Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Abstract

Background: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

Methods: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.

Results: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.

Conclusions: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Figure 1. Participant Milestones

Milestones for each participant assigned to undergo myeloablative hematopoietic stem-cell transplantation (Panel A) or to receive cyclophosphamide (Panel B) are depicted from the time of informed consent. Organ failure refers to respiratory, renal, or cardiac failure. For early withdrawals from the trial, death was investigated with the use of site and public records. In Panels A and B, each black hash mark represents a clinical evaluation with pulmonary-function tests at the transplantation center. In Panel B, the asterisk identifies a participant who gave consent more than 12 months before randomization. The vertical dashed line at 54 months indicates participant status at the time of the primary end point.

Figure 2. Primary and Key Secondary Outcomes

Panel A shows the distribution of global rank composite scores (GRCSs) at month 54 in the intention-to-treat population according to treatment group. Black represents deaths (score, −58). Remaining scores range from −30 to 52 on a red (worst)–yellow–green (best) scale. P = 0.01 for the comparison between treatment groups (Wilcoxon signed-rank test). Panel B shows components of the GRCS at month 54 for participants in the intention-to-treat population. Each row represents an individual participant. In the first column, black indicates death at month 54 and white indicates alive. In the second column, dark gray indicates an event of respiratory, renal, or cardiac failure; light gray indicates no event of respiratory, renal, or cardiac failure; and blank indicates that event-free survival (EFS) status could not be evaluated at month 54. In columns 3 through 5 (percent of predicted forced vital capacity [FVC], score on the Disability Index of the Health Assessment Questionnaire [HAQ-DI], and modified Rodnan skin score [mRSS]), green represents improvement, yellow no change, and red worsening, as compared with baseline values. All deaths (black) are treated equally. The figure shows the last available assessment before death, but boxes are faded to indicate that these steps in the hierarchy were not used for GRCS evaluation. Similarly, if EFS status could not be evaluated (blank), the outcome status for the last available assessments is shown as faded, and participants were ranked on the basis of survival status alone. Panel C shows the Kaplan–Meier estimates of overall survival and event-free survival in the intention-to-treat population (all the participants who had undergone randomization), and Panel D shows such estimates in the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide). In Panels C and D, the vertical dashed line represents the 54-month time point.