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The Cyclophosphamide Conundrum rheumatism

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The Cyclophosphamide Conundrum rheumatism Powered By Docstoc
					       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:             Saw   his GP
     General  malaise  Amoxicillin and ASA
     URTI with cough
     Fatigue, chills   Stopped them
     Single episode       side effects
      hemoptysis           progression of symptoms
     Improved
      spontaneously

   3 weeks ago:
     Symptoms   recurred
                           HPI
   Additional symptoms:         March      1
     night sweats                   one episode of hemoptysis
     anorexia, weight loss           and therefore came to ED
     R sided pleuritic chest
                                 In   ED:
      pain                         Hemoptysis!
                                   Hemoptysis!
   He denied:                     Hemoptysis!
     epistaxis
     oral/nasal ulcers
     dermatologic changes
     arthralgias
     GU and GI symptoms
            Physical Exam / Labs
   BP 135/70 HR 88 RR 24                     Hb 52, MCV 78, pencil
    T36.9C                                     forms, anisocytosis
   93% on RA; 97% on 50% FiO2
    by FM                                     WBC 10.5, PLT 346
   Chest: diffuse R crackles, L basilar      Cr 219, urea 8
    crackles                                  U/A: +++blood,
   CVS: JVP at earlobe, normal HS,            ++protein, no casts
    no murmurs, edema ankles
    bilaterally                               CXR…
   Neurologically: no asterixis
   Derm: nil. MSK: nil
       What happened next?
 Resuscitation

 Respirology/Nephrology/ICU

        diagnosis: pulmonary – renal
 Working
 syndrome
 Admitted   to ICU - observation
 Treated   empirically:
   Solumedrol1gm IV daily
   Plasmapheresis x2
               The Results!
 cANCA    1:160
 Anti-GBM   negative, ANA negative
 Anticardiolipin positive, PTT 41.8, INR 1.36,
 1:1 mix 47.4 (inhibitor)
      Biopsy: focal segmental necrotizing
 Renal
 glomerulonephritis, pauci-immune on IF
 The   diagnosis…
             The Dilemma…
 Short   stay in the ICU
 Transferred   to Respirology
           steroids, plasmapheresis and
 Treatment:
 cyclophosphamide
 The dilemma: how do we give the
 cyclophosphamide?
What do we use for induction?
 <1970;before immunosuppressants:
   50% 5 month survival
   90% 2 year mortality

 With glucocorticoids:
   mean survival 12.5 months

 1970’s:Fauci et al. GC and CYC:
   remission in 75%, improvement 91%

 Now:
   80%     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?
   The Answer:
       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.
       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)                    cCYC ARM (n=25)


       1. q4weeks IV                      1. Daily PO
       2. 0.75gm/m2                       2. 2 mg/kg/d
       3. Treatment x 1 yr                3. Treatment x 1 yr
    Glucocorticoid Protocol
 Days   1-3: 0.5 gm methylprednisolone IV
 Days   4-14: 1mg/kg prednisolone PO
 Day   15: steroid taper 10mg/week
 30mg/d:   taper of 5mg/week
 15mg/d:   taper of 2.5mg/week
                End Points
 PRIMARY:
  1. Progression of disease

 SECONDARY:
  1. Remission
  2. Relapse
  3. Adverse effects
                  Results
   Result        pCYC           cCYC         P
Total CYC      16.4+/-3.7    38.4+/-14.0   <0.001
dose (grams)
Deaths         0 during tx   3 during tx    NS
                 3 total       4 total
Remission        22/22          21/25       NS
                 2-9/12       1.5-12/12
Relapses       5/20 during   3/21 during    NS
                3/20 after    3/21 after
            Toxicity Results
    Toxicity          pCYC        cCYC          P
Leucopenia             18%         60%       <0.01
Severe Infections      15%        47.6%      <0.056
                     0 deaths    3 deaths    <0.044
                                             (1 tailed)

Gonadal Toxicity    10.1+/-7.1   40.2+/-37   <0.05
(IU/L)
                    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         Group B
                      pCYC            cCYC
                      N=27            N=23

                    IV q3weeks      Daily PO
                     0.7gm/m2       2mg/kg/d
        Glucocorticoid Protocol
 1mg/kg    for 6 weeks
 If   complete remission
 Taper   by 2.5mg/10days until half initial dose
 Maintained    3 weeks
 Taper   by 2.5mg/10d to 20mg/d
 Taper   by 1mg/month until d/c
                   End Points
   PRIMARY:
    1. Remission
    2. Death
   SECONDARY:
    1. Relapses
    2. Side effects
                      Results
   Result              pCYC         cCYC         P
Remission              88.9%        78.3%        NS
Time to               224.1 +/-     200 +/-      NS
remission             178.5 days   129.9 days
Long term               47.8%        70.6%       NS
sustained remission
Relapses               52.2%        17.6%       <0.05
  Outcome    pCYC (%) cCYC (%)    P
6 months
Remission      88.9     78.3
Tx Failure     11.1     21.7
Death          14.8     26.1
Long Term
Remission      47.8     70.6      NS
Relapse        52.2     17.6     <0.05
Death          21.7     23.5
Final
Remission      66.7     56.5
Death          33.3     43.5
                     Toxicity
      Toxicity          pCYC        cCYC         P
Cumulative dose      27.8+/-19.2 43.9 +/- 31.1 <0.001
                        grams        grams
CYC
Infectious side         40.7%         69.6%        <0.05
effects
Deaths due to side      11.1%         26.1%         NS
effects
Amenorrhea           50% (at risk) 20% (at risk)    NS
                   Bottom Line
 EQUALLY          EFFECTIVE
    pCYC is equally effective at inducing a remission as cCYC

 LESS    SIDE EFFECTS
    Side effects were less frequent in the pCYC

 HIGHER         RATES OF RELAPSE
    pCYC had higher rates of relapse in the maintenance phase

 RECOMMEND               pCYC
    recommended using pCYC for induction therapy
                    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
   Secondary endpoints:
       survival
       relapses
              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)

   Remission Phase (weeks 13-52)
     Azathioprine PO 1.5mg/kg/d
     Prednisolone taper

   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           Week      Pulse # Route CYC dose Pred dose
Induction         0,2,4       1-3    IV   15 mg/kg 10 mg/kg
                                              x1         x1
Induction       7,10,13,17,   4-9    PO    5 mg/kg  3.3 mg/kg
                   21,25                      x3         x3
Remission       30,35,40,46 10-14    PO    5 mg/kg  3.3 mg/kg
                    52                        x3         x3
Consolidation   58,64,70,76 15-21    PO    5 mg/kg  3.3 mg/kg
                                              x3         x3
Maintenance         >76       ---    PO       ---  0.15 mg/kg
                                                     alt. days
                    Results
          Result       PCYP    CCAZP     P
Complete Remission     33.3%    23.3%   0.69
Partial Remission       50%     63.3%   0.69
Treatment Failure      16.6%    13.3%   0.69
Death                  20.8%    13.3%   0.35
Relapse                29.6%    26.6%   0.70
Chronic Dialysis       8.3%     10%     0.75
                        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             EFFECTIVE
     PCYP     as effective in inducing a remission as CCAZP.
        Improvement in renal function, survival and relapses
        were similar in both groups

   LESS SIDE EFFECTS
       trend toward less toxicity in the PCYP group, n too small
   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)
 Escalation   therapies
 Poorly   developed remission phase
          De Groot et al (2001)
 Meta-analysis   of randomized, controlled
 trials
3   trials previously described
 WG    and MPA only (cPAN excluded)
 Outcome   measures: remission, relapses,
 infection, leukopenia, death and renal failure
 Total   143 patients
 101   WG, 42 MPA
                        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
           lower cumulative dose CYC in
 Significantly
 pCYC compared to cCYC (2/3 studies)
 No    differences in ESRD
     OR 1.29, 95% CI 0.51-3.25

 No    differences in deaths
     OR 0.80, 95% CI 0.34-1.86

                  significant increased
 Non-statistically
 frequency of relapses on pCYC
     OR 1.79, 95% CI 0.85-3.75
                 Bottom Line
 pCYC   is…
 MORE       EFFECTIVE
 LESS   TOXIC
 Slightly   higher rate of relapse (maintenance)
 Need a larger, prospective, randomized,
 controlled trial with a large n to solve these
 issues...
                    CYCLOPS
        population: adults with a new diagnosis
 Patient
 of WG or MPA
 Primary     end-point:
   disease-freeperiod; the period of time from remission
   until relapse or study end
 Secondary     end-points:
   adverse effects
   cumulative drug dosages
   remissions and relapses

 Timing
                                 Entry
(diagnosis of generalized, previously untreated WG or MPA, Cr > 150, < 500)

                          Randomisation
                           (80 patients per limb)


            daily oral CYC                      pulse CYC
                (2mg/kg/day               (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        Prednisolone
       (weeks)                Dosage
                            (mg/kg/day)
            0                    1
            1                  0.75
            2                   0.5
            3                   0.4
            6                  0.33
            8                  0.25
    Time from entry        Prednisolone
          (weeks)          Dosage (mg/day)
reduce at end of month 3       12.5

reduce at end of month 5        10

during months 12 - 15           7.5
during months 15 - 18            5
  Preliminary Data CYCLOPS
 Dr.Jayne - preliminary results on 80% data
 at ASN 2004
 No    difference in time to remission
 No    difference in time to “flare”
            My Thoughts…
 I’m  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
                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.   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.
2.   Haubitz M et al. Intravenous pulse administration of cyclophosphamide versus
     daily oral treatment in patients with antineutrophil cytoplasmic antibody-
     associated vasculitis and renal involvement. Arthritis and Rheumatism
     1998;41(10):1835-44.
3.   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.
4.   De Groot et al. The value of pulse cyclophosphamide in ANCA-associated
     vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001;16:2018-
     27.
5.   Wung P and Stone J. Therapeutics of wegener’s granulomatosis. Nat Clin Pract
     Rheumatol 2006;2(4):192-200.
6.   Tesar V et al.Current treatment strategies in ANCA-positive renal vasculitis –
     lessons from European randomized trials. Nephrol Dial Transplant 2003;18(s5)v2-
     v4.
7.   Levy J. New aspects in the management of ANCA-positive vasculitis. Nephrol Dial
     Transplant 2001;16:1314-1317.

				
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