S Seropian 1, R Nadkarni 1, AP Jillella 1, E Salloum 1, B Burtness 1,GLHu 2, D Zelterman 2 and DL Cooper 1. Summary:

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1 Bone Mrrow Trnsplnttion, (1999) 23, Stockton Press All rights reserved /99 $ Neutropenic infections in 100 ptients with non-hodgkin s lymphom or Hodgkin s disese treted with high-dose BEAM chemotherpy nd peripherl blood progenitor cell trnsplnt: out-ptient tretment is vible option S Seropin 1, R Ndkrni 1, AP Jillell 1, E Slloum 1, B Burtness 1,GLHu 2, D Zeltermn 2 nd DL Cooper 1 1 Section of Medicl Oncology, Deprtment of Internl Medicine, Yle University School of Medicine; nd 2 Deprtment of Biosttistics, Yle University School of Medicine, Yle Cncer Center, New Hven, CT, USA Summry: A retrospective nlysis ws performed on 100 ptients with non-hodgkin s lymphom (NHL, n = 75) or Hodgkin s disese (HD, n = 25) who underwent peripherl blood progenitor cell trnsplnt (PBPCT) following high-dose chemotherpy (HDCT) with BCNU, etoposide, cytrbine nd melphln (BEAM) between Mrch 1994 nd June Following PBPCT nd until engrftment ll ptients received orl ciprofloxcin nd fluconzole, ptients with positive Herpes simplex virus serology received cyclovir nd 91 ptients received filgrstim. The medin dys of neutropeni nd dys to n bsolute neutrophil count (ANC) 500/mm 3 were 6 nd 9, respectively. Febrile neutropeni occurred in 68 ptients. Grm-positive bcteremi occurred in 14 ptients. No grm-negtive infections, invsive fungl infections, intensive cre visits or deths occurred during the period of neutropeni or in the first 30 dys following trnsplnt. In multivrite logistic regression the risk of development of ny infection ws ssocited only with the durtion of neutropeni (P = 0.02) nd the risk of bcteremi ws ssocited only with the number of CD34 + cells infused (P = 0.046). Among 49 ptients treted in the outptient setting, 14 (28%) were never dmitted. High-dose chemotherpy with BEAM supported by PBPCT, prophylctic ntibiotics nd filgrstim resulted in low incidence of infections nd no cute mortlity. WBC engrftment occurred rpidly llowing for predictble course during which lengthy hospitl stys nd mphotericin therpy could be voided. Keywords: neutropeni; utologous stem cell trnsplnttion; infection The use of filgrstim-mobilized peripherl blood progenitor cells (PBPC) hs improved the supportive cre of ptients Correspondence: Dr S Seropin, WWW211, Section of Medicl Oncology, Yle University School of Medicine, 333 Cedr Street, New Hven, CT 06510, USA Received 20 July 1998; ccepted 22 October 1998 receiving HDCT. In comprison with utologous bone mrrow, PBPC support following high-dose chemotherpy results in quicker time to engrftment of white blood cells nd pltelets nd is ssocited with reductions in the use of blood products, shorter hospitl stys nd lower costs. 1,2 Despite these dvnces, ptients receiving myelobltive chemotherpy with PBPC support hve profound nd occsionlly prolonged neutropeni, remining t risk for the development of serious infections, prolonged hospitliztion, morbidity nd mortlity. PBPC support hs lso been ssocited with more fvorble profile of infectious complictions post-trnsplnt, when retrospectively compred to mrrow, primrily becuse the durtion of neutropeni is reduced when PBPC re employed. 3,4 A number of other vribles hve the potentil to ffect the risk, s well s the spectrum of infections post-trnsplnt, including ptient popultion treted, conditioning regimen employed, number of CD34 + cells infused nd supportive cre mesures used post-trnsplnt, such s prophylctic ntibiotics nd hemtopoietic growth fctors. The role these fctors ply with regrd to infectious outcome is not well defined. Few studies of infectious complictions following HDCT with PBPC support hve been reported nd most hve included heterogeneous ptient popultions treted with vriety of conditioning regimens. We hve conducted retrospective study of infectious complictions occurring during the period of neutropeni in 100 ptients with Hodgkin s disese (HD) nd non-hodgkin s lymphom (NHL) treted over 3-yer period with high-dose BEAM chemotherpy supported with PBPC, filgrstim nd uniform prophylctic ntibiotic strtegy. Ptients nd methods Ptients Inptient nd outptient medicl records of ll ptients with HD nd NHL undergoing high-dose chemotherpy with PBPC support in the Yle Section of Medicl Oncology between Mrch 1994 nd June 1997 were reviewed. One hundred ptients with NHL nd HD underwent high-dose chemotherpy with BEAM followed by PBPC trnsplnt

2 600 during this time period. No ptients received lterntive conditioning regimens or utologous mrrow trnsplnttion in our deprtment during this time period. Ptient chrcteristics re presented in Tble 1. The mjority of ptients with NHL were treted in chemotherpy-sensitive relpse or in first complete/prtil remission for high-risk disese. Nine ptients were treted with primry resistnt or relpsed resistnt disese. Two ptients with NHL received syngeneic stem cell rescue. One ptient received sequentil trnsplnts with identicl doses of BEAM nd two ptients received BEAM nd PBPC rescue s the second of sequen- Tble 1 Chrcteristic Ptient chrcteristics Ptients 100 Trnsplnts performed 101 Age (yers) Medin (rnge) 46 (16 73) Sex Femle 43 Mle 57 Dignosis HD 25 NHL 75 Prior regimens 2 (1 7) Prior cycles of chemotherpy 8 Disese sttus Primry resistnt/resistnt relpse 9 First CR/PR 25 Sensitive relpse 67 NHL histologic subtype Diffuse lrge cell 32 Folliculr mixed 7 Folliculr smll cleved 5 Ki-1 nplstic lrge cell 4 Lrge cell with sclerosis 3 Mntle cell 10 Lymphoblstic 4 Smll lymphocytic lymphom 2 Peripherl T cell 3 Other 5 Trnsformed 4 Tndem trnsplnt 3 Prior BMT 1 PBPC + BM 1 Syngeneic PBPC 2 Selected CD34 + cells 6 Mobilizing regimen DI-CE 53 Mod DI-CE b 15 Other 30 None 2 Tretment loction Inptient 52 Outptient 49 Vsculr ccess Permcth/Hickmn 40 Temporry quint/tlc 61 HD= Hodgkin s disese; NHL = non-hodgkins lymphom; PBPC = peripherl blood progenitor cell; BM = bone mrrow; TLC = triple lumen ctheter; Quint = Quinton ctheter. DI-CE, cyclophosphmide, 2.5 g/m 2 dily for 2 dys nd etoposide 150 mg/m 2 twice dily for 3 dys. b Modified DI-CE, cyclophosphmide, 1.5 mg/m 2 dily for 1 dy nd etoposide 150 mg/m 2 once dily for 3 dys. No. til trnsplnts for high risk disese. One ptient hd undergone previous utologous bone mrrow trnsplnt. One ptient received utologous bone mrrow plus PBPC following high-dose therpy. Four ptients were trnsplnted with histologic evidence of disese trnsformtion to higher grde lymphom t the time of relpse. Six ptients prticipted in study of CD34 + cell selection vi n immunomgnetic ntibody technique nd received CD34 + selected peripherl blood progenitor cells following conditioning. Dt collected included ge, sex, histologic dignosis, sttus of disese t trnsplnt, type of venous ccess, number of CD34 + cells/kg infused, dose of filgrstim post-trnsplnt, dys of neutropeni, dys to WBC engrftment, dys of fever, dys of hospitliztion, dys in intensive cre, ntibiotic therpy, culture results, nd mortlity t dy 30 nd dy 100. Ptients referred to the center by community physicins were frequently treted with mobilizing chemotherpy by the referring physicin following initil consulttion. Mny ptients were dischrged following trnsplnt for follow-up cre to privte physicins offices when engrftment of white blood cells hd occurred, but often prior to chievement of pltelet trnsfusion independence. Relible dt on pltelet trnsfusions nd short-term pltelet engrftment were therefore not vilble for ll ptients. Ptients routinely returned 6 to 8 weeks post-trnsplnt for restging evlution. PBPC mobiliztion Ninety-eight ptients received ggressive chemotherpy followed by filgrstim (Amgen, Thousnds Oks, CA, USA), g/kg/dy, for the dul purpose of treting the underlying mlignncy, s well s to mobilize PBPC. A vriety of chemotherpy regimens were used for mobiliztion (Tble 1). The most commonly used mobilizing regimen (DI-CE) included cyclophosphmide, 2.5 g/m 2 dily for 2 dys nd etoposide 150 mg/m 2 twice dily for 3 dys. All ptients receiving DI-CE for mobiliztion received prophylctic orl ciprofloxcin until resolution of neutropeni. PBPC collection ws strted when the white blood cell count recovered from ndir to greter thn 3000/mm 3 nd/or when peripherl blood CD34 + cells were greter thn 10/mm 3. Filgrstim ws continued until the lst dy of collection. The trget PBPC cell collection ws CD34 + cells/kg, however, fter severl dys of pheresis, if greter thn CD34 + cells/kg were collected, ptients went on to receive high-dose chemotherpy rther thn nother course of mobilizing chemotherpy. Two ptients undergoing syngeneic trnsplnt received PBPC hrvested from donors with filgrstim lone. During the initil 17 months of the study period, cells were collected through tunneled double lumen permctheter which ws left in plce throughout the trnsplnt period. Becuse of difficulties with clotting nd infection, temporry centrl lines or peripherl veins were preferred for pheresis in the ltter 22 months of the study nd subcutneous portctheters were used for venous ccess during the trnsplnt period, if necessry. PBPC were reinfused through peripherl intrvenous line or temporry centrl venous ctheter ws plced for reinfusion nd then removed.

3 High-dose chemotherpy BEAM chemotherpy ws given over 6 dys: BCNU: 300 mg/m 2 on dy 6; etoposide: 200 mg/m 2 every 12 h, dys 5 to 3; cytrbine 100 mg/m 2 every 12 h, dys 5 to 2 nd melphln 140 mg/m 2 on dy 1. The cumultive doses of the drugs were BCNU 300 mg/m 2, etoposide 1200 mg/m 2, cytrbine 800 mg/m 2, melphln 140 mg/m 2. Doses were given ccording to the ptient s ctul weight except in ptients whose weight ws greter thn 30% bove their idel body weight, in which cse the body surfce re ws clculted ccording to the idel body weight plus 30%. On dy 0, PBPC were given through centrl line by slow intrvenous push. In ptients who required severl collections in order to chieve the trget number of cells, infusions were sometimes given on 2 consecutive dys in order to void the dministrtion of n excessive volume of dimethylsulfoxide. Supportive cre During the initil 22 months of the study period ll ptients were hospitlized for dministrtion of high-dose chemotherpy nd remined in the hospitl until neutrophil engrftment occurred. On dy 0, filgrstim, 5 10 g/kg subcutneously, ciprofloxcin 500 mg p.o. twice dily nd fluconzole 200 mg p.o. once dily were strted nd continued until engrftment. Acyclovir, 200 mg p.o. five times dily ws dministered to ptients with positive HSV serology nd/or pst history of HSV infection. Nine ptients during the initil study period did not receive filgrstim post-trnsplnt. During the second hlf of the study period ll ptients received 10 g/kg filgrstim. CMV-negtive, irrdited blood products were given to ll ptients. Pltelets were trnsfused for counts below /mm 3 or t higher counts if evidence of bleeding ws present. Following cultures of the peripherl blood, centrl lines nd urine, ptients were given intrvenous ntibiotics for orl tempertures greter thn 38.0 C or if the ptient hd chills or chnge in clinicl sttus suggestive of infection. Once intrvenous ntibiotics were strted ciprofloxcin ws discontinued, but fluconzole ws mintined until the neutrophil count ws greter thn 500/mm 3. The choice of initil empiric ntibiotics ws left to the discretion of the dmitting physicin nd in the mjority of cses included combintion of third genertion cephlosporin nd gentmycin. Vncomycin ws dded initilly if clinicl evidence of grm-positive infection ws present or fter h for persistent fevers or positive cultures for grm positive orgnisms. During the ltter hlf of the study, vncomycin ws frequently included in the initil ntibiotic regimen given the incidence of grm-positive infections during the initil study period. Outptient therpy Beginning in Jnury 1996, the entire tretment progrm ws moved to the outptient setting. To receive outptient therpy ptients hd to hve n vilble cretker t home nd live close enough to the hospitl to rrive in timely fshion for evlution in the event of fever or other difficulties post-trnsplnt. Between Jnury 1996 nd the end of the study period, 49 ptients were treted s outptients. Nine ptients filing to meet the bove criteri were treted s inptients during this time period. Outptients received chemotherpy nd were seen by physicin in the clinic during weekdys. Visiting nurses dministered the remining chemotherpy doses in the evenings nd on weekends t the ptient s home. PBPC were reinfused in the outptient clinic nd ptients were then seen dily for blood work nd exmintion strting on dy + 2 until the time of WBC engrftment. Prophylctic orl ntibiotics nd filgrstim were dministered to ll ptients s described bove. Ptients with n orl temperture greter thn 38.0 C during the period of neutropeni were dmitted for intrvenous ntibiotic therpy. Once dily ceftrixone nd once dily gentmicin were used s initil empiric intrvenous ntibiotics in most of these ptients with the gol of erly dischrge with continued outptient i.v. ntibiotic therpy if cultures remined negtive nd the ptient ws cliniclly stble. Definitions Infectious episodes were clssified into one of four groups: (1) microbiologiclly documented infection with bcteremi; (2) microbiologiclly documented infection without bcteremi; (3) cliniclly suspected infection without microbiologicl documenttion; nd (4) fever of unknown origin (FUO). Dys to WBC engrftment were clculted from the dy of PBPC infusion to the first of 3 consecutive dys with n ANC 500/mm 3. Pltelet engrftment dt were not collected s the mjority of ptients received cre in referring physicins offices fter neutrophil engrftment nd hospitl dischrge, t which time some ptients were still pltelet trnsfusion-dependent. Sttisticl methods Dt were nlyzed using multivrite liner nd logistic regressions in SAS (SAS Institute, Cry, NC, USA). The number of dys of neutropeni nd dys to WBC engrftment were modeled s liner functions of ptientrelted vribles (ge, disese type) nd tretment covrites (filgrstim dose, CD34 + cell dose, type of mobilizing regimen, number of cycles of prior therpy). A multivrite liner logistic regression model ws used to test the ssocition of filgrstim dose, CD34 + cell dose, dys of neutropeni, time to WBC engrftment, type of vsculr ccess nd tretment loction with the occurrence of bcteremi or ny infection. Sttisticl significnce ws defined s P vlue Results Infectious complictions Febrile neutropeni occurred in 68 ptients nd the medin number of dys with fever 38.0 C ws 1 for the entire group. Thirty-four microbiologiclly documented infections occurred in 28 ptients nd included 15 episodes of bctere- 601

4 602 mi in 14 ptients (Tble 2). The most commonly isolted orgnism ws cogulse-negtive Stphylococci. No grmnegtive infections occurred during the period of neutropeni lthough one ptient developed recurrent infection with Acinetobcter bumnni on dy 0 (prior to the development of neutropeni) relted to previously infected portctheter tht hd not been removed. No episodes of bcteremi occurred in the group of ptients receiving 10 g/kg filgrstim nd CD34 + cells/kg (n = 38). A vriety of other infections ws documented, the mjority of which were minor. Among the more serious non-bcteremic infections were one ptient with virl pneumoni (prinfluenz) nd one ptient with clinicl findings consistent with typhilitis, both of whom recovered. A number of relted fctors ws ssocited with the development of infection or bcteremi including the durtion of neutropeni, time to WBC engrftment, number of PBPC infused, type of vsculr ccess nd tretment loction (Tble 3). In multivrite nlysis, the risk of development of ny infection ws ssocited only with the durtion of neutropeni (P = 0.02) nd the risk of bcteremi ws ssocited only with the number of CD34 + cells infused (P = 0.046). Morbidity nd mortlity No intensive cre unit hospitliztion ws required nd no deths occurred during the period of neutropeni or in the Tble 2 Neutropenic fever nd infection Episodes of neutropenic fever 68 Medin dys with fever (rnge) 1 (0 12) FUO 41 Microbiologiclly documented infections 34 Episodes of bcteremi 15 Grm-positive 14 Cog stph 10 Enterococcus 2 Strep mitis 1 Strep viridns 1 Grm-negtive (cinetobcter) 1 Bcteremi with permcth 11 Bcteremi with temporry venous ccess 4 Other documented infections Herpes simplex 4 Urinry trct 3 GI Clostridium difficile colitis 9 Cmpylobcter 1 Pulmonry 1 Other 1 Fungl isoltes 0 Cliniclly suspected infections 4 HSV 3 Typhilitis 1 Amphotericin use 4 Acute mortlity ( 30 dys) 0 Dy 100 mortlity 5 FUO = fever of unknown origin; HSV = Herpes simplex virus. Recurrent Acinetobcter infection developed on dy 0, prior to development of neutropeni or institution of ciprofloxcin prophylxis, in ptient with previous history of infection of portcth which hd not been removed. No. first 30 dys. Eighteen ptients received totl prenterl nutrition (TPN) becuse of mucositis or prolonged poor orl intke. The medin number of dys on TPN for the entire popultion ws 0. One ptient expiring on dy 74 post-trnsplnt hd clinicl findings suggestive of progressive lymphom but ws found on utopsy to hve untreted legionell pneumoni without evidence of disese. Four other ptients died prior to dy 100 of relpsed or progressive disese. Engrftment PBPC nd engrftment dt re presented in Tbles 4 nd 5. All ptients engrfted white blood cells nd pltelets (pltelet dt not shown) following PBPC trnsplnttion. The dose of filgrstim nd the number of CD34 + cells 10 6 /kg infused were both negtively correlted with the durtion of neutropeni (P ), dys to n ANC 500/mm 3 (P ) nd durtion of hospitliztion (P ). The most rpid engrftment of WBC ws observed in 38 ptients receiving 10 CD34 + cells 10 6 /kg nd 10 g/kg filgrstim. The medin durtion of neutropeni nd dys to n ANC 500/mm 3 in this group were 5 nd 8 dys, respectively, nd no ptient took longer thn 9 dys to chieve neutrophil engrftment. As the mjority of ptients receiving 10 CD34 + cells 10 6 /kg lso received 10 g/kg filgrstim, n nlysis of the effect of filgrstim on WBC engrftment in ptients receiving high numbers of CD34 + cells ws not possible. Outptients Forty-nine ptients received tretment in the outptient setting. Nine ptients were treted s inptients during the sme time period becuse of concerns over complince, distnce from the hospitl or lck of cregiver t home. Comprtive dt for ptients treted s inptients nd outptients re presented in Tble 5. Chrcteristics of ptients receiving therpy s outptients were similr to those treted s inptients. The mjority of ptients treted in the outptient setting received high dose of CD34 + cells/kg supported by 10 g/kg filgrstim nd engrfted white blood cells promptly with very little vrition. Only four of these ptients hd externl-dwelling venous ccess devices during the trnsplnt period. Sixty-five percent of outptients developed febrile neutropeni nd 71% of the group were dmitted. Outptients spent medin of 4.5 dys in the hospitl nd 14 ptients (28%) were never dmitted. Discussion Few reports dedicted to the study of infectious outcomes following utologous PBPCT hve been published. 3 5 In the present series, 100 ptients received BEAM nd PBPCT followed by uniform ntibiotic prophylctic regimen. Our objective ws to develop supportive cre strtegy which would llow the sfe dministrtion of high-dose therpy nd subsequent follow-up in the outptient setting. Since Jnury 1996, 49 ptients hd high-dose BEAM dministered in the clinic nd t home with decline in the verge

5 Tble 3 Logistic regression nlysis of risk fctors for infection or bcteremi 603 Event Vrible Medin (rnge) Univrite Multivrite P vlue P vlue Infection (ny type) Bcteremi Time to WBC engrftment (dys) 10 (7 20) Dys of neutropeni (dys) 7.5 (5 16) CD34 + cell/kg ( ) Dose of filgrstim ( g) 5.8 (0 11.6) Vsculr ccess Tretment loction Time to WBC engrftment (dys) 10 (8 13) Dys of neutropeni (dys) 8 (6 10) CD34 + cell/kg ( ) Dose of filgrstim ( g) 5.4 (0 10.8) Vsculr ccess Tretment loction Sttisticlly significnt. Tble 4 PBPC nd engrftment dt Tble 5 Comprison of ptients by tretment loction No. CD34 + cells infused ( 10 6 /kg medin) 7.27 ( ) No. of ptients receiving CD34 + ( 10 6 /kg) Filgrstim dose post-trnsplnt None 9 5 g/kg g/kg 74 Medin dys of neutropeni (rnge) 6 (4 16) Medin dys to ANC 500 (rnge) 9 (7 20) Medin dys of hospitliztion (rnge) 15 (0 40) number of dys of hospitliztion from 19 to 4.5. Despite liberl pproch towrd dmission (fever F, chills or filure to thrive) 14 ptients (28%) did not require dmission to the hospitl. The mjor fctors which fcilitted this trnsfer of cre included the predictbly rpid engrftment of white blood cells provided by PBPC, effective prophylxis ginst potentilly life-thretening infections, especilly erobic grm-negtive bcteri, nd lck of severe mucositis thus obviting the need for prenterl nutrition or lrge volume hydrtion. A number of fctors were ssocited with the development of infection, lthough the durtion of neutropeni, s noted in other reports, ws the only vrible retining sttisticl significnce in multivrite nlysis. During the initil study period, the use of n externl dwelling permctheter, which ws left in plce from the time of mobiliztion of PBPC through the trnsplnt, ws ssocited with high incidence of bcteremi (10 of the first 40 ptients) nd prompted chnge in clinicl prctice to the use of temporry ctheters. Nevertheless, the type of ctheter used did not retin sttisticl significnce in the multivrite nlysis, possibly becuse the chnge in ctheter use ws ccompnied by chnges in other prctices (PBPC dose, Inptients Outptients No. (%) No. (%) No Age No No Dignosis Hodgkins NHL Disese sttus Primry resistnt/resistnt relpse 4 5 First CR 9 15 Sensitive relpse Medin No. CD34 + cells infused ( 10 6 /kg) Filgrstim dose post-trnsplnt 0 g/kg g/kg g/kg Fever/neutropeni 36 (70) 32 (65) Hospitl dmissions 35 (72) Dys with fever 2 1 Dys of hospitliztion Microbiologiclly documented infections 22 (43) 9 (18) Dys of neutropeni 7 (4 16) 6 (4 9) Dys to ANC (7 20) 8 (7 11) Episodes of bcteremi 11 (21) 3 (7) Amphotericin use 4 0 Ptients were treted s outptients during the ltter hlf of the study period when there ws policy of using higher dose of post-trnsplnt filgrstim (10 g/kg) nd higher dose of CD34 + cells/kg. filgrstim dose) tht my impct on the development of fever nd infection. As in other studies, the use of hemtopoietic growth fctors nd PBPC significntly reduced the durtion of neutropeni compred with historicl experiences with bone mrrow. In the current group the medin time to neutrophil engrftment ( /l) ws 9 dys. By comprison, using bone mrrow without hemtopoietic growth fctors

6 604 fter BEAM, Mills et l 6 nd Colombt et l 7 reported medin time to neutrophil engrftment of 21 nd 20 dys, respectively. Perhps of greter importnce ws the nrrow rnge in the time to engrftment in ptients who received /kg CD34 + cells nd 10 g/kg of filgrstim. In this group of ptients the medin durtion of neutropeni ws 5 dys, no ptient required more thn 9 dys to chieve neutrophil engrftment, nd no episodes of bcteremi occurred. As ptients with n expected durtion of neutropeni of less thn 7 dys hve been identified by others s being t low risk for serious morbidity from infection, 8,9 it seems likely tht n even greter proportion of cre cn be dministered in the outptient setting. 10,11 The bsence of neutropenic grm-negtive infections, despite reltively high incidence of febrile neutropeni is consistent with the findings of other studies in which prophylctic quinolone ntibiotics hve been used Although the etiology of fever in mny of these ptients remins obscure, we believe tht the low incidence of grm-negtive infections my be especilly importnt in ptients treted in the outptient setting, where there my be longer period of time between signs nd symptoms of n infection nd the dministrtion of (dditionl) ntibiotic tretment. Nevertheless, given the concerns over the emergence of quinolone-resistnt bcteri, nd the bsence of dt supporting reduction in mortlity in ptients given prophylctic ntibiotics, this point will hve to be tested in rndomized trils A mjor fctor which fcilitted the trnsfer of cre to the outptient setting ws the lck of severe mucositis fter BEAM chemotherpy, dministered t the current doses. In contrst, Mills et l 6 described nerly universl pn mucositis, nd three-qurters of the ptients required nrcotic nlgesi nd TPN. In these reports the dose of cytrbine rnged from mg/m 2 compred with the current study, in which the VP-16 nd cytrbine doses were 1200 mg/m 2 nd 800 mg/m 2, respectively. Chopr et l 23 reported 10% tretment-relted mortlity including 5.6% in the first 21 dys in study in which 90% of the ptients received doses of VP-16 nd cytrbine of 1600 mg/m 2 nd 800 mg/m 2, respectively. Interestingly, in these studies prophylctic ntibiotics were not used in the mjority of ptients nd growth fctors, which hve been shown in some studies to reduce the durtion of mucositis, were used in only few ptients. The lck of mucositis my hve impcted on the incidence of infection, prticulrly Strep viridns bcteremi, which my result in significnt morbidity following high-dose cytrbine. Thus, it my not be possible to extrpolte our results to other regimens in which severe mucositis is common, such s rdition-bsed progrms, or versions of BEAM in which higher doses of cytrbine re used. In view of the lck of demonstrble superiority of regimen in which higher doses of cytrbine nd VP-16 re used, we hve elected to continue the doses used in the current study. In summry, we hve reported low incidence of infections nd no cute mortlity in 100 ptients with NHL nd Hodgkin s disese who were treted with high-dose BEAM chemotherpy followed by PBPCT, filgrstim nd uniform strtegy of ntibiotic prophylxis. The low incidence of severe toxicity or serious infections in the initil ptients hs llowed ll of the tretment nd most of the follow-up to be trnsferred to the outptient setting. Future directions will include compring the use of prophylctic ntibiotics vs the use of orl brod spectrum ntibiotics t the time of fever. It lso seems likely, given the brief durtion of neutropeni, tht ntifungl prophylxis my be unnecessry. References 1 Schmitz N, Linch D, Dreger P et l. Rndomised tril of filgrstim-mobilised peripherl blood progenitor cell trnsplnttion versus utologous bone-mrrow trnsplnttion in lymphom ptients. Lncet 1996; 347: Hrtmnn O, Le Corroler A, Blise D et l. Peripherl blood stem cell nd bone mrrow trnsplnttion for solid tumors nd lymphoms: hemtologic recovery nd costs. Ann Intern Med 1997; 126: Nosnchuk JD, Sepkowitz KA, Perse RN et l. Infectious complictions of utologous bone mrrow nd peripherl stem cell trnsplnttion for refrctory leukemi nd lymphom. Bone Mrrow Trnsplnt 1996; 18: Mossd SB, Longworth DL, Goormstic M et l. Erly infectious complictions in utologous bone mrrow trnsplnttion: review of 219 ptients. Bone Mrrow Trnsplnt 1996; 18: Kolbe K, Domkin D, Derigs HG et l. Infectious complictions during neutropeni subsequent to peripherl blood stem cell trnsplnttion. Bone Mrrow Trnsplnt 1997; 19: Mills W, Chopr R, McMilln A et l. BEAM chemotherpy nd utologous bone mrrow trnsplnttion for ptients with relpsed or refrctory non-hodgkin s lymphom. J Clin Oncol 1995; 13: Colombt P, Biron P, Lporte J et l. Bem protocol nd utologous bone mrrow trnsplnttion in first chemosensitive relpse of non-hodgkin s lymphoms. Eur J Cncer 1990; 26: Pizzo PA. Mngement of fever in ptients with cncer nd tretment-induced neutropeni. New Engl J Med 1993; 328: Bodey GP, Buckley M, Sthe YS et l. Quntittive reltionships between circulting leukocytes nd infection in ptients with cute leukemi. Ann Intern Med 1996; 64: Mlik IA, Khn WA, Krim M et l. Fesibility of outptient mngement of fever in cncer ptients with low-risk neutropeni: results of prospective rndomized tril (see comments). Am J Med 1995; 98: Rubenstein EB, Rolston K, Benjmin RS et l. Outptient tretment of febrile episodes in low-risk neutropenic ptients with cncer. Cncer 1993; 71: Prevention of bcteril infection in neutropenic ptients with hemtologic mlignncies. A rndomized, multicenter tril compring norfloxcin with ciprofloxcin. The GIMEMA Infection Progrm. Gruppo Itlino Mlttie Emtologiche Mligne dell Adulto (see comments). Ann Intern Med 1991; 115: Bow EJ, Mndell LA, Louie TJ et l. Quinolone-bsed ntibcteril chemoprophylxis in neutropenic ptients: effect of ugmented grm-positive ctivity on infectious morbidity. Ntionl Cncer Institute of Cnd Clinicl Trils Group (see comments). Ann Intern Med 1996; 125: Lew MA, Kehoe K, Ritz J et l. Ciprofloxcin vs trimethoprim/sulfmethoxzole for prophylxis of bcteril infections in bone mrrow trnsplnt recipients: rndomized, controlled tril. J Clin Oncol 1995; 13:

7 15 Bow EJ, Loewen R, Vughn D. Reduced requirement for ntibiotic therpy trgeting grm-negtive orgnisms in febrile, neutropenic ptients with cncer who re receiving ntibcteril chemoprophylxis with orl quinolones. Clin Infect Dis 1995; 20: Crucini M, Rmpzzo R, Mlen M et l. Prophylxis with fluoroquinolones for bcteril infections in neutropenic ptients: met-nlysis (see comments). Clin Infect Dis 1996; 23: Engels E, Lu J, Brz M. Efficcy of quinolone prophylxis in neutropenic cncer ptients: met-nlysis. J Clin Oncol 1998; 16: Crrtl J, Fernndez-Sevill A, Tubu F et l. Emergence of quinolone-resistnt Escherichi coli bcteremi in neutropenic ptients with cncer who hve received prophylctic norfloxcin. Clin Infect Dis 1995; 20: ; discussion Crrtl J, Fernndez-Sevill A, Tubu F et l. Emergence of fluoroquinolone-resistnt Escherichi coli in fecl flor of cncer ptients receiving norfloxcin prophylxis. Antimicrob Agents Chemother 1996; 40: Comett A, Clndr T, Bille J et l. Escherichi coli resistnt to fluoroquinolones in ptients with cncer nd neutropeni (letter) (see comments). New Engl J Med 1994; 330: Kern WV, Andriof E, Oethinger M et l. Emergence of fluoroquinolone-resistnt Escherichi coli t cncer center. Antimicrob Agents Chemother 1994; 38: Bll P. Editoril response: is resistnt Escherichi coli bcteremi n inevitble outcome for neutropenic ptients receiving fluoroquinolone s prophylxis? Clin Infect Dis 1995; 20: Chopr R, McMilln AK, Linch DC et l. The plce of highdose BEAM therpy nd utologous bone mrrow trnsplnttion in poor-risk Hodgkin s disese. A single-center 8-yer study of 155 ptients. Blood 1993; 81: