The article by Dr. Burt provides an excellent summary of the rationale for using high-dose therapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with severe autoimmune diseases (SADS). The article also describes the approach to BMT adopted by Dr. Burt and colleagues at Northwestern University. Enthusiasm for this form of therapy has been contagious, and numerous US investigators have initiated similar trials, which are outlined in Table 1 of the article.
In the majority of cases, the initiation of an autoimmune disease requires both exposure to an environmental trigger and an underlying genetic predisposition to the disease. As Dr. Burt points out, the likelihood that a regimen of high-dose therapy will lead to prolonged remissions depends on: (1) the importance of the genetic predisposition for disease development, and (2) the persistence of the environmental trigger.
If the triggering environmental stimulus persists and there is an inherent propensity of the stem cells to produce autoreactive lymphocytes due to this antigen, there is little chance that a more aggressive form of immunosuppression could completely eradicate the disease. In this situation, only a replacement of the defective stem-cell compartment using allogeneic transplantation would be likely to lead to long-term disease remissions.
In contrast, if temporary exposure to an environmental trigger led to autoreactivity, aggressive immunosuppression followed by the replacement of autologous stem cells might be sufficient for long-term control. Even if the original antigen persists, if this antigen is not presented in a manner capable of initiating an immune response, tolerance could develop if a completely naive immune system is allowed to develop under these circumstances.
For autologous transplantation to be successful, the reinfusion of a lymphocyte-purged product appears to be essential. Animal data suggest that a threshold dose of immunosuppression is required for curative purposes and that reinfusion of unpurged lymphocytes regenerates disease. Furthermore, early reports from Europe imply that unmanipulated peripheral blood or bone marrow autografts are inadequate, as all of the patients who received such grafts developed disease recurrence after high-dose chemotherapy. It is entirely possible that the 66 or more, ×106 lymphocytes/kg body weight reinfused in each of these patients contributed to early disease recurrence.
In contrast, a patient with systemic sclerosis who was transplanted with a CD34-selected, T-cell-depleted autograft (0.04 ×106 CD3 cells/kg body weight) after conditioning with 200 mg/kg of cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) showed significant disease improvement, although clearly longer-term follow-up will be required to confirm this effect. Since approaches to remove lymphocytes that have little impact on treatment-related toxicity are available, the theoretical benefit from these purging procedures seems to be warranted if autologous transplantation is used.
Allogeneic vs Autologous BMT
As with any procedure or treatment, the decision to implement BMT is based on an assessment of potential risk vs potential benefit. Although there is evidence that allogeneic transplantation can lead to long-term disease remissions in patients with aplastic anemia and coincidental autoimmune disease, given the 20% to 30% treatment-related mortality, it is unlikely that this approach can be justified for the majority of patients with autoimmune disease.
Since it remains unclear whether allogeneic transplantation will be required for reversal of human autoimmune diseases, it seems prudent to first test its efficacy using the least toxic procedure. Fortunately, the risks related to autologous transplantation have been falling, presumably because of improved supportive care and better methods of identifying adequate autografts based on CD34+ cell yields. As an example, autotransplant-related mortality was 1.5% in the recently completed 134-patient multicenter trial comparing CD34- enriched vs unselected autografts in patients with multiple myeloma. Preliminary evidence suggests that if identical exclusionary criteria are used to select patients with autoimmune disease, the tolerability of autotransplantion will be similar.
Is Total-Body Irradiation Necessary?
The conditioning regimens chosen by the various centers have been modeled after programs for the treatment of aplastic anemia. Although the addition of total-body irradiation (TBI) may be more immunosuppressive and seems to be a rational approach for patients with multiple sclerosis (MS) due to the existence of the blood-brain barrier, the use of radiation may substantially increase short- and long-term toxicity.
Radiation-induced pulmonary toxicity may be significant for patients with systemic lupus erythematosus (SLE) or systemic sclerosis, who are likely to have abnormal baseline lung function. The long-term risk for solid tumor development was also notably increased in a multivariate analysis of aplastic anemia patients treated with TBI instead of antithymocyte globulin (ATG) during allogeneic transplantation (relative risk, 3.9; P less than .05). Finally, whereas 56 of 103 patients recovered ovarian function after cyclophosphamide/ATG, almost all of the patients who received irradiation became sterile. This latter toxicity may be especially significant for the population of patients most likely to undergo this type of therapy (young females).
In order to address whether TBI is required, a protocol for the treatment of patients with systemic sclerosis was developed jointly at the University of California, Los Angeles (UCLA) and the Fred Hutchinson Cancer Center (FHCC). Identical entry criteria and follow-up evaluations are in place, but patients at UCLA will be treated with cyclophosphamide (200 mg/kg) and ATG (90 mg/kg), while those at FHCC will receive TBI and a lower dose of cyclophosphamide (120 mg/kg). Hopefully, sufficient patients will be enrolled at both institutions to permit preliminary efficacy/toxicity comparisons.
Dr. Burt does an excellent job of outlining the rationale for subjecting patients with MS, rheumatoid arthritis (RA), or SLE to autologous transplantation. His group identified patients with a significant risk of early mortality--an approach similar to that taken at UCLA. Consequently, our inclusion criteria for SLE and RA patients are nearly identical, being based on an estimated 5-year mortality 30% or more.
We have also defined a cohort of systemic sclerosis patients with a similar risk of early mortality based on the existence of diffuse skin involvement (skin score or more 16 using the modified Rodman method) and significant heart, lung, or renal dysfunction. Although prolongation of survival is the ultimate goal, quality-of-life improvement may also be a valid long-term goal and will be measured in these initial patients.
Other autoimmune diseases not mentioned by Dr. Burt and yet potentially severe enough to warrant this form of therapy include patients who develop a lupus anticoagulant and recurrent thromboembolism while receiving warfarin(Drug information on warfarin) and patients with severe refractory autoimmune thrombocytopenia. Two English patients with the latter condition are in remission following high-dose cyclophosphamide and peripheral blood stem-cell transplantation.
At present, relatively few patients have disease severe enough to warrant BMT. Furthermore, many of these patients will then be excluded from treatment because of excessive irreversible organ damage. If transplants prove successful for these initial patients, the entry criteria will be expanded to include prevention of long-term morbidity, and therefore, will broaden the scope of this procedure.
The Biggest Hurdle for Clinical Trials
Unfortunately, the biggest hurdle in initiating these studies at UCLA has not been the identification of interested and qualified patients, but rather, a financial constraint. As health-care costs have assumed more importance, it has become increasingly difficult to investigate new but expensive forms of therapy. Hopefully, a recently completed agreement between the hospital, clinical research center, and individual insurance companies will permit the initiation of these studies so that the concept of immune ablation for patients with life-threatening autoimmune disease can be assessed.