maintenance) were respectively: dose level I, 60/30 (n ϭ 5 patients); dose level II, 120/60 (n ϭ 4 levels I and 2/4 patients at dose levels II, 3/5 patients at patients); dose level III, 120/90 (n ϭ 5 patients) and dose level IV, dose levels III and 1/6 patients at dose level IV. Of these, 120/120 (n ϭ 6 patients). four in group I, II and three in group III, IV occurred during treatment with foscarnet and two and one, respectively, after foscarnet was discontinued (Figure 2). calcemias possibly/probably related to foscarnet sodium, whereas the hypernatremia was assessed as unlikely to be related to foscarnet treatment. Renal dysfunction was CMV disease: CMV disease occurred in 3/8 patients (37%) concomitantly reported in these patients. at dose level I and II, and 0/12 at dose levels III and IV (P ϭ 0.07) (Figure 2). Albumin: Seven patients experienced reductions below the lower reference limit, probably due to the underlying dis- Engraftment: There was no influence on white blood cells ease, but considered to be of negligible significance. engraftment: in the first group the median of the day of engraftment was 16 (11–18), in the second group 22 (11– Creatinine kinase: Increased levels were not recorded for 23), in the third 16 (14–21), in the fourth 15 (13–18). any patient. Transplant-related mortality (TRM): In groups I, II 4/9 Hematology: There were no reports of adverse hematolo- patients died on days ϩ344 (hepatitis), ϩ107 (CMV gical events due to foscarnet. All patients experienced treat- pneumonia), ϩ80 (acute GVHD) and ϩ53 (multiorgan ment-related decreased platelet counts, leukocyte counts failure). Three of these had developed CMV antigenemia. and hemoglobin levels due to the underlying hematological In groups III, IV, 2/11 patients died on days ϩ95 (aGVHD) disease and the conditioning therapy. and ϩ30 (aGVHD). The overall actuarial 1 year TRM is 31%: it is 47% vs 18% for patients in group I, II and III, Urinalysis: Urine samples from 12/20 patients were ana- IV respectively (P ϭ 0.1) (Figure 3). lyzed for presence of albumin, glucose and erythrocytes using qualitative methods. Erythrocytes appeared in the urine of seven patients, albumin and glucose in one, 100 albumin only in one and glucose in three patients. 90 80 CMVAg-emia CMV disease 80 Adverse events 70 60 Nine patients experienced serious adverse events which 60 constituted a definite hazard or handicap including death, 50 permanent or severe disability or inpatient hospitalization. 40 40 Five patients had reversible renal failure with complete 40 % of patients recovery, one patient had hematuria (complete recovery), 30 25 one hypertension and cerebral hemorrhage, and two general 20 16 physical impairment. The following adverse events were 10 reported in more than one patient: anxiety, depression, 0 0 0 vomiting, hematemesis, melena, ulcerative stomatitis, BUN Dose level I Dose level II Dose level Dose level increase, glycosuria, hyperkalemia, hypernatremia, hypo- III IV calcemia, weight increase, hypertriglyceridemia, hyperten- Figure 2 Proportion of patients (%) experiencing CMV antigenemia and sion, cardiac failure, vasodilatation, coughing, pulmonary CMV disease, according to the dose of foscarnet administered. Dose levels edema, respiratory insufficiency, anuria, pain. I–IV, see Figure 1 and text.

Bone Marrow Transplantation Foscarnet prophylaxis of CMV infection S Bregante et al 28 100 six reactivations in nine patients (66%) at dose levels I and 90 II, and four reactivations in 11 patients (36%) at dose levels

80 III and IV. CMV disease was seen in 3/9 patients (33%) A = Dose level III: No. patients 9 47% at dose levels I and II and 0/11 at dose levels III and IV. 70 B = Dose level IIIIV: No. patients 11 18% The median number of CMV antigen positive cells was also 60 different: 13 at dose levels I and II and two at dose levels A ϭ 50 III–IV (P 0.01). Therefore, increasing the dose of foscarnet reduces the % of TRM 40 incidence and severity of CMV antigenemia and this has P = 0.1 30 an impact on transplant-related mortality: TRM was 47% 20 B at dose levels I and II and 18% at dose levels III and IV. If one considers that the eligibility for this study called for 10 either T cell depletion, or an unrelated donor, or advanced 0 disease and that eight patients had at least two of these 6121824adverse factors, an overall actuarial TRM of 31% at 1 year Months from BMT is low, and the 18% mortality at dose levels III and IV is Figure 3 The effect of prophylactic foscarnet dose on transplant-related very encouraging. Only one patient died of CMV pneumo- mortality (TRM): A ϭ dose level I–II, B ϭ dose level III–IV. nitis at dose levels I and II. We are currently using dose level III, with a reduction during the induction phase (day Discussion ϩ1/ϩ30): 30 mg/kg twice daily from day Ϫ7 to day ϩ30 and 90 mg/kg/day 5 days a week from day ϩ31 to day This study suggests that (1) foscarnet causes dose-related ϩ100.25 reversible renal toxicity; (2) foscarnet can be used from day In conclusion, this study shows that foscarnet can be ϩ1 after allogeneic BMT without interfering with hemopo- used successfully, with appropriate dosing, in the preven- ietic engraftment; (3) there is a dose-related prophylactic tion of CMV antigenemia after allogeneic BMT. The dose effect of foscarnet on CMV antigenemia and CMV disease of foscarnet administered has an impact on CMV reacti- with associated reduction of transplant-related mortality. vation. It remains to be determined whether improved sur- Adverse events are of primary concern when drugs are vival will also result, when foscarnet prophylaxis is used prophylactically, and renal toxicity has been reported compared to controls not receiving the agent. with the use of foscarnet.18 Renal toxicity was seen in this study and was dose dependent. Because adjustment of the foscarnet dose was allowed, according to creatinine levels, Acknowledgements the actual dose of foscarnet was reduced when creatinine levels increased: at dose level 1 the actual dose received in The study was also made possible by the support of Astra Arcus, the first 30 days was 93% and at dose levels III, IV it was Sodertaljie, Sweden. The study was also supported by Associa- 84%. The actual dose administered between day ϩ31 and zione Italiana Recerca contro il Cancro (AIRC) Milano grant to day ϩ100 was 88%, 84%, 71% and 60% for dose levels I, AB and Associazione Recerca Trapianto Midollo Osseo II, III, IV, respectively. It should be noted that nephrotoxic (ARITMO) Genova. agents were used together with foscarnet in all patients, including cyclosporin and amphotericin B. Five patients had renal failure at a median interval from BMT of 33 days References (range ϩ7–ϩ49). There was complete recovery of renal function in four patients, whereas one died of acute GVHD 1 Winston DJ, Gale RP. Prevention and treatment of cytomega- with a creatinine level of 1.9 mg%. One patient had anuria lovirus infection and disease after bone marrow transplan- due to urethral bleeding and severe hemorrhagic cystitis: tation in the 1990s. Bone Marrow Transplant 1991; 8: 7–11. he recovered after dialysis. 2 Weiner RS, Bortin N, Gale RP et al. 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