The use of intensive chemoradiotherapy with stem cell rescue offers an opportunity to deliver maximally tolerated immunosuppression. This conceptual approach is similar to that used in autografting for lymphoma in which patients who have failed conventional chemotherapy regimens may respond to high-dose chemoradiotherapy and autologous SCT. Although the pathogenesis of MS is not fully understood, and lymphoid effector cells are not well defined, evidence implicates a role for autoreactive T and B lymphocytes. If these effectors could be eradicated or severely depleted by HDIT, sustained disease remissions may be induced In the FAE mouse model, immunoablation with TBI followed by allogeneic, syngeneic, or autologous marrow rescue can prevent or ameliorate clinical disease.14,13,35,36
The goal of HDIT in this clinical study was to achieve sustained remissions of the autoimmune process and prevent further loss of neurologic function.
During the initial phases of the study, one patient developed a flare of MS during the administration of only G-CSF for the mobilization. This experience was previously reported along with several other cases.37
G-CSF has previously been associated with flares of autoimmune diseases during treatment for neutropenia or mobilization before HDIT.38–42
Although mobilization with G-CSF is associated with a type 2, anti-inflammatory cytokine profile, the clinical relevance of this observation even for the development of alloimmune reactions after hematopoietic SCT are unclear.43
The addition of a 10-day course of prednisone administered during mobilization appears effective in reducing the risk of MS flares, but more experience is required to increase confidence in this strategy. The addition of cyclophosphamide to G-CSF during mobilization has also been effective for preventing flares. However, the disadvantage of combining cyclophosphamide with G-CSF during mobilization is the increased risk to the patient due to an additional pancytopenic interval, the increased cost of management of patients receiving chemotherapy, and the delay in proceeding to HDIT. Mobilization using G-CSF with prednisone has been safe and effective and may prove to be the preferred approach in MS patients.
In preclinical studies of HDIT for autoimmune diseases, TBI was a more effective immunosuppressive treatment than chemo-therapeutic regimens.44
The TBI dose described in this current study was decreased from a more standard dose (1200 cGy) used in the treatment of hematologic malignancies so as to minimize the risks of severe regimen-related toxicities. Autologous stem cell support is required after HDIT because fractionated TBI doses to a total of 800 cGy in combination with high-dose cyclophosphamide are extremely myelosuppressive if not myeloablative.45
A noncyto-toxic agent, ATG, was added to the HDIT regimen for in vivo T-cell depletion. Cyclophosphamide in combination with TBI has potent immunosuppressive capabilities and is one of the most common conditioning regimens for allogeneic SCT. The potential efficacy of this HDIT regimen has been demonstrated in another study coordinated by this program in which patients with systemic sclerosis had a significant reduction in the extent of the scleroderma compared with the pretransplantation baseline.46
The combination of TBI and cyclophosphamide at the dose delivered in that study was not associated with severe regimen-related or neurologic toxicities. Patients have not been followed for a sufficient time period to allow for full assessment of long-term complications.
Infection prophylaxis after HDIT was managed in a similar manner to that of patients after allogeneic SCT. Infectious events were relatively infrequent and manageable. UTIs occurred more frequently than in other studies of autologous SCT for hematologic malignancies, but many patients had histories of recurrent UTIs because of abnormal bladder function and the requirement in some cases of a chronic indwelling catheter. The most significant infection-related event after HDIT was the development of an EBV-PTLD, which is a rare diagnosis after autologous transplantation but has been reported.47,48
The development of EBV-PTLD in this group was associated with the pretransplantation administration of rabbit ATG instead of horse ATG, which resulted in the absence of circulating T cells on day 28.49
Another case of EBV-PTLD, developed in a patient with systemic sclerosis after HDIT, was also associated with the administration of rabbit ATG46
It was concluded from both of these cases that rabbit ATG, at the dose and schedule used, was more immunosuppressive than horse ATG. Both of these cases illustrate the potential risk of further intensification of high-dose immunosuppressive regimens for treatment of autoimmune diseases. Noninfectious adverse events observed in this study were mostly transient in nature except for the hypothyroidism.
An engraftment syndrome occurred in 13 of the first 18 patients enrolled in the study. The engraftment syndrome can consist of both rash and noninfectious fever after autologous transplantation and has been identified in up to 59% of patients after autologous SCT.50–52
The onset of fever after HDIT was associated with a transient worsening of neurologic symptoms in these MS patients, and in one case, an irreversible increase of the EDSS by 1.0 point. Transient worsening of weakness with the occurrence of fever is commonly observed in MS patients.53
It is unclear why one patient had irreversible loss of neurologic function associated with the engraftment syndrome. With the development of fever after transplantation, there may have been increased production of endogenous proinflammatory cytokines that exacerbated the disease.54
Flares of MS have been noted during treatment with the recombinant cytokine gamma interferon, suggesting that changes in the endogenous cytokine milieu may be important to disease activity.55
A similar case of an irreversible loss of neurologic function associated with fever after HDIT has been reported previously.56
Corticosteroids have been described as effective for the management of the engraftment syndrome.57
Further experience is required with prednisone to confirm its effectiveness, but strategies for control of the engraftment syndrome and fevers may be required to reduce the risk of adverse neurologic events after HDIT.
Since the primary objective of the protocol was to assess safety of HDIT, the follow-up schedule had not been designed to confirm changes in the EDSS of 0.5 points. Treatment failure was defined as an increase in EDSS of 1.0 point or greater compared with baseline.58
Rates of progression after HDIT observed in this study were comparable with the study of HDIT reported by Fassas et al.59
With a median follow-up of 40 months of 23 patients, it was reported that progression-free survival was 76%.59
At one year after treatment, 2 patients had new or enhancing lesions. Patients with SP MS had a higher probability of remaining progression free than those with PP MS. In another study, HDIT was demonstrated to effectively suppress gadolinium-enhancing activity and the development of new T2 lesions in serial MRI studies of the brain in 10 patients with a median follow-up of 15 months.60
In general, this has been confirmed in other studies, but follow-up has been limited.56, 61, 62
In the present study, 3 of the 25 evaluable patients had MRI evidence of disease activity after HDIT (events not associated with mobilization) and all 3 patients had clinical progression. In general, however, there was no evidence of progression based on T2-weighted burden of disease studies. MRI of the spinal cord was not done, and therefore it cannot be excluded that new lesions there may have been associated with progression in some cases. The presence of oligoclonal bands in the CSF is a potential surrogate marker for an immune response localized to the CNS and, if present, supports the diagnosis of MS. Oligoclonal bands usually persist throughout the course of the disease. In 9 of 12 patients from this current study and in all patients from other published HDIT studies, the CSF remained positive for the presence of oligoclonal bands over time.56, 62
The significance of this observation with respect to the clinical status of the patient is unclear.
Loss of brain volume was minimal in a subset of 12 patients at one year after HDIT, and less than that observed after HDIT in a previous study of 5 patients.56
Decreases in brain volume over time have been documented to be objective and reliable markers for the destructive pathologic processes associated with MS.63–66
The course of the brain atrophy may be influenced by prior inflammatory disease activity, but this has not been observed in all studies.65, 67
A continued loss of brain parenchyma from axonal degeneration as a consequence of chronic demyelination in the absence of inflammation may result from the loss of trophic support. In this HDIT pilot study, most patients had advanced long-standing disease, and further loss of brain parenchyma and neurologic function might be unavoidable because of continued degenerative changes. Brain volume studies will be required in a larger number of patients with longer follow-up to more fully assess the impact of HDIT on preventing further brain atrophy.
As expected, the toxicities associated with HDIT were greater than with other conventional therapies for MS, but in general were mostly transient and reversible. Important clinical issues in the use of HDIT and autologous SCT for MS were identified and led to successful protocol modifications. There are limits to the degree of immunosuppression that can safely be induced by HDIT and autologous SCT. Patients in this clinical trial had advanced MS with a median baseline EDSS of 7.0 points. A strategy of earlier intervention with HDIT in high-risk patients may be the preferred approach before severe brain injury and irreversible degenerative processes have occurred. Although not done in the study, future studies of HDIT for MS should investigate whether specific T-cell immunity to myelin basic protein is altered by treatment. While the disease stabilization observed in this study is encouraging, the clinical role of HDIT and autologous SCT will require a comparison with conventional treatment of MS in a randomized study.