BMT for Severe Autoimmune Diseases: An Idea Whose Time Has Come

July 1, 1997

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.

The article by Dr. Burt provides an excellent summary of the rationalefor using high-dose therapy with autologous or allogeneic bone marrow transplantation(BMT) in patients with severe autoimmune diseases (SADS). The article alsodescribes the approach to BMT adopted by Dr. Burt and colleagues at NorthwesternUniversity. Enthusiasm for this form of therapy has been contagious, andnumerous US investigators have initiated similar trials, which are outlinedin Table 1 of the article.

In the majority of cases, the initiation of an autoimmune disease requiresboth exposure to an environmental trigger and an underlying genetic predispositionto the disease. As Dr. Burt points out, the likelihood that a regimen ofhigh-dose therapy will lead to prolonged remissions depends on: (1) theimportance 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 inherentpropensity of the stem cells to produce autoreactive lymphocytes due tothis antigen, there is little chance that a more aggressive form of immunosuppressioncould completely eradicate the disease. In this situation, only a replacementof the defective stem-cell compartment using allogeneic transplantationwould be likely to lead to long-term disease remissions.

In contrast, if temporary exposure to an environmental trigger led toautoreactivity, aggressive immunosuppression followed by the replacementof autologous stem cells might be sufficient for long-term control. Evenif the original antigen persists, if this antigen is not presented in amanner capable of initiating an immune response, tolerance could developif a completely naive immune system is allowed to develop under these circumstances.

Autograft Purging

For autologous transplantation to be successful, the reinfusion of alymphocyte-purged product appears to be essential. Animal data suggestthat a threshold dose of immunosuppression is required for curative purposesand that reinfusion of unpurged lymphocytes regenerates disease.[1] Furthermore,early reports from Europe imply that unmanipulated peripheral blood orbone marrow autografts are inadequate, as all of the patients who receivedsuch grafts developed disease recurrence after high-dose chemotherapy.[2]It is entirely possible that the 66 or more, ×106 lymphocytes/kgbody weight reinfused in each of these patients contributed to early diseaserecurrence.

In contrast, a patient with systemic sclerosis who was transplantedwith a CD34-selected, T-cell-depleted autograft (0.04 ×106CD3 cells/kg body weight) after conditioning with 200 mg/kg of cyclophosphamide(Cytoxan, Neosar) showed significant disease improvement, although clearlylonger-term follow-up will be required to confirm this effect.[3] Sinceapproaches to remove lymphocytes that have little impact on treatment-relatedtoxicity are available,[4] the theoretical benefit from these purging proceduresseems to be warranted if autologous transplantation is used.

Allogeneic vs Autologous BMT

As with any procedure or treatment, the decision to implement BMT isbased on an assessment of potential risk vs potential benefit. Althoughthere is evidence that allogeneic transplantation can lead to long-termdisease remissions in patients with aplastic anemia and coincidental autoimmunedisease, given the 20% to 30% treatment-related mortality, it is unlikelythat this approach can be justified for the majority of patients with autoimmunedisease.

Since it remains unclear whether allogeneic transplantation will berequired for reversal of human autoimmune diseases, it seems prudent tofirst test its efficacy using the least toxic procedure. Fortunately, therisks related to autologous transplantation have been falling, presumablybecause of improved supportive care and better methods of identifying adequateautografts based on CD34+ cell yields. As an example, autotransplant-relatedmortality was 1.5% in the recently completed 134-patient multicenter trialcomparing CD34- enriched vs unselected autografts in patients with multiplemyeloma. Preliminary evidence suggests that if identical exclusionary criteriaare used to select patients with autoimmune disease, the tolerability ofautotransplantion will be similar.[5]

Is Total-Body Irradiation Necessary?

The conditioning regimens chosen by the various centers have been modeledafter programs for the treatment of aplastic anemia. Although the additionof total-body irradiation (TBI) may be more immunosuppressive and seemsto be a rational approach for patients with multiple sclerosis (MS) dueto the existence of the blood-brain barrier, the use of radiation may substantiallyincrease short- and long-term toxicity.

Radiation-induced pulmonary toxicity may be significant for patientswith systemic lupus erythematosus (SLE) or systemic sclerosis, who arelikely to have abnormal baseline lung function. The long-term risk forsolid tumor development was also notably increased in a multivariate analysisof aplastic anemia patients treated with TBI instead of antithymocyte globulin(ATG) during allogeneic transplantation (relative risk, 3.9; P less than.05).[6] Finally, whereas 56 of 103 patients recovered ovarian functionafter cyclophosphamide/ATG, almost all of the patients who received irradiationbecame sterile. This latter toxicity may be especially significant forthe 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 treatmentof patients with systemic sclerosis was developed jointly at the Universityof 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 doseof cyclophosphamide (120 mg/kg). Hopefully, sufficient patients will beenrolled at both institutions to permit preliminary efficacy/toxicity comparisons.

Patient Selection

Dr. Burt does an excellent job of outlining the rationale for subjectingpatients with MS, rheumatoid arthritis (RA), or SLE to autologous transplantation.His group identified patients with a significant risk of early mortality--anapproach similar to that taken at UCLA. Consequently, our inclusion criteriafor SLE and RA patients are nearly identical, being based on an estimated5-year mortality 30% or more.

We have also defined a cohort of systemic sclerosis patients with asimilar risk of early mortality based on the existence of diffuse skininvolvement (skin score or more 16 using the modified Rodman method) andsignificant heart, lung, or renal dysfunction.[7] Although prolongationof survival is the ultimate goal, quality-of-life improvement may alsobe a valid long-term goal and will be measured in these initial patients.

Other autoimmune diseases not mentioned by Dr. Burt and yet potentiallysevere enough to warrant this form of therapy include patients who developa lupus anticoagulant and recurrent thromboembolism while receiving warfarinand patients with severe refractory autoimmune thrombocytopenia. Two Englishpatients with the latter condition are in remission following high-dosecyclophosphamide and peripheral blood stem-cell transplantation.[8]

At present, relatively few patients have disease severe enough to warrantBMT. Furthermore, many of these patients will then be excluded from treatmentbecause of excessive irreversible organ damage. If transplants prove successfulfor these initial patients, the entry criteria will be expanded to includeprevention of long-term morbidity, and therefore, will broaden the scopeof this procedure.

The Biggest Hurdle for Clinical Trials

Unfortunately, the biggest hurdle in initiating these studies at UCLAhas not been the identification of interested and qualified patients, butrather, a financial constraint. As health-care costs have assumed moreimportance, it has become increasingly difficult to investigate new butexpensive forms of therapy. Hopefully, a recently completed agreement betweenthe hospital, clinical research center, and individual insurance companieswill permit the initiation of these studies so that the concept of immuneablation for patients with life-threatening autoimmune disease can be assessed.


1. Knaan-Shazer S, Houben P, Kinwel-Bohre EP, et al: Remission inductionof adjuvant arthritis in rats by total body irradiation and autologousbone marrow transplantation. Bone Marrow Transplant 8:333-338, 1991.

2. Euler HH, Marmont AM, Bacigalupo A, et al: Early recurrence or persistenceof autoimmune diseases after unmanipulated autologous stem cell transplantation.Blood 88:3621-3625, 1996.

3. Tyndall A, Black C, Finke J, et al: Treatment of systemic sclerosiswith autologous haemopoietic stem cell transplantation. Lancet 349:254,1997.

4. Schiller G, Vescio R, Freytes C, et al: Transplantation of CD34-positiveperipheral blood progenitor cells following high-dose chemotherapy forpatients with advanced multiple myeloma. Blood 86:390-397, 1995.

5. Gratwohl A, Tichelli A, Finke A, et al: Autologous stem cell transplantationin pa- tients severe autoimmune disorders. Blood 88(supp 1):133a, 1996.

6. Deeg HJ, Socie G, Schoch G, et al: Malignancies after marrow transplantationfor aplastic anemia and Fanconi anemia: A joint Seattle and Paris analysisof results in 700 patients. Blood 87:385, 1996.

7. Clements PJ, Medsger TA Jr: Skin involvement, in Clements PJ, FurstDE (eds): Systemic Sclerosis, pp 389-407. Baltimore, Maryland, Williams& Wilkins, 1995.

8. Lim SH, Kell J, Al-Sabah A, et al: Peripheral blood stem cell transplantationfor severe refractory autoimmune thrombocytopenic purpura (ATP). Blood88(supp 1):133a, 1996.