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Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection inAutologous and Allogeneic Marrow Transplant RecipientsPierre Reusser, John G. Gambcrtoglio, Kathy Lilleby,and Joel D. Meyers·

Fred /IutchitlJolI Callcer Research Celller. Sealllt!. lVashillgtoll; Dil'isiOIlofClillical Pharmacy. Ulliw.'rsity ofCalifomia. Sail Francisco

The safety and efficacy of foseamet for prevention of cytomegalovirus (CMV) infection wasevaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients re­eeh'ed intermittent intra\'enous (iv) foscamet: 40 mg/kg every 8 h from 7 days before to day 30after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renaldysfunction, with a >50 pmol/L increase in serum creatinine above baseline in 5 of the 7 auto­graft recipients and in 6 of the 12 allograft recipients. Only4 allograft recipients developed CMVinfection during foscarnet prophylaxis, and no patient s!\()wed evidence ofCMV disease. Because3 allograft recipients receiving concomitant ivamphotericin B showed rapid impairment of renalfunction, foscarnet prophylaxis should not be given to allograft recipients requiring amphoteri­cin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.

Infection due to cytomegalovirus (CMV) causes signifi­

cant morbidity and mortality among bone marrow trans­plant (BMT) recipients [I]. In two published series, thc prob­ability ofCMV infection within the first 100 days after BMTamong patients who were CMV-seropositive before trans­plant was up to 80% and 60% for allograft and autograft recip­

ients. respectively [2. 3]. Mortality was primarily related toCMV pneumonia. which developed in 37% of allograft andin 22% of autogmft recipients who had cvidcncc of activc

CMV infcction [2. 3]. Thus. thc prevcntion of CMV infcc­tion and disease after DMT is of foremost importance.

Antiviral chemotherapy aimed at preventing reactivationoflatent virus may be the most promising approach to CMVprophylaxis both among CMV-seropositivc autograft and al­lograft recipients and among seronegative allograft recipients

who have a seropositive marrow donor. CMV drug prophy­laxis should covcr thc carly pcriod aftcr BMT in which adeficiency in CMV-specific immunity can contribute to therisk of severe CMV disease [4].

Thc antiviral agent acyclovir given intmvenously at high

doses was shown to be partially effective in preventing CMVinfection and disease among seropositive BMT recipients [5].

Recei\'ed 3 January 1992: revised 16 March 1992.Presented in part: 3rd International Cytomegalovirus Workshop. Bo·

logna.ltaly. June 1991 (abstract 130).All patients or their parents or guardians gave informed consent. Human

'experimentation guidelines of the US Department of Health and HumanServices were followed. and the study protocol was approved by the institu­tional review board of Fred Hutchinson Cancer Research Center and the US

Food and Drug Administration.Financial support: Swiss National Research Foundation,and Swiss Cancer

league (to P.R.): National Institutes of Health (CA-,I8029. CA-15704. Hl-36444). ,

Reprints or correspondence (present address): Dr. Pierre Reusser. Depart·ment of Medicine. University Hospital. CH-4031 B.1sel.Switzerland.

• Deceased.

The Journal of Infectious Diseases 1992;166:473-9© 1992 by The Univmily of Chicago. All rights reserved.0022-1 899/92/6603-0002S0 1.00

Ganciclovir. which is more active than acyclovir againstCMV [6]. was cvaluated in two recent prospective random­izcd controlled trials among BMT rccipients [7. 8]. In thesetwo studies of early treatment with 'ganciclovir in patientswho had engrafted (increased neutrophil count after BMT)

and who devcloped CMV e;x;cretion, the incidence ofsubse­

quent CMV discase was significantly reduced. but sevcreneutropenia occurred in 30%-=35% of treated patients [7. 8].

The antiviral drug foscarnet (trisodium phosphonofor­

mate) inhibits herpesvirus DNA polymerasc activity [9. 10]and was shown to suppress replication of both laboratorystrains and clinical isolates ofCMV in vitro [11-13]. Clinicalstudies among transplant recipients and patients with AIDSwho received foscarnet treatment for scvere CMV diseasc

have shown therapeutic effects and indicate that rerial dys­function is the main adverse experience associated with fos­carnet. whereas neutrophil counts do not appear to be sub­stantially affected [14]. Foscarnet could prove as efficient as

ganciclovir in preventing CMV disease in BMT recipientsbut could be Icss toxic to thc bone marrow and could therc­

fore be used as CMV prophyla;x;is starting before BMT. Inview ofcmerging resistance ofCMV to ganciclovir [15-18].foscamet also could be used as an alternative prophylacticregimen if resistance to ganciclovir is documcntcd.

We report a prospective phase I-II trial of intermittentintravcnous foscamet for thc prcvention of CMV infection

and disease among CMV~seropositivc autologous and alloge­neic DMT recipients. Except for one pilot trial in which 10

CMV-scropositivc marrow recipients werc givcn continuous

intravenous administration offoscarnct for prophylaxis [19],no data on prophylactic regimens using foscarnet amongBMT recipients havc yct becn published.

Patients and Methods

Patients admitted over a IO-month period to Fred HutchinsonCancer Research Center or Swedish Hospital Medical Center in

Reusser et aJ.

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474

Scattle were selected for study if they underwent autologous or

allogeneic BMT for hematologic malignancy and if they wereCMV-seropositive before transplant. Exclusion criteria were age<12 years. a known allergy to foscarnet. ongoing treatment withacyclovir or ganciclovir. grafl-versus-host disease (GVHD) pro­phylactic regimen other than cyclosporine plus methotrexateamong allografl recipients [20]. proven CMV disease beforetransplant. or renal insufficiency (serum creatinine> 1331lmol/

L) at the time ofinitiation offoscarnet prophylaxis. Patients whounderwent a second marrow transplant or who received a T

cell-depleted marrow grafl were also excluded.The methods of pretransplant conditioning and posttrans­

plant care have been described [21. 22]. Allogeneic transplant.recipients were given cyclosporine plus a short course of me tho­trexate as GVIID prophylaxis [20]. No patient received intrave­nous immune globulins for prevention of infections or GVHD.Since every patient was CMV-seropositive. blood productstransfused during the study period were not screened for CMV.

Protocol design. Because the main adverse effect offoscarnetis renal dysfunction [14]. foscarnet was first evaluated in auto­graft recipients ...Au tografl recipients do not receive cyclospor­inc. which has known nephrotoxic potential [23]. Once foscar­net proved safe in autografl recipients. the drug wasadministered to allogeneic marrow recipients.

Foscarnet sodium solution (Astra Clinical Associates. Hop­kinton. MA) was supplicd in 500-mL glass bottles at 24 mg/mLin an isotonic solution with HCI to adjust pH to 7.4. Each dosewas administered through a central venous line by using an infu­sion pump. Two regimens offoscarnet were evaluated. The in­patient regimen was a I-h infusion of foscarnet at 40 mglkgevery 8 h beginning 7 days before BMT and continuing to day30 after DMT or until discharge from hospital if earlier. Thecalculated total daily dose of 120 mglkg corresponds to two­thirds of the dosage (180 mg/kglday) used as induction treat­ment for CMV retinitis in patients with AIDS [24. 25]. Theoutpatient regimen was a I-h intravenous infusion of foscarnetdaily at a dose of 60 mg/kg given until day 75 after BMT.

Because foscarnet is eliminated by renal excretion [14]. thedosage was adjusted when the calculated creatinine clearancewas < 1.4 mL/min/kg. Continuous adjustments were made untilclearance dropped to <0.4 mL/min/kg. at which time treatmentwas stopped. Patients who developed CMV disease were eligiblefor available therapy protocols. and participation in the foscar­net trial was·terminated. If treatment of herpes simplex virus orvaricella-zoster virus infection required acyclovir therapy. fos­carnet treatment was interrupted and resumed on discontinua­tion of acyclovir therapy.

Phase I-safety. To assess potential drug toxicity. the follow-. ing data were recorded daily for inpatients and at least three

times a week for outpatients: white blood cell (WBC) countswith differential counts. hemoglobfn level. platelet counts, andserum creatinine level. Serum calcium, magnesium. and phos­phorus concentrations were obtained and liver function testswere done three times a week. Any clinical symptoms or signspossibly related to foscarnet treatment \vere recorded daily. Therapidity of engraflment during foscarnet treatment was evalu­ated by determining the number of days required for patients toreach WOC counts of 1.0 X I09/L. absolute neutrophil counts of

Jlt> 1992:166 (September)

0.5 X 109/L, or platelet counts of20 X 1Q9/Land 50 X 1Q9/Lon2 consecutive days not sustained by platelet transfusions.

Phase Il-ej]icacy. Viral cultures were prepared fromthroat. urine. and blood specimens from each patient beforetreatment and weekly during and after treatment for a minimumof 100 days aner transplant. Viral cultures from other sites orfrom tissue specimens were prepared when clinically indicated.The clinical specimens were inoculated onto monolaycrs ofhu­man foreskin fibroblasts and observed for up to 5 weeks. Positivecultures were identified by the appearance of typical cytopathiceffects, and, in the case of equivocal results, further identifica­tion was done by indirect immunonuorescence with murinemonoclonal antibodies (Syva. Palo Alto. CA). Serum samplesobtained weekly were tested for' IgG antibody to CMV byELISA (CMV Stat: Whittaker M.A. Bioproducts. Walkers­ville. MD).

CMV infection was defined as excretion of the virus or pres­ence of CMV in tissue specimens but without clinical symp­toms. CMV discase was defined as presence of CMV in tissuespecimens or in bronchoalveolar lavage (BAL) nuid with asso­ciated clinical symptoms and signs,

Pharmacokinetics of foscamet. Blood specimens were ob­tained from each patient for pharmacokinetic studies at steadyslate afler I week offoscarnet treatment and at weekly intervalsthereafler. Blood (2 mL) was drawn immediately before and atthe end of a given foscarnet infusion and again before the nextconsecutive infusion of the drug. Foscarnet plasma levels weredetermined by high-performance liquid chromatography withelectrochemical detection as described (26]. The lowest concen­tration offoscarnet detcctable by this assay is 33Ilmol/L. Calcu­lation of plasma half-lives (tl/2) of foscarnet was done as de­scribed (27].

Rcsults

The clinical characteristics of the 19 patients enrolled inthe study are summarized in table I. Duration of foscarnet

prophylaxis. median daily dose. and reasons for prematurediscontinuation. are in table 2.

Safety of Foscarnet

Rel/alful/ctiol/. The main toxicity associated with foscar­

net prophylaxis was impaired renal function (table 3). Of the

7 autograft recipients, 6 (86%) developed renal toxicity. withan increase in serum creatinine above baseline of>50 Ilmol/

L in 5 patients (71%). In 2 of these 5 patients. impairmentwas severe enough to require termination offoscarnet (aller18 and 8 days of foscarnet treatment) and hemodialysis.

Of the 2 requiring hemodialysis, I patient had acute toxic­

ity consisting of diffuse skin rash, hypotension. and renalfailure (peak serum creatinine. 733 Ilmol/L). This patienthad been receiving concomitant treatment with granulocyte­macrophage colony-stimulating factor and intravenous am­

photericin B, which could have contributed to toxicity. Both

foscarnet and amphotericin D were discontinued (on day 10

i,jII,,.III

I1

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JID 1992;166(September) Foscarnet to Prevent CMV Infection 475

Table 1. Characteristics of marrow transplant recipients receivingfoscamet.

Table 3. Toxicity during foscarnet treatment in marrow trans­plant recipients for prevention of cytomegalovirus infection.

Table 2. Duration and dosage of foscarnet treatment in marrowtransplant recipients for prevention of cytomegalovirus infection.

NOTE. Cy. c)'clophosphamide;FfBi. frnctionatedtotal body irrndia·tion; Bu.busulfan;VPI6. etoposide;BCNU.C:lrmustine.

• Includes J patientwho also rcceivedbusulfanforconditioning.

• 2 related to renal toxicity; I died of idiopathic intcrs.titialpneumoniaafter32 daysoftrcatmcnt: I diedofcardiactoxicityrelatedtochemothcrapyaller 26 daysoftreatment; I had leukemicrebpse after44 daysoftreatmen!.

, 3 relatedto renal toxicity;3 requiredintravenousamphotericinBther­apy; 1 requircdacyclovirforornl hcrpessimplexvirusinfection.

after BMT). and renal function was eventually restored. Thesecond patient showed an immediate reaction on the day ofthe marrow infusion that was attributed to dimethyl sulfox­

ide used for cryopreservation of bone marrow. Althoughserum creatinine was 71 /-lmol/L when foscarnet was stopped

(on the day of BMT). creatinine levels rose to a peak of 804/-lmol/L in this patient. with recovery to 141 /-lmol/L by day37 after BMT. Whether renal failure in this patient was re­lated to foscarnet treatment could not be determined.

The remaining 4 autograft recipients who showed renal

toxicity had transient increases in serum creatinine that didnot necessitate discontinuation of foscarnet. All 4 received

concomitant intravenous amphotericin B treatment for a me­

dian of 10.5 days (range. 2-22). The one autograft recipientwho showed no reduction of renal function also received

concomitant intravenous amphotericin B treatment for 28days.

Of the 12 allograft recipients, II (92%) developed in­creases in serum creatinine above baseline that were >50

/-lmol/L in 6 (50%). Three allograft recipients showed rapidimpairment of renal function requiring premature discontin­uation of foscarnet after 16, 17, and 19 days of treatment.Two of the 3 required hemodialysis. One of the dialysed pa­tients did not improve and died on day 40 after BMT (32

days after foscarnet was stopped) from gram-negative sepsis,GVHD, and multiorgan failure. Renal function in the other2 patients normalized within 10 and 14 days after discontin­uation of foscarnet. These 2 patients had received intrave­nous amphotericin B during the 3 days before foscarnet treat­

ment was stopped. An additional allograft recipient who wasgiven foscarnet and concqmitant amphotericin B developeda rapid increase in serum creatinine (peak. 283 /-lmol/L).which did not necessitate premature withdrawal from thestudy but \vhich required temporary discontinuation of fos­carnet for 8 days. On the basis of the experience in these 3patients, concomitant use of foscarnet and intravenous am­

photericin B in allograft recipients also receiving cyclospor­ine was subsequently precluded .

Electrolytes. Hypocalcemia and hypophosphatemia werefrequent after initiation offoscarnet treatment (table 3). Nopatient showed clinical symptoms or signs attributable to

7 (58)'

AllogrnClrecipients(II = 12)

34.5 (J()-83)

116 (56-120)56 (32-60)

AutogrnClrecipients(II = 7)

5 (71)* .

32 (8-83)

112 (73-120)60 (32-60)

Time on foscarnctin days.median(range)

Dailydoseinmg/kg. median(rnnge)Inpatient regimenOutpatient regimen

No. of patientswith prematurediscontinuationoffOSC:lrnettreatmcnt (%)

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476 Reusser et a!. JID 1992;166 (September)

~

~ Ii

Table 4. Hematologic monitoring before and during foscamettreatment in marrow transplant recipients for prevention of cyto­megalovirus infection.

Autograft recipients Allograft recipients

Hemoglobin levelBefore treatment. g/dL

12.3 (11.0-16.9)1\.2 (8.7-14.3)

Minimum level during treatment. g/dL9.5 (9.1-10.2)9.2 (6.8-10.9)

Time to minimum. days

13 (2-35)15 (5-75)No. ofRBC transfusions per palient

16 (4-18)14 (7-30)WilC Before trealment. X 109/L

7.6 (2.6-14.7)9.1 (1.0-23.2)Time to counts •• 1.0 aOer transplant. days'

13 (12-27)18 (11'-23)

Neutrophil counts Before treatment. X 109/L5.6 (2.1-10.1)4.9 (0.6-13.5)

Time to counts ••0.5 aOcr transplant. days'

17 (14-27)17 (11-23)Platelet counts ilefore transplant. X 109/L

199 (87-372)194 (17-2400)

Time to counts "20.~Oer transplant. daystt56 (56-> 75)22 (15->75)

Time to counts ••50 after transplant. dayst'64 (64-> 75)24 (15->75)

evidence of CMV infection while on foscarnet prophylaxis.

One autograll recipient had a BAL for pulmonary infiltratesaller 16 days of foscarnet treatment that was negative forCMV. Two (29%) of the 7 autograll recipients had CMV

recovered from urine specimens 31 and 67 days after foscar­net was stopped. No other viruses were isolated in autolo­

gous BMT recipients.

CMV infection occurred in 4 (33%) of the 12 allograft

recipients during foscarnet treatment. Two were receivingthe inpatient regimen and 2 the outpatient regimen. In 4

additional patients (33%). CMV infection developed a me­

dian of36 days (range, 24-52) aller the drug was discontin­ued.-cMV disease did not develop in any allograft recipient

during'foscarnet prophylaxis. However. 2 allograft recipients

(17%) developed BAL-proven CMV pneumonia 37 and 42days after foscarnet was stopped. and both died.

Herpes simplex virus infec.tion was documented in 4 allo­

graft recipients (33%) during foscarnet treatment and in 2(17%) aller the end of treatment. One allograll recipient (8%)had adenovirus recovered from the throat and from urine 48

days after discontinuation of foscarnet.

r

Table 5. Virologic results during and aller foscamettn:atment inmarrow transplant n:cipients for prevention of cytomegalovirus(CMV) infection.

NOTE. Rile. red blood cells: WBC. white blood cells. Data are median(range).

, Patients who died before reaching specific cell count while on foscarnettreatment were exeluded.

t Counts maintained on at least 2 consecutive days without platelet trans­fusion support. During foscarnet

treatmentAOer foscarnet

treatment

changes in serum calcium, magnesium. or phosphorus levels.but all were supplemented by intravenous infusions whenserum levels were low.

LiI'er flll/ctiol/. Seven patients had liver failure. definedas total serum bilirubin >85 ILmol/L, aspartate aminotrans­ferase >200 units/L. or both (table 3). All cases appeared tobe unrelated to foscarnet use. The decision to terminate fos­

carnet during the study was never based on liver toxicity.Hematologic effects. The results of hematologic monitor­

ing before and during foscarnet treatment are shown in table4. Hemoglobin levels dropped during treatment for all auto­graft recipients and for 10 (83%) of 12 allograft recipients,reaching a minimum at a median of 13 and 15 days. respec­tively, after initiation of foscarnet, which corresponded tothe end of the first week after BMT. The median number of

red blood cell transfusions per patient was similar when the 7patients who completed a full course of foscarnet prophy­laxis were compared with the entire study population (16 vs.14 units). No patient had foscarnet discontinued because of

hematologic toxicity .. ;,

Efficacy of Foscarnet

The virologic results obtained during and aller foscarnettreatment are shown in table 5. Autograft recipients had no

No. ofNo. of

patien tspatientsDays after

Virus. cultureculture-Day ofculture-end of

sitepositivetreatmentpositivetreatment

Autograft recipients

CMVThroat0 0

Urine0 231.67

mood0 0

ilAL0/116

Allograft recipients CMVThroatIII 5t1.5.35.39.59

Urine0 5'I. 10.24.52.56

Blood322.67.77 236.82

BAL2/237.42

Herpes simplex virus Throat417.25.44.4622.69

Adenovirus Throat0 I48

Urine0 I48

NOTE. BAL. bronehoalveolar lavage. If palient had multiple culturesfrom same site positive for specific virus. only first culture result is reported.Ifpatient had positive cultures from different sites. results from each site arcreported once.

'Two patients with CMV viremia during foscarnet treatment began toexcrete CMV from throat and urine aOer completion offoscarnet prophy­laxis.

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JID 1992:166 (Seplember) Foscarnel to Prevenl CMV Infeclion 477

Table 6. Peak and trough foscamet plasma levels at steady state during intermittent intravenous(iv) lreatment in marrow transplant recipients for prevention of cytomegalovirus infection.

AUlograft recipients Allograft recipientsCre31inineclearance

(mL/min{kg)

Inp3tient regimen";.t.4

0.4-1.3

Outpatient regiment;..1.4

0.4-1.3

Peak

256 (86-405)288 (156-547)

306 (177-332)377 (283-382)

Trough

<33 «33-40)48 «33-153)

<33t

<33 «33-243)

Peale

264 (134-780)315 (186-588)

387 (52-895)279 «33-313)

Trough

44 «33-228)170 «33-568)

<33 «33-108)<331

NOTE. D3la are medi3n (range) values in pmoljL." 40 mglkg every 8 h infused iv over I h.t 60 mg/kg/day infused iv over I h.t All values <33 pmol/L (detection limit of assay).

Pharmacokinetics of Foscarnct

Table 6 shows the steady-state peak and trough plasmalevels of foscarnel during the inpatient and outpatient regi­mens at full doses and at reduced doses when the creatinine

clearance was 0.4-1.3 mLfminfkg. Complete data were avail­able for calculations of plasma tl/2 offoscarnet in 3 autograftand 9 allograft recipients. During the inpatient regimen, me­dian plasma tiP of foscarnet was 2.9 h (range, 2.1-8.4)among autograft recipients and 6.2 h (range, 1.6-15.9)among allograft recipients. Because most trough plasma lev­els were below the limit of detectability during the outpatientfoscarnet regimen (table 6). plasma tl/2 could be determinedin only I allograft recipient and was 6 h. There was no corre­lation between the magnitude of plasma tiP offoscamet andthe occurrence ofCMV infeclion.

Discussion

The most serious toxicity associated with foscamet pro-'phylaxis in our patients was impaired renal function. An in­crease in serum creatinine of >50 JlmolfL above baselinelevels was observed in II (58%) of the 19 patients duringfoscarnet treatment. Renal insufficiency led to prematurewithdrawal froin the study of 5 patients (26%). The relation­ship of renal insufficiency to foscarnet use was consideredpossible in 4 of these 5 patients and was judged unevaluat­able in the other. The frequency and severity of renal toxicityin our study was in the range of that in other studies ofalloge­neic BMT recipients and AIDS patients [24, 25. 28-32].

Among our allograft recipients. who all r~ceived cyclo­sporine. it rapidly became clear that foscarnet and amphoter­icin B could not be used simultaneously with!>utdevelop­ment of renal insufficiency. Subsequently, foscarnet wasdiscontinued whenever intravenous amphotericin B wasneeded in a patient receiving cyclosporine. However. foscar-

net could be used safely with amphotericin B among auto­graft recipients who do not receive cyclosporine.

A recent study suggests that renal toxicity associated withthe use offoscarnet can be prevented by hydration with intra­venous isotonic saline given daily during treatment [32]. Inthat study. only I (4%) of27 patients with AIDS and CMVretinitis who received foscarnet with hydration developedacute renal failure. Peak serum creatinine levels in this groupof patients were significantly lower than in a historical con­trol group that had received the same foscarnet regimenwithout hydration [32]. Reduction of renal toxicity wouldallow a larger proportion ofBMT recipients to receive a fullcourse of foscarnet prophylaxis. which may reduce the inci­dence ofCMV infection after transplant.

Abnormalities of serum electrolytes were common but notassociated with clinical symptoms or signs. suggesting theywere minor adverse effects of foscamet prophylaxis. Clinicalmanifestations may have been prevented by intravenous re­placement of these compounds when required. In a study of10AIDS patients. abnormalities of serum calcium and phos­phorus levels were observed in 9 cases but were not accompa­nied by symptoms and normalized after foscarnet inductiontreatment was completed [24]. After BMT, the causes ofhy­pocalcemia. hypophosphatemia. or hypomagnesemia areprobably multifactorial. Thus. the contribution offoscametto these conditions in our study remains unclear.

A decrease in hemoglobin levels was frequently observedin this study and was most common early after BMT. How­ever, the requirements of red blood cell transfusions amongpatients whO'received a full course offoscarnet prophylaxisdid not exceed those reported in earlier studies from ourtransplant center among both allograft and autograft recipi­ents who did not receive foscarnet [33. 34]. The rapidity ofengraftment after BMT was also similar to that among autolo­gous and allogeneic BMT recipients who were not treatedwith foscarnet (3. 35]. Premature discontinuation of foscar­net prophylaxis was not based on hematologic toxicity in any

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478 Reusser et 0'11. J ID 1992; 166 (September)

patient. In contrast, studies ofgancicIovir in BMT recipientshave reported severe neutropenia that required dose modifi­cations or discontinuation of the drug in 30%-35% of pa­

tients (7. 8].

CMV infection was prevented in all of our autograft recipi­

ents but occurred in 33% of allograft recipients during treat­

ment. No patient in this study showed evidence of CMVdisease while receiving foscarnet prophylaxis. These results

compare favorably with those from an earlier pilot study inwhich 50% of CMV-seropositive allogeneic 8MT recipients

receiving continuous infusions of prophylactic foscarnet de­

veloped CMV infection [19]. Peak plasma levels obtainedwith intermittent infusion of the drug in our study were morethan double the levels measured with continuous infusion of

foscarnet in that previous trial. which may explain the im­

proved efficacy.

With one exception [17], earlier studies of foscarnet

among BMT recipients used continuous intravenous infu­

sions to administer the drug [13. 19, 28, 29. 36-38]. In oneof these studies that reported data on pharmacokinetics [29],

the steady-state serum levels of foscarnet in 13 allogeneic

BMT recipients who received a daily dose of foscarnet simi­lar to the dose in our inpatient regimen were 273 ±43 pmol!

L (mean ± SE). In our study. the median peak plasma con­centrations of foscarnet obtained during the inpatient and

outpatient regimens among autograft and allograft recipients

ranged from 256 to 387 pmol/L. The trough plasma levels offoscarnet. however, were usually <33 pmol/L, the detection

limit of the assay (26]. Most clinical isolates of CMV areinhibited at concentrations of foscarnet of200-400 pmol!L

in in vitro cell cultures [14, 18]. Our results indicate thatcontinuously elevated plasma concentrations offoscarnet donot appear to be necessary to prevent CMV infection in8MT recipients.

Prevention of CMV infection and disease appeared effec­

tive only while patients were actively taking the drug. Afterdiscontinuation of foscarnet, CMV infection occurred in ,2

autograft (29%) and 4 allograft recipients (33%), and CMV

pneumonia developed in 2 allogeneic 8MT recipients (17%).However, except for I allograft recipient who had CMV ex­cretion in the throat and urine after a full course offoscarnet

prophylaxis. all of these patients were prematurely with­

drawn from the study and did not receive alternative anti­

viral prophylaxis (data not shown). It remains conjecturalwhether a full course of foscarnet treatment or the replace­ment offoscarnet by drugs such as acyclovir [5] or gancicIo­

vir [7,8] might have altered the course.

Our data suggest that intermittent intravenous foscarnet

prophylaxis is effective in preventing CMV disease amongpatients who tolerate the full course of treatment. However,foscarnel should not be given to allogeneic 8MT recipientsreceiving cyclosporine who require intravenous amphoteri-

cin B. With that exception, prophylaxis at the doses usedappears to be safe after both autologous and allogeneic 8MT.

Acknowledgments

We thank M. Wieckowicz for editorial review and M. Marli

and M. Sporri for assistance in manuscripl preparation.

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predictor of cytomcgalovirus disease after marrow transplantation:importancc of cytomcgalovirus vircmia. J Infect Dis 1990; 162:373­80.

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4. Reu~ser p. Riddell SR. Me)'ers JD. Greenbcrg PD. Cytotoxic T lym­phocyte response to cytomegalovirus following human allogeneicbone marrow transplantation: pattern of recovery and correlationwith c)'tomegalovirus infection and disease. Blood 1991;78:1373­80.

5. Meyers JD. Reed EC. Shepp DH. et al. Acyclovir for prevention ofcytomegalovirus infection and disease aCterallogeneic marrow trans­plantation. N Engl J Med 1988;318:7(}-5.

6. Balfour Hit Jr. Management of cytomegalovirus discasc with antiviraldrugs. Rcv Infect Dis 1990; I2(suppl 7):S849-60.

7. Schmidt GM. Horak DA. Niland JC. et al. A randomized. controlled

trial oC prophylactic ganciclovir for cytomegalovirus pulmonary in­Cectionin recipients of allogeneic bone marrow transplants. N Engl JMed 1991;324:1005-11.

8. Goodrich JM. Mori M. Gleaves CA. et al. Prevention ofC),tomegalovi­rus disease after allogeneic marrow transplantation by early treat­ment with ganciclovir. N Engl J Med 1991;325:1601-7.

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