RESEARCH - CTX with stem-cell rescue has 50% 5-year disease-free survival in lupus

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High-dose CTX with stem-cell rescue has 50% five-year disease-free survival

in refractory lupus

Rheumawire

February 1, 2006

Janis

Chicago, IL - Patients with severe, treatment-refractory, life-threatening

systemic lupus erythematosus (SLE) can be treated safely with

nonmyeloablative high-dose cyclophosphamide (CTX) and autologous

hematopoietic stem-cell transplantation (HSCT). Patients who receive this

salvage regimen have a 50% chance of remaining disease-free for five years

and an overall five-year survival rate of 84%. Dr K Burt

(Northwestern University Feinberg School of Medicine, Chicago, IL) reports

this phase 1 study in the February 1, 2006 Journal of the American Medical

Association [1].

Burt, who will be principal investigator on a randomized, controlled phase 2

trial set to open for accrual within the next few weeks [2], told

rheumawire, " The most important thing we learned in this study was that it

is possible to give high-dose CTX and HSCT safely even to patients such as

these, with severe lupus refractory to standard immunosuppressive therapies

and either organ- or life-threatening visceral involvement. This trial

provides the justification for a randomized comparison of autologous HSCT

and current standard of care. "

Treatment induces remission, salvages residual kidney function

The 50 patients in this trial all required more than 20 mg/day of prednisone

despite the use of CTX and had class 3 or 4 glomerulonephritis (n=25), lung

involvement (n=24), central nervous system (CNS) involvement (n=32),

vasculitis confirmed by biopsy or angiogram (n=9), myositis (n=4),

transfusion-dependent autoimmune cytopenias (n=14), severe serositis (n=30),

ulcerative mucocutaneous disease (n=10), or antiphospholipid syndrome (APS,

n=22).

Burt emphasized that HSCT is a salvage therapy designed to treat refractory

disease and that patients were referred for the trial only after failure of

other available treatments such as mycophenolate mofetil and rituximab.

Patients were treated with 2.0 g/m² of cyclophosphamide and granulocyte

colony-stimulating factor 5 g/kg per day to mobilize peripheral blood stem

cells. Stem cells were harvested, and patients were treated with a

conditioning regimen (CTX total dose 200 mg/kg) and intravenous equine

antithymocyte globulin (ATG). " The conditioning regimen was not started

until at least 14 days after stem-cell apheresis to allow for two-week

microbial cultures on the CD34-selected product to demonstrate sterility, "

the authors write.

Treatment produces high chance of long-term remission

Of 50 patients, 48 had HSCT, with mean follow-up of 29 months. Burt reported

a 50% probability of five-year disease-free survival (defined as requiring

no immunosuppression except prednisone <10 mg/day) and longest continuous

duration of remission of 7.5 years.

Four patients never entered remission, and two subsequently died of active

SLE or its complications. In patients who entered remission, serology and

complement levels normalized, and levels of lupus anticoagulant and

anticardiolipin antibodies improved. Systemic Lupus Erythematosus Disease

Activity Index (SLEDAI) scores decreased by a median of about 19 points

(p<0.05) and remained significantly lower for up to five years.

Renal function remained stable before and after HSCT. Two of the 25 patients

with a history of nephritis had been on long-term dialysis but entered

remission, had successful renal transplants, no longer need dialysis, and

have no recurrence of SLE. Sixteen nephritis patients did not require

post-HSCT dialysis and had stable or improved posttreatment creatinine

clearance.

The treatment protocol initially included hyperhydration for patients

without compromised renal function. This was changed to continuous

intravenous infusion of mesna and bladder irrigation without hyperhydration

after two of the first six patients (both with nephritis) required

intubation and mechanical ventilation for pulmonary edema caused by volume

overload.

Two patients died before receiving the study treatment. There were no

treatment-related deaths among the 48 patients who underwent

transplantation. Six died after HSCT from non-treatment-related events. Two

died without evidence of active SLE, and two in remission died of non-SLE

causes. Four died after HSCT from SLE complications.

Mean time to neutrophil recovery to >500/L was nine days. Infectious

problems included one death from disseminated mucormycosis one week after

stem-cell mobilization (2% treatment-related mortality), one case of

Pneumocystis jiroveci, four gram-positive bacteremias during stem-cell

mobilization (none of whom had bacteremia during transplantation), 14

bacteremias during transplantation, and two cytomegalovirus viremias. None

of the bacteremias developed evidence of sepsis. There were seven late

infections (>100 days after HSCT) in seven patients.

But are stem cells necessary?

In an editorial that accompanies this article [3], Drs Petri and

Brodsky (s Hopkins University School of Medicine, Baltimore, MD)

challenge the need for adding HSCT to high-dose cyclophosphamide, citing a

40% durable complete remission rate in their own study of 14 patients " with

severe lupus " treated with high-dose immunoablative cyclophosphamide [4].

They suggest that mobilization of peripheral stem cells may increase

morbidity and mortality, that the shorter duration of neutropenia (9.4 days

vs 14 days with high-dose CTX alone) was due to greater use of red-cell and

platelet transfusions, and that stem mobilization might increase the risk of

relapse due to reinfusion of contaminating lymphocytes.

However, the patients treated with high-dose CTX without HSCT had

" moderate-to-severe SLE that had been refractory to corticosteroids and one

or more additional immunosuppressive drugs. " Burt says that they had much

less severe disease than the patients in his study and so are not

comparable.

" The reduced duration of neutropenia also shows that HSCT makes the

procedure safer. The incidence of serious infection rises quickly when

neutropenia lasts 12 days or more, " Burt says. " Many of our patients had

neutropenia lasting less than one day. " He also points out that red-cell and

platelet transfusions do not affect the level of neutrophils or reduce the

duration of neutropenia.

Phase 2 trial ready to open

The phase 2 trial will randomize 110 patients to high-dose CTX with HSCT or

to standard care. Eligibility criteria are the same as for the pilot study,

including treatment-resistant SLE with evidence of lupus nephritis, visceral

organ involvement other than nephritis, immune-related cytopenias,

mucocutaneous disease, or arthritis/myositis.

Burt tells rheumawire that the investigators hope to begin accrual within a

few weeks and to report initial data in five years. They also hope to

undertake a cost/benefit analysis of HSCT, noting that continuing failing

therapy is problematic but necessary to confirm that the risk of HSCT is

offset by better disease control and long-term survival.

Sources

1. Burt RK, Traynor A, Statkute L, et al. Nonmyeloablative

hematopoietic stem cell transplantation for systemic lupus erythematosus.

JAMA 2006; 295:527-535.

2. National Institute of Allergy and Infectious Diseases. A

randomized, open label, phase II multicenter study of non-myeloablative

autologous transplantation with auto-CD34+HPC versus currently available

immunosuppressive/immunomodulatory therapy for treatment of systemic lupus

erythematosus. November 2005. Available at:

http://www.clinicaltrials.gov/ct/show/NCT00230035?order=1.

3. Petri M, Brodsky R. High-dose cyclophosphamide and stem

cell transplantation for refractory systemic lupus erythematosus. JAMA 2006;

295:559-560.

4. Petri M, RJ, Brodsky RA. High-dose cyclophosphamide

without stem cell transplantation in systemic lupus erythematosus. Arthritis

Rheum 2003; 48:166-73.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org