Renal allograft immunosuppression. II. A randomized trial of withdrawal of one drug in triple drug immunosuppression. Reduced exposure to calcineurin inhibitors in renal transplantation. Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Randomized trial of chlorambucil for primary biliary cirrhosis. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Controlled trial of cyclophosphamide in rheumatoid arthritis. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Prevention of acute rejection episodes with an anti-interleukin 2 receptor monoclonal antibody. II. Results after a second kidney transplantation. Cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil in advanced prostatic cancer: a randomized trial.
A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n = 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D--81%, 88%, 88%, and 88%, respectively--or in patient survival--88%, 88%, 88%, and 97%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.
                We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival.
                The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).
                A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).
                Copyright 2007 Massachusetts Medical Society. We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up. To compare the efficacy and side effects of intermittent pulse cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide plus prednisolone, followed by azathioprine, in patients with proliferative glomerulonephritis caused by systemic lupus erythematosus (SLE).
                A multicentre randomised controlled trial was conducted between June 1992 and May 1996 involving eight European centres. All patients satisfied the American College of Rheumatology criteria for SLE and had biopsy proven proliferative lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as defined in the protocol, for two years. The trial was terminated after four years as recruitment was disappointing.
                32 SLE patients with lupus nephritis were recruited: 16 were randomised to intermittent pulse cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and 3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded from the pulse therapy group as they were later found to have pure mesangial glomerulonephritis. Two patients in the continuous therapy group developed end stage renal failure requiring dialysis, but none in the intermittent pulse therapy (p = 0.488; NS). There were similar numbers of side effects and withdrawals from treatment in both groups. There were three deaths: two in the intermittent pulse therapy group and one in the continuous therapy group.
                There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications occurred commonly, so careful monitoring is required during treatment. Twenty-four patients with primary biliary cirrhosis were entered into a prospective, randomized trial of chlorambucil therapy. Thirteen patients received chlorambucil (0.5-4 mg/day) and 11 patients received no therapy; all have been followed for 2-6 yr (mean, 4.1 yr). Two control but no treated patients died. Average serum bilirubin, serum aspartate aminotransferase activities, and albumin levels improved or remained unchanged in treated patients but worsened in controls. Serum alkaline phosphatase levels did not change in either group. Immunoglobulin M levels decreased and became normal in all treated patients but in only 3 control patients. Liver biopsy histology revealed an improvement in inflammatory cell infiltrate in treated patients in comparison with controls, but no significant change in degree of fibrosis or the histologic stage of disease. Side effects of therapy included bone marrow suppression necessitating discontinuation of the drug in 4 patients. These findings indicate that chlorambucil therapy may retard the progression of primary biliary cirrhosis. Whether such therapy will ultimately decrease morbidity and improve survival in this disease can only be demonstrated by large-scale, placebo-controlled trials. Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) Twenty-four patients with severe progressive rheumatoid arthritis were randomly assigned to cyclophosphamide or placebo in a double-blind crossover trial. Eleven patients who completed 9 months on cyclophosphamide (average dose: 1.8 mg/kg/day) demonstrated significant decrease in painful joints, swollen joints, and morning stiffness and increase in grip strength when compared to 11 patients on placebo. After crossover, significant improvement was observed in patients switched to cyclophosphamide, and deterioration within 2 months was observed in most patients changed from drug to placebo. Serum immunoglobulins and rheumatoid factor titers decreased with cyclophosphamide but antibody response to Vi antigen was unaffected. Primary delayed immune response to 2,4-dinitrochlorobenzene was markedly depressed. Adverse effects were troublesome--hemorrhagic cystitis affected 4 patients and amenorrhea occurred in 3. Despite striking beneficial effect, cyclophosphamide should be prescribed cautiously and only in severe resistant cases of rheumatoid arthritis. Most studies of adjuvant chemotherapy, radiotherapy, or immunotherapy in non-small-cell lung cancer patients with complete surgical resection of disease have shown negative results. However, two studies of stage II and III disease by our Lung Cancer Study Group suggested an advantage to adjuvant therapy with cyclophosphamide, doxorubicin, and cisplatin (CAP).
                Since neither of those studies had an untreated control, the Lung Cancer Study Group undertook a trial that included a control group and also offered the potential benefit of adjuvant therapy with CAP to patients with T1, N1 or T2, N0 (stage I) non-small-cell lung cancer.
                After complete resection, eligible patients with stage I disease were classified by known prognostic factors and randomly assigned to receive or not to receive four courses of CAP at 3-week intervals beginning on day 30 after surgery. The CAP regimen consisted of 400 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, and 60 mg/m2 cisplatin. Stratification by prognostic factors was as follows: histology (squamous versus nonsquamous), white blood cell count before surgery (> or = 9100/mm3 versus < 9100/mm3), and Karnofsky performance status before surgery (< or = 90% versus 100%).
                Of the 269 patients entered in the study, 101 had recurrence and 127 have died. Mean time since randomization is 6.4 years; mean follow-up is 3.8 years. There were no differences in time to recurrence or overall survival (not stratified by histology) between the two groups, even when analyses were adjusted for prognostic variables. There was one treatment-related death on the CAP arm due to infection during neutropenia. Only 53% of the eligible patients received all four courses of CAP, and only 57% of such patients received all four cycles on time. In 74% of the patients, the site of initial recurrence was distant.
                The most likely explanations for the lack of efficacy of CAP are poor compliance to the protocol and relative inactivity of the regimen, compared with the activity of drug combinations used in more recent studies. On the basis of this trial, adjuvant therapy with CAP should not be recommended for patients with resected stage I lung cancer.
                Further trials to test adjuvant therapy are indicated, but investigators should use better antiemetics to improve patient compliance as well as more active chemotherapy regimens. Renal transplant recipients experience adverse events attributed to corticosteroid therapy.
                This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation.
                There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P<0.01, P<0.01), triglycer. ides (P<0.01, P<0.01), and systolic blood pressure (P<0.001, P<0.001) were lower in the low/stop group. Diastolic pressure was lower (P<0.01) and lumbar spine bone density was greater (P<0.01) in the low/ stop group at 12 months.
                In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events. Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown.
                This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups.
                A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57+/-12, 65.2+/-20, 73.5+/-27 ml/min, P=0.044), the Jelliffe-2 (51.5+/-16, 56+/-19, 59.4+/-19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53+/-17, 58.5+/-20, 61.6+/-22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008).
                Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression. Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients. Primary renal transplant recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate mofetil, were randomized to either corticosteroid withdrawal at day four post-transplantation (n = 40) or standard steroid therapy (n = 43). The primary endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized subjects who underwent transplantation and received at least one dose of basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy-proven acute rejection at 12 months was not significantly different between the steroid withdrawal group (20%) and the standard treatment group (16%). Patient and graft survival was 100% in the steroid withdrawal group while one death in a patient with a functioning graft occurred in the standard steroid group. Seventy-two percent of the steroid withdrawal group remained off steroids at 6 months post-transplant. Allograft function and incidence of adverse events and infections were similar between the two groups. Rapid and early corticosteroid withdrawal among renal transplant recipients receiving basiliximab induction and daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not associated with an increased risk of acute rejection. In 1981, the Gynecologic Oncology Group initiated a prospective randomized study in which patients with poor-prognosis gestational trophoblastic disease received either standard MAC chemotherapy (methotrexate, dactinomycin, and chlorambucil) or the modified CHAMOMA regimen (methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine). The protocol was closed in May 1986 because the modified CHAMOMA regimen was significantly more toxic and possibly less effective. There were 42 patients entered, with 22 receiving MAC and 20 receiving modified CHAMOMA. There have been six deaths due to disease in the modified CHAMOMA group and none in the MAC group. Five MAC failures and one modified CHAMOMA failure have been rescued by surgery and/or chemotherapy. All six of the patients who died on the modified CHAMOMA regimen had developed disease following a previous term pregnancy, but none had prior chemotherapy. All seven patients who were treated for gestational trophoblastic disease after term pregnancy in the MAC group were cured of disease. With the modified CHAMOMA regimen, 44% of patients had life-threatening hematologic toxicity, as compared with only 9% of the MAC patients. Thus, the standard MAC regimen appears to be at least equally effective and much less toxic than the modified CHAMOMA regimen, indicating a more favorable therapeutic index. The focus of progress in transplantation immunosuppression is to achieve more specific immunosuppression with monoclonal antibodies. We have already shown that the efficacy of 33B3.1, a rat monoclonal Ig2A directed against the human IL-2 receptor, was similar to that of rabbit antithymocyte globulin in the prevention of acute rejection in first kidney transplants. A similar comparative analysis has been made in 40-sec renal transplants. ATG (1 mg/kg/day) or 33B3.1 (10 mg/day) was administered during the first 10 days postgrafting in association with corticosteroids and azathioprine. Cyclosporine was introduced on day 9 and azathioprine/CsA constituted the patient's maintenance treatment after day 45. Rejection treatment consisted of equine antilymphocyte globulin in both cases and of steroid boluses when patients were under Cyclosporine. One patient in each group died. Graft survival was 90%, 85%, and 79% in the ATG group (n = 20) and 100%, 89%, and 89% in the 33B3.1 group (n = 20) at 3, 12, and 24 months, respectively. Of the ATG group patients, 45% and 40% in the 33B3.1 group had at least one rejection episode, half the episodes in the MoAb cohort occurring under 33B3.1, vs. none in the ATG group. Transplant function was similar in both groups. Viral infections appeared to be more frequent with ATG (60%) than with 33B3.1 (12%), with CMV accounting for half of these in the ATG group, and none in the MoAb group. Tolerance of both agents was good. Of the 33B3.1 recipients, 70% developed anti-33B3.1 antibodies. From these data, we conclude that this anti-IL-2 receptor MoAb seems less effective than rabbit ATG as induction treatment in second kidney transplant patients. Thirty-two evaluable patients with metastatic carcinoma of the prostate were entered into a prospective randomized trial comparing cyclophosphamide (CYC) with a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF). Progressive disease after endocrine manipulation was noted in 97% (31/32) of patients before entry. Stable disease (S) was observed in 9 of 17 patients treated with CYC. One partial response (PR) and seven stable responses occurred in the 15 CMF patients. Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF. Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months. Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF, respectively. Toxicity was moderate, and no deaths were attributable to sepsis or bleeding. Almost all patients in this study had bone lesions as the dominant site of disease; this made objective assessment of response difficult. There was no significant improvement in response conferred by the combination regimen. Although patients with metastatic prostatic cancer may benefit from chemotherapy, impressive clinical responses are uncommon.
This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil.