High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with Rheumatoid Arthritis
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ARTHRITIS & RHEUMATISM Vol. 44, No. 4, April 2001, pp 754–760 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc. High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients With Rheumatoid Arthritis Results of an Open Study to Assess Feasibility, Safety, and Efficacy Robert J. Verburg,1 Aike A. Kruize,2 Frank H. J. van den Hoogen,3 Willem E. Fibbe,1 Eefke J. Petersen,2 Frank Preijers,3 Jacob K. Sont,1 Rene´e M. Y. Barge,1 Johannes W. J. Bijlsma,2 Leo B. van de Putte,3 Ferdinand C. Breedveld,1 and Jacob M. van Laar1 Objective. To assess the feasibility, safety, and tion and leukapheresis procedures successfully, and 12 efficacy of high-dose chemotherapy and autologous he- proceeded to receive conditioning and transplantation. matopoietic stem cell transplantation (HSCT) in pa- Engraftment occurred in all of these patients, with rapid tients with severe, refractory rheumatoid arthritis (RA). hematologic recovery. No major unexpected toxicity was Methods. Fourteen patients (3 male, 11 female, observed. Marked improvement of disease activity was mean age 43 years, mean disease duration 10 years) with recorded in 8 of 12 patients at >50% of the visits, with active, destructive, refractory RA entered the study. a followup ranging from 7 months to 21 months. The Autologous hematopoietic stem cells were collected by clinical responders included 2 patients who had previ- leukapheresis after mobilization with a single infusion ously failed treatment with tumor necrosis factor (TNF) 2 of cyclophosphamide (CYC; 4 gm/m ) and subcutaneous blocking agents. injections of filgrastim (granulocyte colony-stimulating Conclusion. High-dose chemotherapy followed by ؉ factor). Immunomagnetic selection of CD34 cells from autologous HSCT is feasible and safe, and can result in the leukapheresis products was performed to deplete long-term improvement of disease activity in patients potentially autoreactive lymphocytes. The conditioning whose condition previously did not respond to conven- regimen consisted of intravenous administration of high tional antirheumatic drugs or TNF blocking agents. The doses of CYC (cumulative dose 200 mg/kg), with subse- persistence of active disease in some patients may reflect quent reinfusion of the graft. Patients were monitored for the heterogeneity of the underlying disease process. disease activity, disability, adverse effects, and hematopoi- etic and immunologic reconstitution. A new treatment approach, involving intense im- Results. All 14 patients completed the mobiliza- munosuppression and autologous hematopoietic stem cell transplantation (HSCT), has emerged in recent years for Supported by grant NR-99-1-301 from the Dutch Arthritis Association and by Amgen B.V., The Netherlands. the treatment of severe, refractory rheumatic autoimmune 1Robert J. Verburg, MD, Willem E. Fibbe, MD, Jacob K. diseases including rheumatoid arthritis (RA) (1–4). The Sont, PhD, Rene´e M. Y. Barge, MD, Ferdinand C. Breedveld, MD, rationale of this strategy is based on the concept of Jacob M. van Laar, MD: Leiden University Medical Center, Leiden, The Netherlands; 2Aike A. Kruize, MD, Eefke J. Petersen, MD, immunoablation by intense immunosuppression, with sub- Johannes W. J. Bijlsma, MD: University Medical Center Utrecht, sequent regeneration of naive T lymphocytes derived from 3 Utrecht, The Netherlands; Frank H. J. van den Hoogen, MD, Frank reinfused hematopoietic progenitor cells (5). In several Preijers, MD, Leo B. van de Putte, MD: University Medical Center Nijmegen, Nijmegen, The Netherlands. patients with intractable RA, long-term remissions were Address correspondence and reprint requests to Jacob M. van observed with this strategy, although failures have been Laar, MD, Department of Rheumatology, C4-R, Leiden University reported as well (6,7). Only small numbers of RA patients Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Submitted for publication September 1, 2000; accepted in have been treated thus far. Although different treatment revised form November 20, 2000. protocols have been used, high-dose chemotherapy (HDC) 754 HIGH-DOSE CHEMOTHERAPY AND HSCT IN RA 755 as a means to achieve immunoablation has been invariably tory drugs were continued in the lowest dosage needed to used in all studies. control pain and morning stiffness. The conditioning regimen consisted of CYC at 50 To extend previous findings on selected cases, we mg/kg/day intravenously for 4 consecutive days (total of 200 conducted an open study to investigate the feasibility, mg/kg). Hyperhydration, alkalinization of urine, and mesna safety, and efficacy of HDC ϩ HSCT in a cohort of were given in order to prevent hemorrhagic cystitis. The patients with therapy-refractory, active, destructive RA. interval between the last dose of CYC and infusion of the stem In addition, the extent and duration of immunoablation cells was at least 48 hours. Following transplantation, patients were nursed in laminar flow rooms. All blood products were was assessed, and the relationship between immunologic irradiated (25 Gy) prior to infusion. Antibiotic decontamina- changes and the clinical responses resulting from a tion and antiemetic treatment were given according to local period of intense immunosuppression was examined. practice. The use of corticosteroids as antiemetic therapy was left to the institution’s practice. Patients treated at the Leiden University Medical Center (n ϭ 8) all received methylpred- PATIENTS AND METHODS nisolone at a dose of 2 mg/kg during conditioning, for 6 consecutive days. In the other institutions (University Medical Patient selection. This was a multicenter, open-label Center Utrecht and University Medical Center Nijmegen), no phase I/II study. The protocol was approved by the ethics steroids were given (n ϭ 4). committees from the participating institutions. All patients Assessment of toxicity. Safety was assessed according provided written informed consent. Eligibility criteria were as to the World Health Organization (WHO) toxicity criteria (9). follows: an established diagnosis of RA according to the Furthermore, the units of transfused red blood cells and units American College of Rheumatology (ACR; formerly the of transfused platelets, infections, number of days of hospital- American Rheumatism Association) criteria (8), progressively ization, and rehospitalization records were recorded as well. erosive disease with large joint involvement, failure to respond Assessment of efficacy. The following clinical and to Ն4 second-line drugs including maximal tolerable doses of laboratory investigations were performed at screening, prior to methotrexate and combination therapy, active disease as de- stem cell mobilization (considered baseline), before condition- fined by Ն6 swollen joints and Ն6 tender joints and Ն1 hour ing, and every 3 months after transplantation: physical exam- of morning stiffness, and age 18–60 years. Exclusion criteria ination, including the swollen joint count (0–66), tender joint were as follows: pulmonary impairment that was defined as a count (0–68), and Ritchie articular index (10) (0–78), Health total lung capacity, vital lung capacity, or diffusion capacity Assessment Questionnaire (HAQ [11]; 0–3), patient’s assess- Ͻ70% of predicted values; cardiac impairment that was de- ment of pain on a visual analog scale (VAS; 0–10), patient’s fined as clinical evidence of heart failure with a left ventricular assessment of disease activity on a VAS (0–10), and physician’s ejection fraction of Ͻ50%; liver disease that was defined as an global assessment of disease activity (0–10). Laboratory mea- aspartate aminotransferase (AST) or alanine aminotransferase surements were performed at the same time points and (ALT) or bilirubin level Ͼ2 times the upper limit of normal on included the erythrocyte sedimentation rate, hemoglobin, he- 2 repeated tests; renal impairment that was defined as a matocrit, white blood cell count with differential, platelet creatinine clearance rate of Ͻ70 ml/minute; a white blood cell count, C-reactive protein level, IgM rheumatoid factor, anti- count Ͻ2.0 ϫ 109/liter; a platelet count Ͻ100 ϫ 109/liter; a cyclic citrullinated peptide (anti-CCP), and total serum IgM, IgG, and IgA. hemoglobin level Ͻ6.0 mmoles/liter; acute or chronic infec- Based on the above-mentioned data, efficacy was tion; positive test result for human immunodeficiency virus; determined by the 4-variable Disease Activity Score (DAS) concurrent neoplastic disease or evidence of myelodysplasia; (primary study parameter) (12), the ACR response criteria uncontrolled systemic hypertension; active peptic ulcer dis- (13), and the HAQ. ease; positive pregnancy test result; previous joint arthroplasty; Flow cytometric detection of cell surface antigens. and concomitant therapy with anticoagulant drugs. Immunophenotyping studies were done on peripheral blood Treatment schedule. Autologous hematopoietic stem mononuclear cells obtained at baseline (prior to stem cell cells were mobilized using a single infusion of cyclo- mobilization), prior to conditioning, and at 3, 6, 9, and 12 phosphamide (CYC) at 4 gm/m2 followed by filgrastim (gran- months after transplantation. The following combination of ulocyte colony-stimulating factor [G-CSF]) at 10 g/kg/day markers was used in order to identify different cell types: subcutaneously until leukapheresis. Administration of filgras- CD45–fluorescein isothiocyanate (FITC) (Becton Dickinson, tim commenced 5 days after the CYC infusion.