The Cyclophosphamide Conundrum Dr. Allison Gelfer March by sammyc2007

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									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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