The Cyclophosphamide Conundrum Dr. Allison Gelfer PGY1 Internal Medicine/Dermatology Rheumatology Rounds March 18 2008 A Case ID: 49M, Caucasian PMHx: Hypertension x 10 years Dyslipidemia CVA 2001 (age 42): L lacunar infarct Seizure x 1 post stroke Meds: Divalproex, ASA, Crestor, Atenolol, Coversyl Allergies: Dilantin (rash) HPI 5 weeks ago: malaise URTI with cough Fatigue, chills Single episode hemoptysis Improved spontaneously General Saw his GP and ASA them Amoxicillin Stopped side effects progression of symptoms 3 weeks ago: Symptoms recurred HPI Additional symptoms: night sweats anorexia, weight loss R sided pleuritic chest pain March one episode of hemoptysis and therefore came to ED 1 In He denied: epistaxis oral/nasal ulcers dermatologic changes arthralgias GU and GI symptoms Hemoptysis! Hemoptysis! Hemoptysis! ED: Physical Exam / Labs BP 135/70 HR 88 RR 24 T36.9C 93% on RA; 97% on 50% FiO2 by FM Hb 52, MCV 78, pencil forms, anisocytosis WBC 10.5, PLT 346 Cr 219, urea 8 U/A: +++blood, ++protein, no casts CXR… Chest: diffuse R crackles, L basilar crackles CVS: JVP at earlobe, normal HS, no murmurs, edema ankles bilaterally Neurologically: no asterixis Derm: nil. MSK: nil What happened next? Resuscitation Respirology/Nephrology/ICU Working diagnosis: pulmonary – renal syndrome to ICU - observation empirically: Admitted Treated 1gm IV daily Plasmapheresis x2 Solumedrol The Results! cANCA 1:160 negative, ANA negative Anti-GBM Anticardiolipin positive, PTT 41.8, INR 1.36, 1:1 mix 47.4 (inhibitor) Biopsy: focal segmental necrotizing glomerulonephritis, pauci-immune on IF diagnosis… Renal The The Dilemma… Short stay in the ICU to Respirology Transferred Treatment: The steroids, plasmapheresis and cyclophosphamide dilemma: how do we give the cyclophosphamide? What do we use for induction? <1970; before immunosuppressants: 50% 5 month survival 90% 2 year mortality glucocorticoids: mean survival 12.5 months Fauci et al. GC and CYC: remission in 75%, improvement 91% 80% With 1970’s: Now: 5 year survival How do we give CYC? Fauci’s regimen: Oral cyclophosphamide (CYC) 2mg/kg/d (max 200mg/d) Given for 1 year after remission Dose adjustments for age, renal dysfunction, cytopenias Oral glucocorticoids (GC) starting at 1mg/kg/d Tapered to alternate day regimen and stopped after 1 year Effective. Greatly improved prognosis. Problems with Fauci’s protocol Treatment related morbidity Cystitis (43%) Bladder Cancer (2.8%) Lymphomas (2%) Myelodysplasia (2%) Ovarian failure (57%) Relapses Search for safer but equally effective alternative strategies Evidence for intermittent IV CYC in rheumatoid vasculitis and lupus nephritis Back to the Case The Question: How are we going to give CYC to this patient with newly diagnosed, severe WG? Guillevin L et al. A Prospective, Multicenter, Randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized wegener’s granulomatosis. Arthritis and rheumatism 1997;40(12):2187-98. Haubitz M et al. Intravenous pulse dministration of cyclophosphamiode versus daily oral treatment in patients with antineutrophilcytoplasmic antibody-associated vasculitis and renal involvement. Arthritis and Rheumatism 1998;41(10):1835-44. The Answer: Adu D et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. Q J Med 1997;90:401-09. Haubitz et al (1998) Prospective, randomized, controlled, multicenter trial Patient population: adults with newly diagnosed WG or MPA with renal involvement Inducing a remission Treatment Protocols pCYC ARM (n=22) 1. q4weeks IV 2. 0.75gm/m2 3. Treatment x 1 yr cCYC ARM (n=25) 1. Daily PO 2. 2 mg/kg/d 3. Treatment x 1 yr Glucocorticoid Protocol Days 1-3: 0.5 gm methylprednisolone IV 4-14: 1mg/kg prednisolone PO taper of 5mg/week taper of 2.5mg/week Days Day 15: steroid taper 10mg/week 30mg/d: 15mg/d: End Points PRIMARY: 1. Progression of disease SECONDARY: 1. Remission 2. Relapse 3. Adverse effects Results Result Total CYC dose (grams) Deaths Remission Relapses pCYC 16.4+/-3.7 0 during tx 3 total 22/22 2-9/12 5/20 during 3/20 after cCYC 38.4+/-14.0 3 during tx 4 total 21/25 1.5-12/12 3/21 during 3/21 after P <0.001 NS NS NS Toxicity Results Toxicity Leucopenia Severe Infections pCYC 18% 15% 0 deaths cCYC 60% 47.6% 3 deaths P <0.01 <0.056 <0.044 (1 tailed) Gonadal Toxicity (IU/L) 10.1+/-7.1 40.2+/-37 <0.05 Bottom Line NO DIFFERENCE IN EFFICACY No significant differences with regards to patient survival, remission rate, time of remission, incidence of relapses, effect on renal function and renal survival. REDUCED TOXICITY Total dose of CYC was significantly reduced in the pCYC group (by 57%). Toxicity was significantly reduced in the pCYC group. Guillevin et al (1997) Prospective, randomized, controlled, multi-center trial Patient population: adults with newly diagnosed, severe WG (WG only) Inducing and maintaining a remission 1.Pulse steroids 2.Oral GC 3.Pulse IV CYC Group A pCYC N=27 IV q3weeks 0.7gm/m2 Group B cCYC N=23 Daily PO 2mg/kg/d Glucocorticoid Protocol 1mg/kg for 6 weeks If complete remission by 2.5mg/10days until half initial dose 3 weeks by 2.5mg/10d to 20mg/d by 1mg/month until d/c Taper Maintained Taper Taper End Points PRIMARY: 1. Remission 2. Death SECONDARY: 1. Relapses 2. Side effects Results Result Remission Time to remission Long term sustained remission pCYC 88.9% 224.1 +/178.5 days 47.8% 52.2% cCYC 78.3% 200 +/129.9 days 70.6% 17.6% P NS NS NS <0.05 Relapses Outcome 6 months Remission Tx Failure Death Long Term Remission Relapse Death Final Remission Death pCYC (%) cCYC (%) 88.9 11.1 14.8 47.8 52.2 21.7 66.7 33.3 P 78.3 21.7 26.1 70.6 17.6 23.5 56.5 43.5 NS <0.05 Toxicity Toxicity Cumulative dose CYC Infectious side effects Deaths due to side effects Amenorrhea pCYC cCYC P 27.8+/-19.2 43.9 +/- 31.1 <0.001 grams grams 40.7% 11.1% 69.6% 26.1% <0.05 NS NS 50% (at risk) 20% (at risk) Bottom Line EQUALLY pCYC is equally effective at inducing a remission as cCYC EFFECTIVE LESS Side effects were less frequent in the pCYC pCYC had higher rates of relapse in the maintenance phase SIDE EFFECTS HIGHER RATES OF RELAPSE RECOMMEND recommended using pCYC for induction therapy pCYC Adu et al (1997) Randomized, controlled, prospective, monocentric trial Patient population: adults with new onset, severe, WG, MPA and cPAN Inducing and maintaining a remission Primary endpoint: drug toxicity survival relapses Secondary endpoints: Treatment Protocols Group A (CCAZP): continuous CYC followed by azathioprine n=30, 13/30 WG Induction phase (weeks 1-12) CYC PO 2mg/kg/d Prednisolone 0.85mg/kg/d (max 60mg/d) Azathioprine PO 1.5mg/kg/d Prednisolone taper Remission Phase (weeks 13-52) Maintenance Phase (>week 52) Prednisolone 0.15 mg/kg alternate days Treatment Protocols Group B (PCYP): pCYC and prednisolone N = 24, 16/24 with WG Treatment Protocol – Group B Phase Induction Pulse # Route CYC dose Pred dose 1-3 IV 15 mg/kg 10 mg/kg x1 x1 7,10,13,17, 4-9 PO 5 mg/kg 3.3 mg/kg 21,25 x3 x3 30,35,40,46 10-14 PO 5 mg/kg 3.3 mg/kg 52 x3 x3 58,64,70,76 15-21 PO 5 mg/kg 3.3 mg/kg x3 x3 >76 --PO --0.15 mg/kg alt. days Week 0,2,4 Induction Remission Consolidation Maintenance Results Result Complete Remission Partial Remission Treatment Failure Death Relapse PCYP 33.3% 50% 16.6% 20.8% 29.6% 8.3% CCAZP 23.3% 63.3% 13.3% 13.3% 26.6% 10% P 0.69 0.69 0.69 0.35 0.70 0.75 Chronic Dialysis Toxicity Leucopenia: CCAZP 13/30 PCYP 7/24 P=0.39 Infective episodes per group: CCAZP 1.66/pt PCYP 1.7/pt Deaths from infections only in CCAZP: 2 died septicemia Other toxicities: only in the CCAZP group: 3 thrombocytopenia, 1 steroid induced DM, 1 osteoporosis, 1 BCC Bottom Line EQUALLY PCYP EFFECTIVE as effective in inducing a remission as CCAZP. Improvement in renal function, survival and relapses were similar in both groups trend toward less toxicity in the PCYP group, n too small LESS SIDE EFFECTS Problems with the studies Many issues with the 3 independent studies mostly related to the differences between them: (differences in the doses of cyc, steroid protocols, definition of disease state, remission, relapse, severity of disease) therapies developed remission phase Escalation Poorly De Groot et al (2001) Meta-analysis trials of randomized, controlled 3 trials previously described and MPA only (cPAN excluded) WG Outcome Total measures: remission, relapses, infection, leukopenia, death and renal failure 143 patients WG, 42 MPA 101 Results pCYC significantly less likely to fail to induce a remission than cCYC OR 0.29, 95% CI 0.12-0.73 pCYC had a significantly lower risk of infection than cCYC OR 0.45, 95% CI 0.23-0.89 pCYC had a significantly lower risk of leucopenia OR 0.36, 95% CI 0.17-0.78 Results Significantly lower cumulative dose CYC in pCYC compared to cCYC (2/3 studies) differences in ESRD differences in deaths No OR 1.29, 95% CI 0.51-3.25 OR 0.80, 95% CI 0.34-1.86 No Non-statistically significant increased frequency of relapses on pCYC OR 1.79, 95% CI 0.85-3.75 Bottom Line pCYC is… EFFECTIVE higher rate of relapse (maintenance) TOXIC MORE LESS Slightly Need a larger, prospective, randomized, controlled trial with a large n to solve these issues... CYCLOPS Patient population: adults with a new diagnosis of WG or MPA disease-free Primary period; the period of time from remission until relapse or study end end-point: Secondary adverse effects cumulative drug dosages remissions and relapses end-points: Timing Entry (diagnosis of generalized, previously untreated WG or MPA, Cr > 150, < 500) Randomisation (80 patients per limb) daily oral CYC (2mg/kg/day pulse CYC (15mg/kg every 2-3 weeks) Induction phase continue CYC until remission + 3 months, minimum 6 months, maximum 12 months) Remission maintenance phase (start azathioprine, 2mg/kg, at remission + 3 months) (evaluations every 3 months) Study end (18 months) Glucocorticoid Protocol Time from entry (weeks) 0 1 2 3 6 8 Time from entry (weeks) reduce at end of month 3 Prednisolone Dosage (mg/kg/day) 1 0.75 0.5 0.4 0.33 0.25 Prednisolone Dosage (mg/day) 12.5 reduce at end of month 5 during months 12 - 15 during months 15 - 18 10 7.5 5 Preliminary Data CYCLOPS Dr. Jayne - preliminary results on 80% data at ASN 2004 difference in time to remission difference in time to “flare” No No My Thoughts… hopeful that CYCLOPS trial data will help clarify the answer to this dilemma I’m skeptical as it’s been 4 years since the expected date of publication and it’s still not published It’s not always possible to practice evidence based medicine I’m Conclusions pCYC is equal to or greater than cCYC in inducing a remission pCYC gives a smaller cumulative dose of CYC than cCYC pCYC is associated with less adverse effects than cCYC May be a higher relapse rate with pCYC, likely only important in the maintenance phase Thoughts and Questions References 1. 2. 3. 4. 5. 6. 7. Guillevin L et al. A Prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized wegener’s granulomatosis. Arthritis and Rheumatism 1997;40(12):2187-98. Haubitz M et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibodyassociated vasculitis and renal involvement. Arthritis and Rheumatism 1998;41(10):1835-44. Adu D et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. Q J Med 1997;90:401-09. De Groot et al. The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001;16:201827. Wung P and Stone J. Therapeutics of wegener’s granulomatosis. Nat Clin Pract Rheumatol 2006;2(4):192-200. Tesar V et al.Current treatment strategies in ANCA-positive renal vasculitis – lessons from European randomized trials. Nephrol Dial Transplant 2003;18(s5)v2v4. Levy J. New aspects in the management of ANCA-positive vasculitis. Nephrol Dial Transplant 2001;16:1314-1317.
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