Three strategies of autologous hematopoietic stem cell transplantation in multiple sclerosis

Introduction

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to treatment of multiple sclerosis (MS) patients, since there are no effective treatment methods for this disease [4-7, 10]. HDCT+ASCT has been performed in more than 700 MS patients since 1995 all over the world. However, the patient selection criteria for HDIT +ASCT are still unclear and the proper selection of patients for transplantation remains the key issue [3, 9, 11]. In Russia more than 180 transplantations in MS patients were done within 10 years within a prospective Phase II multicenter trial coordinated by the Russian Cooperative Group for Cellular Therapy. The follow-up results of the patients who were enrolled in the Military Medical Academy (St. Petersburg) and Pirogov National Medical Surgical Center (Moscow) since 1999 are reported here. We focused on the efficacy of HDIT +ASCT in patients with different types and stages of MS. The patients underwent early, conventional, or salvage/late transplantation in accordance with the concept of HDIT +ASCT in MS [12, 13]. There are 3 strategies of HDIT +ASCT (Table 1). Early ASCT (in MS patients with EDSS 1.5–3.0) is performed soon after diagnosis in the case of primary refractory disease or poor prognosis. Conventional ASCT (EDSS 3.5–6.5) is performed in patients with secondary refractory disease. Salvage ASCT (EDSS 7.0–8.0) is an option in the case of high disease activity and rapid neurological deterioration in late stages of the disease.

Patients and Methods

132 MS patients were included in this study with a mean age of 33.0, and a male/female split of 58/74. The distribution according to the disease type was as follows: secondary progressive (SPMS): 57 patients, primary progressive (PPMS): 23, progressive-relapsing (PRMS): 9 and relapsing-remitting (RRMS): 43. 

Criteria for patient selection were: age between 18 and 55 years, diagnosis of multiple sclerosis verified by clinical and laboratory findings, EDSS score 1.5–8.0, normal mental status, and absence of severe concomitant diseases.  
The disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6 months preceding enrollment. 

Table 1. Classification of HDIT +ASCT in MS patients

All three strategies of HDIT +ASCT were applied: 43 patients (32.7%) underwent early transplantation; 82 (62.0%), conventional transplantation; and 7 (5.3%) received salvage/late transplantation.

Neurological evaluation was performed at baseline, at discharge, at 3, 6, 9, and 12 months, and every 6 months thereafter; and MRI examinations at baseline, at 6, and 12 months, and at the end of follow-up.

According to the EBMT criteria of response, patients with steady EDSS scores representing halt of disease progression or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment. Clinical improvement was defined as a 0.5-point decrease in EDSS score as compared to the baseline. Progression was defined as an increase of at least 0.5 points. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24-hour duration, in the absence of fever in a previously (4 weeks) stable patient.

A BEAM or BEAM-modified conditioning regimen was used.

Median EDSS at baseline was 4.5 (range 1.5-8.5). The mean follow-up duration was 21 months (range 6-120 months).

A separate group of patients was identified to whom consolidation therapy (Mitoxantrone) after HDIT +ASCT was administered. These were patients with a number of risk factors. 34 patients were enrolled in this group. The preliminary analysis of treatment outcomes in this group will be conducted by December 2009.

Results

Adverse events
No transplant-related deaths were reported; transplantation procedure was well tolerated by the patients. Mobilization was successful in all cases with a median number of 2.1 x10⁶/kg (range 1.5-5.5 x10⁶/kg) CD34+ cells collected; no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with PMN <0.5x10⁹ and Plt <50x10⁹ were 8 (range from 5 to 11) and 10 days (from 2 to 26), respectively.

Common adverse effects following the immunoablative regimen were thrombocytopenia (100%), neutropenia (100%), fatigue (100%), anemia (80%), alopecia (80%), neutropenic fever (51.6%), hepatic toxicity grade I and II (48.1%), transient neurological dysfunction (22.2%), and enteropathy (18.5%). Documented sepsis was registered in one patient. 

Clinical outcomes
Eighty-seven patients with a follow-up period of at least 9 months or longer were included in the clinical outcome analysis. All patients responded to the treatment. At 6 months post-transplant the following distribution of patients according to clinical response was observed: 46 patients (52.8%) achieved an objective improvement of neurological symptoms (defined as a 0.5 point decrease in the EDSS score as compared to the baseline and confirmed over 3 months), and 41 patients (47.2 %) had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 3 months). At long-term follow-up the clinical response in 40 patients (50.6%) was classified as improvement; 34 patients (43.1%) remained stable. Two patients deteriorated to a worse score after 18 months of stabilization (SPMS and PPMS; conventional auto-HSCT), and one patient after 6 months of stabilization (SPMS, conventional auto-HSCT); 2 others progressed after 12 and 30 months of improvement (RRMS, early auto-HSCT and SPMM, conventional auto-HSCT, respectively). No active, new, or enlarging lesions were registered in patients without disease progression.

The analysis of clinical outcomes at long-term follow-up was performed separately for the groups after early, conventional, and salvage transplantation. Out of 24 patients who underwent early ASCT 14 patients (58.3%) improved, 9 patients (37.5) stabilized, and one patient (4.2%) progressed (after improvement). Out of 48 patients who underwent conventional ASCT 24 patients (50%) improved, 20 patients (42%) stabilized, and 4 (8%) progressed (3 after stabilization, and 1 after improvement). In the group of patients who underwent salvage ASCT 2 patients (29%) improved and 5 (71%) were stable during the follow-up.

Remarkably, nine patients improved dramatically (1.5 points by EDSS). Patients with different types of MS were observed in this group. As an illustration, in an SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0 point decrease on the EDSS scale at 1 month post-transplant, an additional 1.5 point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months post-transplant. In another case, an RRMS patient with a baseline EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month post-transplant with a further decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with a baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5 and then showed further improvement at 30 months post-transplant to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years post-transplant) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5 point EDSS decrease and maintained this score during 3.5 years of follow-up.

Conclusions
- The results of our study demonstrate the benefits of HDIT +ASCT in patients with various types of MS. The transplantation procedure was well tolerated by patients, with no transplant-related deaths at all. All the patients included in the efficacy analysis responded to treatment. At long-term follow-up clinical response in terms of improvement or stabilization was registered in more than 90% of patients.

- The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDIT +ASCT as compared to both SPMS and RRMS, the information about the outcomes of HSCT in patients with various types of MS is limited. The results of our study confirm that transplantation is effective not only in SPMS and RRMS patients but in PPMS as well. Thus, patients with different types of MS might benefit from HDIT +ASCT.

- Another advantage of our study is the performance of early, conventional, or salvage transplantation, while most patients in the previous studies had late stages of MS. Our data supports the idea that HDIT +ASCT is more effective in young patients with early stages of rapidly progressing disease. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDIT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail and the damage to CNS tissue is too significant to expect a neurological recovery after HDIT +ASCT. Indeed, failure of HDIT +ASCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [1] and in clinical studies [8, 2].

- The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate the clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.

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