New research helps delineate some of the benefits and potential limitations of high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with severe refractory rheumatoid arthritis (RA).

The new study, released in the current issue of Arthritis & Rheumatism,¹ followed 8 transplant patients for 5 years. According to the findings, improvements in functionality and health status were most marked during the first 9 months after transplantation and lasted up to 2 years.

Autologous HSCT has been used experimentally to treat severe RA since 1996. The European Group for Blood and Marrow Transplantation reported that treatment-related mortality (TRM) after HDC + HSCT occurred in 1 out of 76 or 1.3% of RA patients.

"Our study indicates that in a hypothetical 50-year-old RA patient with a life expectancy of 20 years, HDC + HSCT results in superior health status compared with conventional therapy," conclude the researchers, led by J. M. van Laar, MD, a rheumatologist at Leiden University Medical Center in Leiden, The Netherlands. "Nevertheless, the treatment is not curative, as reflected in the return of health status to near-baseline levels 2 to 5 years posttransplantation. Therefore, new experimental therapies should aim at prolonging the initial benefit of high-dose immunosuppression without significantly increasing TRM."

Treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) was reinstituted in 50% of patients at 9 months, suggesting that the improved health status was directly related to the transplantation, according to the study.

Health status was assessed by the Health Assessment Questionnaire (HAQ), the RAND-36 version of the Short Form 36 (SF-36) health survey, and the Arthritis Impact Measurement Scales (AIMS), before and after transplantation. Utility scores were calculated with the EuroQol (EQ-5D) questionnaire and the SF-36–derived utility index (called the SF-6D), which was used to derive quality-adjusted life years (QALY).

In the first 2 years following transplantation, HAQ and AIMS scores as well as scores on the functional status, general health, and health change summary scales of the RAND-36 version of the SF-36 improved compared with baseline. Moreover, the utility scores derived from the EQ-5D questionnaire and the SF-6D also increased significantly after transplantation, resulting in 0.28 QALYs gained compared with baseline.

For a putative 50-year-old patient with severe RA and a life expectancy of 20 years, a threshold analysis revealed that HDC + HSCT yielded more QALYs than conventional therapy when treatment-related mortality (TRM) was <2.8%, the researchers concluded. For older patients with shorter life expectancy, however, the threshold for TRM is higher because TRM leads to a smaller QALY loss.

Putting it into perspective

These results confirm that "there is a high level of major responses in patients who failed standard therapies; frequently such responses are impressive, with massive improvements of function," says Steven Pavletic, MD, head of the Graft-versus-Host and Autoimmunity Unit of the Experimental Transplantation and Immunology Branch at the National Cancer Institute in Bethesda, Maryland.

"Patients go from severe disability to near normal, mortality risk is <2%—actually no deaths occurred worldwide in ~80 patients using regimens similar to those in the Leiden study—but unfortunately responses are not durable, and in most patients effects are lost by 24 months posttransplant," Dr. Pavletic tells CIAOMed.

Stem cell transplantation "is an expensive, complex procedure, and our expectations should be much higher from it than temporary relief," Dr. Pavletic asserts. "We should aim toward long-lasting partial or complete responses—cure—however, such temporary improvement in quality of life may be of high value to individual patients, as confirmed by this study," he notes. The new study "shows that patients are happy to take such risk for 2 years of quality of life."

According to Dr. Pavletic, in the bigger picture, the main obstacle for the use of HSCT in RA is the fact that it is a recurrent disease. "We need better and novel strategies," he declares. "New and safer nonmyeloablative allotransplantation regimens are on the horizon or already available. RA is the prime candidate for such transplants due to its high remission rate, [but] the obstacles include the high number of new competing agents and the reluctance of rheumatologists to consider patients for referrals," he explains.

Moreover, Dr. Pavletic observes, "it is frequently forgotten that new biologics do not work in all patients, [and] if they work, patients need to take them indefinitely, which creates cumulative toxic and financial damage within a few years that may be higher than after transplantation."

Reference

1. Teng YK, Verburg RJ, Sont JK, et al. Long-term follow-up of health status in patients with severe rheumatoid arthritis after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. Arthritis Rheum. 2005;52:2272-2276.