J Am Soc Nephrol 14: 440–447, 2003 15-Deoxyspergualin in Patients with Refractory ANCA- Associated Systemic Vasculitis: A Six-Month Open-Label Trial to Evaluate Safety and Efficacy

RAINER BIRCK,* KLAUS WARNATZ,† HANNS M. LORENZ,‡ MIRA CHOI,§ MARION HAUBITZ,¶ MATHIAS GRU¨ NKE,† HANS H. PETER,‡ JOACHIM R. KALDEN,† URSULA GO¨ BEL,§ JOHANNES M. DREXLER,ʈ OSAMU HOTTA,# RAINER NOWACK,* and FOKKO J. VAN DER WOUDE* *Department of Nephrology, University Hospital Mannheim, Mannheim, Germany; §Department of Nephrology, Berlin-Buch, Germany; and ¶Department of Nephrology, Hannover, Germany; †Department of Clinical Immunology and Rheumatology, University Freiburg, Freiburg, Germany; ‡Department of Rheumatology, Erlangen-Nu¨rnberg, Germany; ʈEuro Nippon Kayaku GmbH, Frankfurt, Germany; and #Department of Nephrology, Sendai Shakaihoken Hospital, Japan.

Abstract. The combination of cyclophosphamide (CYC) and was given for 2 to 3 wk until the WBC count dropped to oral corticosteroids is effective in the majority of patients with 3000/␮l followed by a rest until at least a WBC of 4000/␮l was antineutrophil cytoplasmic antibody-associated vasculitis reached again. This was repeated up to six cycles. During the (AASV), but it carries substantial risk of drug-related morbid- study, no other immunosuppressants besides steroids were ity and mortality. New regimens are desired, especially in allowed. Disease improvement during treatment with DSG was refractory cases. The immunosuppressant 15-deoxyspergualin achieved in 70% of cases (six cases of complete remission; (DSG) is effective in experimental autoimmune disease and eight cases of partial remission). Leucopenia occurred in each transplantation as well as in acute kidney transplant rejection in patient in a regular pattern during the cycles and was transient humans. To assess the efficacy and safety of DSG, an open without exception. No mortality or septicemia was observed. label multicenter trial was conducted in patients with AASV Mild to moderate infections mainly in the respiratory tract were who were either unresponsive or had contraindications for observed but resolved under adequate treatment without se- standard immunosuppressants. Included were 19 cases of We- quel. It is concluded that treatment with DSG is successful in gener granulomatosis and one case of microscopic polyangiitis. patients with refractory Wegener granulomatosis under careful Nine of them had received CYC shortly before study entry monitoring of WBC count. without apparent therapeutic success. DSG (0.5 mg/kg per d)

Antineutrophil cytoplasmic antibody (ANCA)-associated regimen in the majority of patients, up to 25% achieve no small-vessel vasculitis (AASV) is the most common primary complete remission (2) and relapses are seen in up to 50% (3). small-vessel vasculitis in adults, encompassing Wegener gran- Moreover, it is associated with serious treatment-related risks ulomatosis (WG), microscopic polyangiitis (MPA), and the in 42% of patients, including severe infections, increased in- Churg-Strauss syndrome. The introduction of the combination cidence of malignancies, as well as gonadotoxicity (3). Thus, of cyclophosphamide (CYC) and oral corticosteroids (OCS) new treatment strategies combining less toxicity with compa- for the treatment of active WG in the early seventies changed rable efficacy are warranted, especially in frequently relapsing a formerly almost invariably fatal disease with a lethality rate or refractory cases or in patients suffering from severe side of 82% in the first 12 mo (1) into a treatable condition of a effects of CYC. more chronic-relapsing nature associated with a 5-yr survival 15-Deoxyspergualin (DSG; 1-amino-19-guanidino-11-hy- rate of 80% (2). Despite the efficacy of the above-mentioned droxy-4, 9, 12-triazanona-decane-10, 1–3-dione; generic name, Gusperimus) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus (4). Spergualin, Received July 28, 2002. Accepted October 22, 2002. a peptidomimetic compound containing a spermidine-moiety Correspondence to Dr. Rainer Birck, Fifth Department of Medicine, (Nephrol- within its structure, was discovered in 1981 by Umezawa et al. ogy/Endocrinology/Rheumatology), University Hospital Mannheim, Theodor- Kutzer-Ufer 1-3, D-68135 Mannheim, Germany. Phone: 49-621-383-2674; in a culture filtrate while screening for natural products that Fax: 49-621-383-732110; E-mail: [email protected] inhibit the transformation of chicken embryo fibroblasts 1046-6673/1402-0440 through Rous sarcoma virus (5). Although initially developed Journal of the American Society of Nephrology as an anti-cancer drug (6), strong immunosuppressive proper- Copyright © 2003 by the American Society of Nephrology ties were discovered and studied in several animal models of DOI: 10.1097/01.ASN.0000048716.42876.14 transplantation (7–8) and of autoimmune disease (9–10). In J Am Soc Nephrol 14: 440–447, 2003 15-Deoxyspergualin and Vasculitis 441 clinical trials including patients with recurrent kidney trans- Group (EUVAS) (18). The primary endpoint of the study was the plant rejections, DSG led to remission in 79% of cases (11). remission rate after six cycles of DSG respectively after study Moreover, in a randomized trial in patients with steroid-resis- termination. Complete remission was indicated by complete ab- tant kidney transplant rejections, DSG was as effective as the sence of clinical signs of disease activity. Partial remission was monoclonal antibody OKT3, showing reversal of acute rejec- defined as absence of acute or newer clinical activity, although minor persistent activity was allowed to be present. Relapse was tion in 59% respectively 62% (12). Recently, Hotta et al. (13) defined as recurrence or first appearance of typical organ involve- demonstrated that DSG shows therapeutic efficacy in patients ment characteristic of the underlying disease. ANCA titers were with crescentic proliferative glomerulonephritis. From preclin- irrelevant for the purpose of this protocol. The effect of treatment ical and clinical data, DSG appears to be a potent immunosup- on disease activity, further organ-damage, and on functional as- pressant with a favorable side effect profile exerting no renal, pects was also assessed before and after each cycle with the BVAS, liver, or diabetogenic toxicity and only reversible bone marrow before the first and after the third and the sixth cycle with the VDI, suppression (11–14). To assess the efficacy and tolerability of and before the first and after the sixth cycle with the SF-36 DSG, we conducted a pilot trial in patients with active WG or functional assessment questionnaire. The scores were used as MPA refractory or with contraindications to standard secondary endpoints within this trial, adding to the clinical judg- immunosuppressants. ment of the responsible physicians but not restricting it. The BVAS is calculated from new or deteriorated symptoms and signs within the previous month attributable to active vasculitis in nine separate Materials and Methods organ systems that are weighed according to their relative contri- Patients bution on mortality and morbidity of systemic vasculitis. Chronic In this open-label multicenter trial, three nephrology and two irreversible organ damage attributable to systemic vasculitis was rheumatology departments in tertiary care centers within Germany scored by the VDI. To count for VDI, the signs or symptoms had participated. Eligible were patients with WG, MPA, or renal limited to be present for at least 3 mo. All patients were also reevaluated vasculitis with or without histologic confirmation and c- or p-ANCA 6 mo after study termination with respect to efficacy and safety of positivity with specificity for proteinase 3 (PR-3) or myeloperoxidase prior DSG treatment. (MPO). ANCA-negative cases could be included if confirmed histo- Due to the low patient number, mainly descriptive statistical anal- logically. Furthermore, these patients had to have a history of intrac- yses were performed with respect to variables like BVAS scores, table course, severe side effects, frequent relapses, or constantly steroid dosages, demographic characteristics, etc. For comparing grumbling disease under standard immunosuppressants or denied to means between BVAS scores and steroid dosages at the beginning and be treated with cytostatics. Exclusion criteria were a leukocyte count the end of the study the paired t test was used. P Ͻ 0.05 was Ͻ ␮ 4000/ l, pregnancy and lactation, the presence of uncontrolled considered to be significant. acute or chronic infections, anticonvulsive treatment, and inadequate contraception. The study was in accordance with the Declaration of Helsinki as well as the requirements of Good Clinical Practice (GCP). All patients gave written informed consent before inclusion, and Results ethical approval was obtained in each participating center. Reliability Treated Patients of the data in the record books was checked throughout the study by Clinical characteristics and demographic details of the in- a professional monitoring company (Omnicare Clinical Research cluded 20 patients are summarized in Tables 1, 2, and 3. GmbH, Germany). Seventeen patients were enrolled in the official study according to GCP from May 1999 to July 2000. Before the official study, Treatment Protocol three patients (patients 1, 2, and 6) were treated on compas- After entry to the study, all but three patients were given DSG in sionate-use basis with commercial DSG (from May 1998 to a dosage of 0.5 mg/kg daily by subcutaneous injection. Patients 1 to September 1999), and their treatment modalities and evalua- 3 received the first week of treatment by intravenous injection with tions were performed according to the same protocol. In this the same dosage. The aim within each cycle was to reach a leukocyte report, those 17 and 3 patients were summed up and used for nadir of 3000/␮l. WBC were therefore monitored every other day. safety and efficacy analysis. Nineteen patients had WG, and Treatment was then discontinued for 2 wk to allow the leukocyte one patient (patient 17) suffered from MPA. All patients with number to recover, and the cycle was repeated up to six times. exception of two (patient 7: no biopsy results available; patient Treatment was continued by subcutaneous injection by the patient in 13: nonspecific inflammation) had biopsy-proven necrotizing the same dosage to facilitate therapy in an outpatient setting. Besides vasculitis, granulomatous inflammatory changes, or both in a steroids, no other immunosuppressive drugs were allowed during the typical organ system during their disease history. Fifteen of study period. The steroid regimen was not restricted by the study ϩ ϩ protocol and was chosen individually by each investigator on clinical nineteen WG patients were cANCA /PR3 at entry, and the ϩ ϩ grounds. MPA case was pANCA /MPO . Mean age at study entry was 51.3 yr (range, 34 to 78 yr), mean disease duration was 5.54 yr Assessment of Disease Activity (range, 0.25 to 25.3 yr) and mean number of relapses before The definitions for refractory disease, remission, and relapse as study entry was 4.3 (range, 0 to 13) times. Previous immuno- well as the use of the Birmingham Vasculitis Activity Score suppressive medications had been taken by all patients (for (BVAS) (15), the Vasculitis Damage Index (VDI) (16) and the details, please see Table 1). The mean cumulative CYC dosage Short-Form-36 (SF-36) (17), were adopted from the criteria used in patients ever receiving CYC (18 of 20) was 78 g (range, 4.5 within the therapeutic trials of the European Vasculitis Study to 199 g). 442 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 440–447, 2003

Table 1. Clinical and demographic characteristicsa

VDI BVAS Patient Age (yr)/ Pretreatment History IS/OCS at Entry Gender (with Cumulative CYC Dosage) Scores are (in mg/d p.o. Unless Otherwise Indicated) given at entry

1 37/m CYC 4.5 g, AZA, MMF, IVIG, PPS, MTX 5 12 MTX 15 s.c. weekly/MP 16 2 52/f CYC 34 g, AZA, MMF 3 19 MMF 2000/MP 4 3 78/m CYC 68 g 3 12 CYC 75/MP 32 4 34/m CYC 46 g, CyA, MTX, MMF, AZA 7 10 MMF 1000, AZA 100/MP 10 5 36/f CYC 73 g, AZA, MTX, CyA 7 6 CYC 100/PREL 7.5 6 64/m CYC 90 g 4 25 PREL 75 7 58/f CYC 90 g, AZA, MTX 9 11 MTX 15 s.c. weekly/PREL 50 8 59/f CYC 64 g, MMF 4 9 MMF 1000/MP 4 9 39/m CYC 50 g, AZA 3 7 CYC 100/0 10 68/m CYC 96 g 3 5 CYC 150/PRED 6 11 42/f CYC 138 g, MTX 1 12 MTX 25 s.c. weekly/MP 20 12 56/f MTX 1 13 MTX 15 s.c. weekly/PRE 100 13 39/f CyA, MTX 1 5 CyA 300/PRED 30 14 60/f CYC 36 g 5 6 CYC 75/PRE 30 15 57/f CYC 189 g 3 3 CYC 25/PRED 6 16 55/m CYC 9 g 2 7 CYC 750/m2 i.v. monthly/MP 28 17 39/m CYC 79 g, MMF 5 11 CYC 1000/m2 i.v. monthly, MMF 2000/PRE 15 18 36/f CYC 199 g, MTX, AZA 8 3 CYC 50/PRE 20 19 62/f CYC 85 g, MTX, CyA, AZA 4 8 AZA 100/PRE 10 20 55/m CYC 50 g 4 12 MP 80

a BVAS, Birmingham Vasculitis Activity Score; VDI, vasculitis damage score; OCS, oral steroids; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; MP, methylprednisolone; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; ATG, anti-thymocyte globulin; PPS, plasmapheresis; IVIG, intravenous immunoglobulin; CyA, cyclosporine A; IS, immunosuppressant; f, female; m, male.

Treatment Directly before Study Entry previous cycle. One patient (patient 8) did not respond at all to Immediately before initiation of DSG therapy, all patients DSG treatment showing disease progression. Of the nine pa- had received immunosuppressants (for details, Table 1) that tients on CYC treatment (patients 3, 5, 9, 10, 14 to 18) right either failed to control disease activity or could not be contin- before the study entry, one patient (patient 5) achieved com- ued due to severe side effects. Nine of these patients (patients plete remission, and four patients (patients 9, 10, 15, and 17) 3, 5, 9, 10, and 14 to 18) received CYC either orally (n ϭ 7; achieved partial remission. Beneficial effects of DSG treatment mean dosage, 82 mg/d; range, 25 to 150 mg) or intravenously were observed in all organ systems typically affected by sys- (n ϭ 2; mean dosage, 875 mg/m2 monthly; range, 750 to 1000 temic vasculitis. Thus, regression or resolving of pulmonary mg/m2) directly before the study entry without sufficient ther- lesions (Figure 1) and subglottic granuloma, reversal of ne- apeutic effect. CYC was contraindicated in four patients due to phritic urinary sediment and improvement of proteinuria and hemorrhagic cystitis (patients 7, 8, 10, and 15) and in one renal function (data not shown), as well as disappearance of patient due to toxic hepatitis (patient 1). At study entry, the palsies and constitutional signs were noted. mean daily oral steroid dosage was 27.2 mg (range, 0 to 100 The mean BVAS showed a significant improvement from 11 mg). One patient (patient 12) received during cycle 1 pulse Ϯ 5.8 to 4 Ϯ 2.9 (P ϭ 0.002) in responders and an increment intravenous steroids up to 500 mg. Individual steroid dosages in nonresponders from 8 Ϯ 3to11Ϯ 5.8 during the study are given in Table 1. being congruent to the investigators’ clinical judgment in al- most all patients. Responsiveness to DSG was also associated Treatment Effects with a decreased usage of OCS. In responding patients, the Six (30%) of twenty patients went into complete remission, mean daily oral steroids dosage could be significantly reduced and 8 (40%) of 20 showed partial remission after study termi- from 30.0 Ϯ 32.18 mg at entry to 7.5 Ϯ 4.17 mg/d at study nation. Thus, 14 (70%) of 20 patients showed improvement termination (P ϭ 0.029). Individual numbers of the BVAS and after DSG treatment. Of the remaining six patients, three the concomitant OCS treatment in each patient at study entry (patients 4, 14, and 16) relapsed in cycle 6 under DSG treat- and at study termination as well as 6 mo thereafter are given in ment despite achieving partial or complete remission in the Tables 1, 2, and 3. The VDI was constant, indicating no further J Am Soc Nephrol 14: 440–447, 2003 15-Deoxyspergualin and Vasculitis 443

Table 2. Treatment and outcomes in respondersa

Outcome at Study Termination/6 mo later Cycles Therapy during the 6 mo Follow-Up after Study Patient Treated Termination (n) Clinical BVAS OCS (mg/d)

1 6 CR/CR 0/na MP 8/3 Maintenance with DSG 2 6 CR/CR 6/na MP 4/2 Maintenance with DSG 5 6 CR/CR 3/na PRE 7.5/5 Maintenance with DSG 6 6 PR/REL 7/na PREL 4 Maintenance with DSG; PREL could be tapered off completely; relapse in month 6; switch to CYC and high-dose steroids 7 6 PR/CR 4/na PREL 10/7.5 Maintenance with OCS 9 6 PR/CR 4/na PREL 20/5 Maintenance with AZA 10 6 PR/PR 10/na PRED 3/3 Maintenance with AZA 11 6 PR/PR 5/na MP 6/4 Maintenance with MTX 12 6 CR/REL 1/na PRE 5 Maintenance therapy with AZA, after 2 mo severe renal relapse; switch to CYC and high-dose steroids; then fatal pneumocystis carinii pneumonia 13 6 CR/CR 5/na PRED 6/6 Maintenance with MTX 15 2 PR/PR 3/na PRED 6/4 Maintenance with MTX 17 6 PR/PR 5/na PRE 10/5 Maintenance with AZA 19 2 CR/REL 3/na PRE 10 Maintenance with AZA, MMF; relapse after 6 mo; switch to CYC and high-dose steroids 20 6 PR/CR 7/na MP 6/0 Maintenance with AZA

a PR, partial remission; CR, complete remission; REL, relapse; OCS, oral steroids; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; DSG, 15-deoxyspergualin; na, not applicable. progress in organ damage and the short-form 36 showed no were necessary to comply with the treatment protocol. Slight significant changes (data not shown). When the same cohort decreases in hemoglobin levels and thrombocytes were also was reevaluated 6 mo after study termination, in 11 of the 14 noted, but they were clinically insignificant with the exception patients initially responding to DSG, the achieved clinical of the above-mentioned patient 3 (data not shown). This patient condition was sustained respectively, even further improved developed thrombocytopenia during the first cycle, but throm- (Table 2). Only three patients experienced a relapse. bocytes recovered to baseline levels again after stopping the Five patients did not complete six cycles of DSG due to treatment. This patient was 78 yr old, had been pretreated with premature study termination. Patient 3 developed severe but 68 g of CYC, and had moderate thrombocytopenia already transient thrombocytopenia during cycle 1 and discontinued before initiation of DSG treatment. the treatment. Patient 8 did not respond to DSG, showing a The major side effects encountered during the study were primary treatment failure and was switched to another therapy mainly infections of the upper respiratory tract, which quickly after three cycles. Patient 15 showed recurrent urinary tract resolved with the use of antibiotics without further sequel. infection with bleeding episodes from preexisting teleangiec- There were also some cases of oral candidiasis and one infec- tasias and discontinued the treatment after two cycles while in tion with herpes zoster, which necessitated antifungal or anti- partial remission. Patient 18 discontinued the treatment after viral therapy. The infections were not related to the neutro- two cycles, as infection had mimicked vasculitis activity at penic phases during the cycles within the study. Besides the entry. Patient 19 reached complete remission after cycle 2 and above-mentioned side effects, local and systemic tolerability of was lost to follow-up. DSG was excellent, and most patients were basically willing to Treatment duration within the cycles was determined by the continue on DSG after study termination. Details concerning time necessary to reach target leucopenia levels. Cycles lasted adverse events encountered during the study are shown in on average 20.0 d (range, 8 to 37 d). Duration of treatment and Table 4. leucopenia did not change significantly during the whole study period. In all cases, leucopenia was transient and followed a Discussion foreseeable course without any signs of an accumulation effect. The present study was conducted to evaluate the safety and DSG affected mainly neutrophil counts; the changes in lym- efficacy of DSG for refractory patients with ANCA-associated phocyte counts were NS (Figure 2). A dose decrease in one vasculitis. It shows that DSG is able to stabilize disease or to patient (patient 5) and a dose increase in another (patient 9) induce complete remission in patients with active ANCA- 444 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 440–447, 2003

Table 3. Treatment and outcomes in nonresponders

Outcome at Study Termination Cycles Patient Treated Comments (n) OCS Clinical BVAS (mg/d)

3 Ͻ1 OTHERS 7 MP 32 During the first DSG cycle transient thrombocytopenia, switch to CYC and PREL; disease progress; adding plasmapheresis; partial remission; then lost to follow-up 4 6 REL 18 MP 14 Switch to CYC and high-dose steroids; then still grumbling disease under maintenance with DSG, MMF, and leflunomide with progression to end- stage renal failure 8 Ͻ3 OTHERS 15 MP 4 Initially disease progression under DSG; switched to ATG and high-dose steroids; partial remission; maintenance with steroids, MMF, and etanercept 14 6 REL 11 PRE 5 Switched to CYC and high-dose steroids; maintenance with MTX 16 6 REL 7 MP 150 Switched to CYC and high-dose steroids; death 2 mo later due to cerebral granuloma and septicemia 18 Ͻ2 OTHERS 4 PRE 20 Infection mimicking vasculitis at entry; retrospectively no active disease; maintenance with AZA; PRE reduced to 5

a REL, relapse; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; MP, methylprednisolone; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; DSG, 15-deoxyspergualin.

Figure 1. Lung computed tomography scans showing a pulmonary nodule on the right side as indicated by the arrow before (left panel) and after two cycles of 15-deoxyspergualin (DSG) treatment (right panel) in patient 19. associated vasculitis, even when prior immunosuppressive drugs and no restrictions concerning concomitant steroids us- agents, including CYC, have failed. This was an open-label age; therefore, a postponed effect of the other immunosuppres- trial in patients pretreated with a variety of immunosuppressive sants given before study entry or of initially increased steroid J Am Soc Nephrol 14: 440–447, 2003 15-Deoxyspergualin and Vasculitis 445

Figure 2. A representative differential white blood cell count (patient 11) is shown during the study period (ordinate gives 1000 leukocytes/␮l). Start and end points denote beginning and end of DSG treatment.

dosages in many patients cannot be excluded. However, the Despite the significant reduction in neutrophil counts within patients included were chosen by investigators who were all each cycle, all experienced infections were of mild to moderate experienced in the field of vasculitis on the assumption that the intensity and resolved after adequate treatment. No signs of current immunosuppressive medications of the patients were cumulative toxicity of the drug after repeated cycles were seen either not sufficiently effective or contraindicated due to severe since the pattern and duration of leukocyte depression did not side effects. Thus, it seems unlikely that steroids alone or a change over time in the patients. In phase I studies in patients standard immunosuppressant given shortly before study entry with advanced cancer, DSG was well tolerated at doses ranging would stabilize vasculitis over the treatment time of six cycles from 20 to 500 mg/m2 per d by 3-h infusion or from 80 to 2792 (6 to 8 mo) in such a cohort of refractory patients. Moreover, mg/m2 per d (2 to 75 mg/kg per d) by 24-h infusion for 5 d. The in most patients responding to DSG, the beneficial effects were main adverse effects were reversible hypotension and transient sustained as indicated by the follow-up results 6 mo after study perioral numbness at the higher dose ranges. Mild myelosup- termination. Noteworthy, in a recent open-label study with a pression was also observed. Importantly, DSG showed no derivative of DSG, anisperimus, in patients with persisting or diabetogenic, hepatotoxic, or nephrotoxic properties in this relapsing primary systemic vasculitis (mostly AASV), prelim- setting (20–22). Excellent tolerability of DSG was also re- inary results showed beneficial effects in a substantial amount ported in a randomized double-blind controlled study in mul- of included patients (30), thereby confirming our novel thera- tiple sclerosis including 236 patients where DSG was given in peutic approach. doses of 2 mg/kg or 6 mg/kg intravenously in five 4-d courses Treatment with DSG, given subcutaneously or intravenously at 4-wk intervals. During the follow-up of 2 yr, the number and at dosages of 0.5 mg/kg per day until the target leukocyte count severity of adverse effects did not significantly differ from the of 3000 cells/␮l is reached was feasible and safe. For treatment placebo-treated groups. Within the treatment phases, a mild of acute kidney rejection, DSG is normally used in doses and transient myelosuppression with anemia and leucopenia ranging from 3 to 5 mg/kg per d intravenously infused for 5 to was noted (29). These data are also in accordance with an 10 d (11–12,14). However, on the basis of the data from animal adverse side effect report to the Japanese health authorities in experiments (19) as well as on the basis of clinical experience 1998, where in 385 cases of acute renal rejection a total of 38 from patients with various forms of crescentic proliferative infections were described without any severe septicemia (29). glomerulonephritides (13), the efficacy of DSG may rather be Noteworthy, in contrast to current immunosuppressive drugs in dependent on the duration of application than on the absolute preclininical toxicology studies used for registration, in Japan amount given. in 1994, DSG revealed no mutagenicity, teratogenicity, or 446 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 440–447, 2003

Table 4. Adverse events observed under treatment with also affects monocyte/macrophage/antigen-presenting cells. 15-deoxyspergualin Thus, decreased generation of reactive oxygen species and hydrolytic enzymes (25), diminished expression of MHC class Relationship (no. of patients) Adverse event II antigens (26), as well as inhibition of proliferation and Definitely Probably Possibly antigen processing/presentation have been observed (27–28). In conclusion, DSG appears as an effective and safe agent to Fever 5 treat patients with AASV refractory or with contraindications Diarrhea 5 to standard immunosuppressants. The observed side effects Headache 2 were mainly infections of mild to moderate intensity, all of Bronchitis 5 which could be controlled with appropriate therapy. Our pro- Nausea 4 posed treatment regimen necessitates determination of blood Upper respiratory tract infection 1 3 cell counts in regular intervals to monitor the myelosuppressive Anemia 1 5 effects of the drug. However, long-term treatment with subcu- Fatigue 3 taneous injection on an outpatient basis was feasible and safe. Paresthesia 2 1 Further studies are warranted to investigate DSG as secondary Sinusitis 3 or even primary agent in patients with systemic vasculitis. Conjunctivitis 1 Infection 4 Acknowledgment Oral moniliasis 4 This study was sponsored by Euro Nippon Kayaku GmbH, Parageusia 4 Staufenstr. 4, D-60323 Frankfurt, Germany. Pharyngitis 1 Urinary tract infection 1 3 References Coughing 2 1. Walton EW: Giant cell granuloma of the respiratory tract (We- Dyspnea 1 gener’s granulomatosis). Br Med J 2: 265–270, 1958 Injection pain 1 1 2. Fauci AS, Haynes BF, Katz P, Wolff SM: Wegener‘s granulo- Renal function abnormal 3 matosis: Prospective clinical and therapeutic experience with 85 Rhagades 3 patients for 21 years. Ann Intern Med 98: 76–85, 1983 Sore throat 3 3. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Acne 1 1 Travis WD, Rottem M, Fauci AS: Wegener’s granulomatosis: Dysuria 2 An analysis of 158 patients. Ann Intern Med 116: 488–498, 1992 Heartburn 2 4. Maeda K, Umeda Y, Saino T: Synthesis and background chem- Influenza-like symptoms 2 istry of 15-deoxyspergualin. Ann NY Acad Sci 685: 123–135, 1993 Vomiting 2 5. Takeuchi T, Iinuma H, Kunimoto S, Masuda T, Ishizuka M, Takeuchi M, Hamada M, Naganawa H, Kondo S, Umezawa H: A new antitumor antibiotic, spergualin: Isolation and antitumor cancerogenicity (29). In the above-mentioned trial with its deriv- activity. J Antibiot 34: 1619–1621, 1981 ative anisperimus (30), cardiotoxicity was suspected in two cases 6. Nishikawa K, Shibasaki C, Takahashi K, Nakamura T, Takeuchi due to some changes in left ventricular function as indicated by T, Umezawa H: Antitumor activity of spergualin: A novel anti- echocardiography (personal communication Dr. David Jayne, tumor antibiotic. J Antibiot 39: 1461–1466, 1981 Cambridge, UK). However, the findings in both cases were not 7. Itoh J, Takeuchi T, Suzuki S, Amemiya H: Reversal of acute rejection episodes by deoxyspergualin (NKT-01) in dogs receiv- unequivocal; neither in the available literature (14,20–22,29) nor ing renal allografts. J Antibiot 41: 1503–1505, 1988 in our trial were any signs of cardiotoxicity noted. Thus, DSG 8. Reichenspurner H, Hildebrandt A, Human PA, Boehm DH, Rose appears, despite its considerable immunosuppressive properties, AG, Odell JA, Reichart B, Schorlemmer HU: 15-Deoxyspergua- as a drug with a favorable side effect profile when compared with lin for induction of graft nonreactivity after cardiac and renal standard immunosuppressants. allotransplantation in primates. Transplantation 50: 181–185, The precise mechanism of action of DSG, however, remains 1990 obscure. From the available data, it seems that it influences the 9. 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