<J. OJ 'I. Cyclophosphamide for Clinical Renal and Hepatic Transplantation

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1 OJ 'I U (fl <J. Cyclphsphamide fr Clinical Renal and Hepatic Transplantatin By T. E. Starzl, C. G. Grth, C. W. Putnam, J. Crman, C. G. Halgrimsn, I. Penn, B. Husberg, A. Gustafssn, S. Cascard, P. Geis, and S. Iwatsuki SINCE March, 1971, cyclphsphamide (Cytxan) has had a prminent rle in the immunsuppressin administered t recipients f whle rgans at ur center. This reprt will be cncerned with the results in these patients, abut tw-thirds f whm nw have a ptential fllw-up f mre than 1 yr. MATERIALS AND METHODS Renal Hmtransplantatin Frm Related Dnrs: Dnrs fr 32 recipients included 16 siblings (six were duble hapltype HL-A identical), 14 parents, ne aunt, and ne grandmther. Except fr the search fr HL-Aidentical siblings, the results f HL-A matching were nt given weight in dnr selectin. An attempt was made t avid transplantatin when the crssmatch was psitive fr cyttxic antibdies. Hwever, in ne case, such antibdies develped in the perid between testing and peratin with a resulting hyperacute rejectin. Cyclphsphamide, prednisne, and hrse antilymphcyte glbulin (ALG) were started several days in advance f peratin and cntinued afterwards in varius mdificatins f the general regimen described in detail eisewherel2 and shwn in Figs. 1 and 2. Pstperatively, ALG was usually cntinued fr 2-4 m. Befre September 1971 mst patients were treated with cyclphsphamide fr many mnths after which a change was eventually made in almst every case t maintenance therapy with azathiprine (Fig. 1). In cntrast, patients treated in the last 3 m f the study (Octber t December 1971) had a shrter curse f cyclphsphamide therapy (1-2 m) befre switching t aza- Frm the Department f Surgery, University f Clrad Schl f Medicine and the Veterans Administratin Hspital, Denver, Clrad. Supprted by research grants frm the Veterans Administratin, by grants RR and RR frm the general clinical research centers prgram f the Divisin f Research Resurces, Natinal Institutes f Health, and by grants AI , AI-AM-08898, and AM by Crune & Strattn, Inc. thiprine (Fig. 2). Dses f cyclphsphamide in milligram per kilgram bdy weight were usually ne-half t tw-thirds thse later emplyed with azathiprine. With either f these ptentially radimimetic agents, an effrt was made t avid leukpenia. Cadaveric Transplantatin: The crssmatch test fr cyttxic antibdies was negative in all cases. HL-A typing was perfrmed, but since the results were nt taken int cnsideratin fr dnr-recipient pairing, all recipients were given mre r less badly matched kidneys (5 C, 10 D, and 18 E)*. Therapy after cadaveric transplantatin was similar t that after cnsanguineus transplantatin except that immunsuppressive pretreatment was nt feasible. The cadaveric recipients, by and large, presented mre cmplicated prblems f management than did related cases. Their average age was 33 ± 12.7 (SD) yr as ppsed t 27 ± 11.2 (SD) yr fr the cnsanguineus recipients. In additin whereas nly ne f the 32 recipients f related kidneys was underging retransplantatin, nine f the 29 cadaveric recipients had already rejected ne r mre hmgrafts at sme previus time. Hepatic Hmtransplantatin There were 16 patients, aged 1-53 yr, wh received rthtpic hepatic hm grafts frm 2-19 m ag and wh were treated with a cyclphsphamide-cntaining, triple drug regimen similar t that used fr recipients f cadaveric kidneys (Fig. 3). The indicatins fr liver replacement were biliary atresia (seven cases), chrnic aggressive hepatitis (fur cases), biliary cirrhsis (three cases), Wilsn's disease (ne case) and hepatic hemangiendthelial sarcma (ne case). RESULTS Frm Related Dnrs (Table 1): Three (9.4%) f the 32 recipients died, 2 frm Pneumcystis carinii pneumnia, and the *C = ne mismatched HL-A antigen; D = ne mismatch f each HL-A lcus; E = duble mismatch at ne HL-A lcus, usually with mismatches at ther lcus as well. Transplantatin Prceedings, Vl. V, N.1 (MarCh),

2 512 STARZL ET AL. BUN (mg 'Y) TRANSPLANT Weighl Kg 25 year ld rj +-~ ~ CYCLOPHOSPHAMIDE c::::::j AZATH IOPRINE (mg/day) PREDNISONE 1 ALG (4cc) I i I TIME IN DAYS Fig. 1. The chrnic use f cyclphsphamide in cnjunctin with prednisne and early ALG in the recipient f a parental renal hmgraft. Treatment was changed t azathiprine after 10 m, with an increase in the milligram per day dse. The patient has a perfect result after 11/2 yr. BUN (mg%) TRANSPLANT Weight 36.4 t 53,2 Kg 15 year ld «20 ~ ~~---- ~ ~ CYCLOPHOSPHAMIDE c::= AZATHIOPRINE 1 PREDNISONE 1 ALG (2cc) I I I II I I I II I I, iii iii i i TIME IN DAYS Fig. 2. The use f cyclphsphamide fr the first pstperative mnth with subsequent azathiprine treatment. The result was excellent after almst a year.

CYCLOPHOSPHAMIDE Table 1. Results with Renal Hmtransplantatin: Fllw-up 9-18 Mnths Ttal Lst Dnr Number Per cent Cnsanguineus Patients 32 3 9.4 Grafts 32 6 18.8 Cadaveric Patients 29 7' 24.

3 CYCLOPHOSPHAMIDE Table 1. Results with Renal Hmtransplantatin: Fllw-up 9-18 Mnths Ttal Lst Dnr Number Per cent Cnsanguineus Patients Grafts Cadaveric Patients 29 7' 24.1 Grafts 33 11' 33.3 'Fur f the seven deaths and seven f the 11 graft lsses were in nine patients underging retransplantatin. third frm perfratin f a sigmid clnic diverticulum. Three additinal grafts were lst, tw frm hyperacute rejectin and ne frm a technical surgical accident, fr a ttal kidney lss rate f 6 in 32 (18.8%). Frm 9-18 m pst-transplantatin, the remaining 26 cnsanguineus renal hmgrafts have average functins as fllws: BUN 25.6 :!: 10.3 (SO) mg/mt and creatinine clearance 70.9 :!: 20.4 (SO) mllmin. The clinical result is presently cnsidered excellent with 24 f these 26 kidneys and fair in the ther tw. Cadaveric Transplantatin (Table 1): Seven (24%) f the 29 recipients died; all but 1 frm causes that were apparently directly related t immunsuppressin. These included brain tumr (gliblastma multifrme), hindquarter gangrene due t Pseudmnas, a fungal brain abscess (Aspergillus), Pneumcystis carinii pneumnitis, perfrated sigmid diverticulitis and giant cecal ulcer. The seventh patient died f a recently described cmplicatin f hyperparathyridism-cnsisting f widespread skin and muscle gangrene apparently due t calcium plugging f multiple small arteries.3 There were fur deaths (44%) amng the 9 patients underging ertransplantatin (after a previus graft had been in residence fr 1 hr t 5 yr, average 18 ml cmpared t three (15%) amng the 20 receiving primary hmgrafts. 513 The 29 recipients f cadaver kidneys were given 33 transplants. Tw f the fur extra rgans were used in the classic sequence after the initial grafts had been rejected and remved but in the ther 2 cases secnd transplants were inserted 11/2 and 5 wk after the first because f pr initial functin. In these latter recipients, bth the first and secnd hm grafts eventually functined fr lng perids. Twenty-tw f the 33 grafts (67%) are still functining after 9-18 m. The 11 lst rgans failed fr the fllwing reasns: Seven frm recipient death; tw frm uncntrlled rejectin; ne frm hyperacute rejectin; and ne because it was remved fr wund pain 14 m pst-transplantatin (ne f the duble hmgrafts described in the preceding paragraph). Twenty-ne f the 22 surviving patients have life-supprting urine excretin, the exceptinal patient being back n dialysis. The hmgrafts have average functin as fllws: BUN 26.1 :!: 10.2 (SO) mg/ml and creatinine clearance 67.9 :!: 23.3 (SO) mll min. The clinical result is currently cnsidered excellent r gd in 19 f these 21 survivrs wh bear functining grafts, fair in ne, and pr in ne. Liver Hmtransplantatin Nine f the 16 recipients f hepatic hmgrafts died after 2-87 days. Causes f failure were biliary tract bstructin (three cases), biliary fistula (tw cases), hmgraft rejectin (tw cases), acute liver infarctin (ne case), and tumr recurrence (ne case). All five patients with biliary tract cmplicatins succumbed, fur f sepsis in spite f surgical crrectin f the lesin and/r drainage, and the fifth after an attempt at retransplantatin. Seven patients are alive 18, 14, 7, 5, 5, 4, and 2 m after transplantatin fr Wilsn's disease (ne case), biliary atresia (ne case), cngenital biliary cirrhsis (tw cases), and chrnic aggressive hepatitis

4 514 STARZL ET AL. (three cases). One f the patients has mderate hepatic dysfunctin due t chrnic rejectin at 14 mnths (bilirubin 2 mg%) and the ther six have nrmal r near nrmal liver functin. DISCUSSION In this cmmunicatin, mst f the case material cnsisted f patients wh received cyclphsphamide as the initial cyttxic agent in a triple drug prgram with the frequent later substitutin f azathiprine. In previus publicatins,1.2 cnsiderable experience was reprted with the reverse rder f administratin, using cyclphsphamide t replace azathiprine. Under bth circumstances, cyclphsphamide has seemed equivalent t azathiprine in its txicity as well as in its immunsuppressive effectiveness. It is f interest that in kidney recipients tw drugs belnging t such different chemical families and having such fund a- mentally different mdes f actin as cyclphsphamide and azathiprine can be substituted freely fr each ther. It remains t be seen if switching agents will have real benefits such as, fr example, if the depletin f sensitized immuncmpetent cells was mre effective. At the mment, this remains a pssibility, but ne which has by n means been prven. In the therapeutic prgram that has evlved during the last 18 mnths and is nw in rutine use, cyclphsphamide has been used as the first-line agent fr 2 m r fr whatever fractin f that time during which dses f at least 1 mg/kg/ day can be tlerated withut bne marrw depressin. Even in these small quantities, cyclphsphamide may cause leukpenia, in which case the substitutin f azathiprine is made prematurely. Using this manipulatin f the cyclphsphamide-azathiprine cmplex in a system that als includes prednisne and We~ht ~ 46 K. 15 year ld r:i BILIRUBIN (mg %) TRANSPLANT O++~~==~~~~ ~~~~=-==~~-=~--~~~ ~ CYCLOPHOSPHAMIDE 1 CJ AZATHIOPRINE 100 (mg/day) PREDNISONE 1 ALG (4 ee) AUSTRALIAN ANTIGEN (CF) iii i TIME IN DAYS Fig. 3. Triple drug treatment, including cyclphsphamide, in an rthtpic liver recipient. N rejectin was diagnsed, but serum hepatitis in the secnd and third pstperative mnths caused jaundice. After 9 m, azathiprine was substituted fr cyclphsphamide. I

5 CYCLOPHOSPHAMIDE ALG, patient and graft-survival in renal cases have been essentially the same as with the precyclphsphamide triple-drug cmbinatin f azathiprine, prednisne, and ALG.2 The quality f graft functin in the cyclphsphamide-treated patients has been at least as gd and pssibly even superir. In analyzing results with immunsuppressive prgrams in the mdern era f transplantatin, mre than passing cnsideratin must be given t the increasing cmplexity f case material, which is ging t make it difficult t achieve results as gd as thse btained in highly selected series f a few years ag. Mre and mre, candidates are being accepted wh, until recently, wuld have been excluded because f age, assciated diseases, r ther reasns. In additin, a third f all cadaveric renal hmgrafts in the present reprt were used fr retransplantatin under cnditins which prved t have a very high risk (44% mrtality). In cntrast, patients receiving primary cadaveric hmgrafts faced nly a 15% mrtality, apprximately the same with 9-18-m fllw-ups as with cnsanguineus transplantatin. The essential equivalency f results after renal transplantatin under primary cyclphsphamide, as ppsed t azathiprine therapy, will nt be a strng inducement fr ther grups, mainly interested in the kidney, t change their present regimen f azathiprine management, except fr specific indicatins such as drug hepatxicity. But with liver transplantatin, future pssibilities are mre expansive. The disadvantages f azathiprine fr liver transplantatin have been well recgnized, including its ptential hepattxicity, as well as its dependence upn liver functin fr bth activatin and degradatin.4,5 Recently, Bach and Dardenne6,7 have prvided striking evidence, with the rsette inhibitin biassay, that azathiprine lses its immunsuppressive qualities in human 515 tin. Their wrk has been cnfirmed in human liver recipients by Mitchell et al.b beings if there is significant liver malfunc- If, as seems likely frm Bach's data, the rsette inhibitin test is a discriminating biassay f immunsuppressin, hepatic damage frm ischemia, rejectin, r ther causes culd cancel the efficacy f azathiprine at a crucial time, especially early pstperatively. This culd explain why rejectin has been s difficult t cntrl in human liver recipients, particularly when ALG has been mitted,5 in spite f impressive evidence frm animal research4,5,9-11 that the liver shuld be "easier" than ther rgans. It is pssible that the ptency f cyclphsphamide is similarly turned ff during hepatic dysfunctin, since cyclphsphamide is als activated in the liver. Studies f rsette inhibitin during cyclphsphamide treatment, t settle this questin, will be f great interest. Our experience with cyclphsphamide is cnsistent with the hypthesis that this drug retains sufficient ptency thrughut variatins in pstperative hepatic functin. During the learning perid, mistakes in cyclphsphamide dsage, technical surgical cmplicatins, and recurrence f malignancy caused several deaths. Nevertheless, seven f 16 patients (44%) are still alive, including five f the six recipients treated in the present year. This last grup is the best cnsecutive series f liver cases we have ever seen and may herald the transitin f hepatic transplantatin frm clinical investigatin t true patient service. SUMMARY Cyclphsphamide was given as the initial cyttxic drug in cmbinatin with prednisne and ALG t 61 renal recipients. After 1 m r lnger, azathiprine was substituted fr cyclphsphamide fr maintenance therapy. After 9-18 m, the patient and kidney survivals with cnsanguineus transplantatin are 91 % and 81 %, respec-

6 516 STARZL ET AL. tively, and after cadaveric renal transplantatin the figures are 76% and 67%, respectively. These results are similar t thse btained in the past with azathiprine alne. Sixteen recipients f rthtpic cadaveric livers were similarly treated with seven (44%) living after 2-18 m. With avidance f technical accidents and increased experience with cyclphsphamide, the 1. Starzl, T. E., Halgrimsn, C. G., Penn, 1., Martineau, G., Schrter, G., Amemiya, H., Putnam, C. W., and Grth, C. G.: Lancet 2:70, , Putnam, C. W., Halgrimsn, C. G., Schrter, G. P., Martineau, G., Launis, B., Crman, J. 1., Penn, 1., Bth, A. 5., Jr., Prter, K. A., and Grth, C. G.: Surg. Gynecl. Obstet. 133 :981, Massry, 5. G., Grdn, A., Cburn, J. W., Kaplan, 1., Franklin, S. 5., Maxwell, M. H., and Kleeman, C. R.: J. Med. 49:416, Starzl, T. E., Marchir, T. 1., and Prter, K. A.: In Welch, C. (Ed.): Advances in Surgery. Chicag, Year Bk, 1966, p , and Putnam, C. W.: Experience in Hepatic Transplantatin. Philadelphia, Saunders, Bach, J. F., and Dardenne, M.: Paper presented at the Furth Internatinal Cngress f REFERENCES recrd since January 1972 is five survivrs f six. In these patients, little difficulty was encuntered with cntrl f rejectin. This bservatin, plus recent evidence that azathiprine may nt be immunsuppressive in patients with significant hepatic dysfunctin, suggests that cyclphsphamide is the preferable primary cyttxic drug fr the early treatment f liver recipients. Nephrlgy, Stckhlm, June, Prgram abstract quted by Mitchell et ai., see Ref , and Dardenne, M.: Prc. Ry. Sc. Med. 65 :260, Mitchell, C. G., Eddlestn, A. 1. W. F., Smith, M. G. M., and Williams, R.: Lancet 1 :1196, CaIne, R. Y., White, H. J. 0., Yffa, D. E., Binns, R. M., Maginn, R. R., Herbertsn, R. M., Millard, P. R., Mlina, V. P., and Davis, D. R.: Br. Med. J. 4:645, Terblanche, J., Peacck, J. H., Bwes, J., Davies, R., Tierris, E. J., Palmer, D. B., and Hunt, A. c.: Br. J. Surg. 54 :231, Garnier, H., Clt, J. P., Bertrand, M., Camplez, P., Kunlin, A., Grin, J. P., Gaziu, F. 1., Levy, R., and Crdier, G.: C. R. Acad. Sci. (Paris), 260:5621, 1965.

THROUGH 1979, immunosuppressive

THROUGH 1979, immunosuppressive Five-Year Survival After Liver Transplantatin THROUGH 1979, immunsuppressive therapy fr liver transplantatin at ur center was with aathiprine (r cyclphsphamide) and sterids, t which antilymphcyte glublin