The Cyclophosphamide Conundrum

1
The Cyclophosphamide Conundrum

• Dr. Allison Gelfer
• PGY1 Internal Medicine/Dermatology
• Rheumatology Rounds
• March 18 2008

2
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)

3
HPI

• 5 weeks ago
• General malaise
• URTI with cough
• Fatigue, chills
• Single episode hemoptysis
• Improved spontaneously
• 3 weeks ago
• Symptoms recurred

• Saw his GP
• Amoxicillin and ASA
• Stopped them
• side effects
• progression of symptoms

4
HPI

• Additional symptoms
• night sweats
• anorexia, weight loss
• R sided pleuritic chest pain
• He denied
• epistaxis
• oral/nasal ulcers
• dermatologic changes
• arthralgias
• GU and GI symptoms

• March 1
• one episode of hemoptysis and therefore came to
  ED
• In ED
• Hemoptysis!
• Hemoptysis!
• Hemoptysis!

5
Physical Exam / Labs

• BP 135/70 HR 88 RR 24 T36.9C
• 93 on RA 97 on 50 FiO2 by FM
• 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

• Hb 52, MCV 78, pencil forms, anisocytosis
• WBC 10.5, PLT 346
• Cr 219, urea 8
• U/A blood, protein, no casts
• CXR

6
(No Transcript)
7
What happened next?

• Resuscitation
• Respirology/Nephrology/ICU
• Working diagnosis pulmonary renal syndrome
• Admitted to ICU - observation
• Treated empirically
• Solumedrol 1gm IV daily
• Plasmapheresis x2

8
The Results!

• cANCA 1160
• Anti-GBM negative, ANA negative
• Anticardiolipin positive, PTT 41.8, INR 1.36, 11
  mix 47.4 (inhibitor)
• Renal Biopsy focal segmental necrotizing
  glomerulonephritis, pauci-immune on IF
• The diagnosis

9
Wegener's Granulomatosis
10
The Dilemma

• Short stay in the ICU
• Transferred to Respirology
• Treatment steroids, plasmapheresis and
  cyclophosphamide
• The dilemma how do we give the cyclophosphamide?

11
(No Transcript)
12
What do we use for induction?

• lt1970 before immunosuppressants
• 50 5 month survival
• 90 2 year mortality
• With glucocorticoids
• mean survival 12.5 months
• 1970s Fauci et al. GC and CYC
• remission in 75, improvement 91
• Now
• 80 5 year survival

13
How do we give CYC?

• Faucis 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.

14
Problems with Faucis 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

15
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
  wegeners granulomatosis. Arthritis and
  rheumatism 199740(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
  199841(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
  199790401-09.

16
Haubitz et al (1998)

• Prospective, randomized, controlled, multicenter
  trial
• Patient population adults with newly diagnosed
  WG or MPA with renal involvement
• Inducing a remission

17
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

18
End Points

• PRIMARY
• Progression of disease
• SECONDARY
• Remission
• Relapse
• Adverse effects

19
Results
20
Toxicity Results
21
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.

22
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

23
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

24
End Points

• PRIMARY
• Remission
• Death
• SECONDARY
• Relapses
• Side effects

25
Results
26
(No Transcript)
27
Toxicity
28
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

29
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

30
Treatment Protocols

• Group A (CCAZP) continuous CYC followed by
  azathioprine
• n30, 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 (gtweek 52)
• Prednisolone 0.15 mg/kg alternate days

31
Treatment Protocols

• Group B (PCYP) pCYC and prednisolone
• N 24, 16/24 with WG

32
Treatment Protocol Group B
33
Results
34
Toxicity

• Leucopenia
• CCAZP 13/30
• PCYP 7/24
• P0.39
• 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

35
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

36
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

37
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

38
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

39
Results

• Significantly lower cumulative dose CYC in 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
• Non-statistically significant increased frequency
  of relapses on pCYC
• OR 1.79, 95 CI 0.85-3.75

40
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...

41
CYCLOPS

• Patient population adults with a new diagnosis
  of WG or MPA
• Primary end-point
• disease-free period the period of time from
  remission until relapse or study end
• Secondary end-points
• adverse effects
• cumulative drug dosages
• remissions and relapses
• Timing

42
(No Transcript)
43
Glucocorticoid Protocol
44
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

45
My Thoughts

• Im hopeful that CYCLOPS trial data will help
  clarify the answer to this dilemma
• Im skeptical as its been 4 years since the
  expected date of publication and its still not
  published
• Its not always possible to practice evidence
  based medicine

46
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

47
Thoughts and Questions
48
References

• Guillevin L et al. A Prospective, multicenter,
  randomized trial comparing steroids and pulse
  cyclophosphamide versus steroids and oral
  cyclophosphamide in the treatment of generalized
  wegeners granulomatosis. Arthritis and
  Rheumatism 199740(12)2187-98.
• 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
  199841(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
  199790401-09.
• De Groot et al. The value of pulse
  cyclophosphamide in ANCA-associated vasculitis
  meta-analysis and critical review. Nephrol Dial
  Transplant 2001162018-27.
• Wung P and Stone J. Therapeutics of wegeners
  granulomatosis. Nat Clin Pract Rheumatol
  20062(4)192-200.
• Tesar V et al.Current treatment strategies in
  ANCA-positive renal vasculitis lessons from
  European randomized trials. Nephrol Dial
  Transplant 200318(s5)v2-v4.
• Levy J. New aspects in the management of
  ANCA-positive vasculitis. Nephrol Dial Transplant
  2001161314-1317.