Chinese Medical Journal 2006;119(22):1851-1855
Clinical outcomes after autologous haematopoietic stem cell transplantation in patients with progressive multiple sclerosis
XU Juan, JI Bing-xin, SU Li, DONG Hui-qing, SUN Xue-jing, LIU Cong-yan
XU Juan (Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)
JI Bing-xin (Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)
SU Li (Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)
DONG Hui-qing (Department of Neurology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)
SUN Xue-jing (Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)
LIU Cong-yan (Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China)Correspondence to:XU Juan,Department of Haematology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China (Tel: 86-10-83198476. Fax:86-10-63042809. E-mail:email@example.com)
Background Multiple sclerosis (MS) is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantation (ASCT) has been introduced in the treatment of refractory forms of multiple sclerosis. In this study, the clinical outcomes followed by ASCT were evaluated for patients with progressive MS.
Methods Twenty-two patients with secondary progressive MS were treated with ASCT. Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony stimulating factor. Etoposide, melphalan, carmustin and cytosine arabinoside were administered as conditioning regimen. Outcomes were evaluated by the expanded disability status scale and progression free survival. No maintenance treatment was administered during a median follow-up of 39 months (range, 6 to 59 months).
Results No death occurred following the treatment. The overall confirmed progression free survival rate was 77% up to 59 months after transplantation which was significantly higher compared with pre-transplantation (P=0.000). Thirteen patients (59%) had remarkable improvement in neurological manifestations, four (18%) stabilized their disability status and five (23%) showed clinical recurrence of active symptoms.
Conclusions ASCT as a therapy is safe and available. It can improve or stabilize neurological manifestations in most patients with progressive MS following failure of conventional therapy.
Multiple sclerosis (MS) is considered a T cell-mediated autoimmune-origin inflammatory demyelinating disorder of the central nervous system.1 It mainly affects young adults and leads to substantial disability. Patients suffer from relapsing remitting disease, which later evolves into a secondary progressive process. Once the secondary progressive course has set in, the disease advances relentlessly increasing disability. Experimental and clinical observations have indicated that autologous haematopoietic stem cell transplantation (ASCT) can induce remissions in patients with progressive MS.2,3 The use of intensive chemotherapy with stem cells offers an opportunity to deliver maximally tolerated immuno- suppression. The first goal of ASCT in this clinical study was to arrest the autoimmune process for preventing further loss of neurological functions by immunosuppression. Long-term immunological reconstitution after ASCT and sustained clinical remissions remain to be evaluated.
From 2001 to 2006, 22 patients with secondary progressive MS treated with ASCT were included in the trial. The guideline proposed at the Milan Consensus Conference of European Group for Blood and Marrow Transplantation was used in selecting patients for the ASCT.4 The pre- transplantation characteristics are summarized in the Table. There were 17 women and 5 men with median age 35.5 (range 20－51) years. The median interval from diagnosis to transplantation was 36 (range 15－156) months. Considering patient’s safety, transplantation was selected during a remission stage in each patient. Median scores of expanded disability status scale (EDSS) were 6.0 (range 4.5－7.5) in remission before transplantation as the baseline and 7.5 (range 6.0－8.0) at the time of last relapse prior to transplant. Median follow-up time was 39 (range 6－59) months. The study was approved by the Ethics Committee of the Hospital and all patients signed the written informed consents.
Table. Charicteristics and clinical outcomes of all patients enrolled in this study
Haematopoietic stem cells were mobilized with daily subcutaneous injection with granulocyte colony stimulating factor (Filgrastim, USA) at the dose of 5 µg/kg for 4 to 6 days. The peripheral mononuclear cells were leukapheresed by CS-3000 Plus Cell Separator (Baxter, USA). The conditioning regimen (etoposide, melphalan, carmustin and cytosine arabinoside) was administered followed by ASCT.4 Details of the conditioning regimen and supportive care are the same described previously.5
Assessment of treatment response
Evaluation of disease status in EDSS was performed prior to haematopoietic cell mobilization (baseline), at 6 and 12 months post-transplantation, and then at yearly intervals. Neurological improvement was defined as a decrease of 1.0 point or more maintained over 6 months after transplantation. Neurological stabilization was defined as without EDSS change or EDSS decrease less than 1.0 point after transplantation. Neurological progression, considered as disease relapse or exacerbation, was defined as an increase in EDSS of 1.0 point or greater compared with baseline beyond 6 months after transplantation, without other explanations about the change in function.6 The time of the first increase to 1.0 or more EDSS points was taken as the time to disease progression.
Progression free survival was defined as the probability to be alive without disability progression after transplantation compared with the baseline. These included both neurological improvement and stabilization.
Outcomes were reported based on the last follow-up of each patient. Progressive free survival was estimated using the Kaplan-Meier method. Statistical significance was defined at 0.05 and analysis was performed using SPSS10.0.
Stem cell collections and engraftment
The median number of CD34+ cells collected by leukapheresis was 2.41×106/kg (range 0.89×106/kg－5.76×106/kg). The median intervals of the absolute neutrophil more than 0.5×109/L and platelet more than 50×109/L were 13 days (range 9－17 days) and 16 days (range 11－21 days) after transplantation, respectively. No death occurred following the treatment.
Regimen related complications
Diarrhoea without infection evidence lasted for 3 to 7 days in 13 patients immediately following the conditioning regimen. The treatment of diarrhoea included maintaining fluid and sodium balances and using anti-diarrhoeic agents. Six patients developed abrupt fever and were treated with antibiotics. Eight patients had transient neurological worsening including fatigue, headache, numbness and paraesthesia during the transplantation. Their neurological deterioration was often associated with infections and diarrhoea and intermittent use of corticosteroids relieved the neurological worsening.
Bacterial infections occurred in 7 patients, five had urinary system infection because of bladder dysfunction and two had a perianal soft tissue infection. Broad spectrum antibiotics were used and the symptoms were controlled. No fungal or viral infection was observed.
Neurological function assessment
Median EDSS score of 22 patients at the last follow-up was 4.3 (1.0－8.0) with median follow-up interval of 39 months (range 6－59). Patients formed three groups according to the clinical outcomes: neurological improvement group (n=13, No. 1, 2, 4, 6, 12, and 15－22), median EDSS scores decreased from 6.0 (4.5－7.0) to 3.0 (1.0－4.5) at the last follow-up; neurologically stable status group (n=4, No. 3, 7, 9, and 14); and disease progression or relapse group (n=5, No. 5, 8, 10, 11, and 13), patients appeared neurological deterioration within 6－19 months post-transplantation and needed further immunosuppression treatment. At 59 months post-transplantation, the confirmed progression free survival rate was 77% according to Kaplan and Meier survival curve, and the median length of remission reached 43 months (95% CI 33－53), significantly greater than 9 months (95% CI 7－11) of pre-transplantation (P=0.000, Fig.).
Fig. Comparing progression free survival of post- transplantation with pre-transplantation (P=0.000).
MS represents a heterogeneous disorder with genetic, environmental and individual aetiological factors. Immunosuppression and immunomodulation are basic therapeutic strategies and are generally employed with success.7 Nonetheless, patients without response require more toxic drugs to achieve or maintain remissions. Patients with relapse despite continuing therapy present a therapeutic challenge.8 ASCT could be a viable option; otherwise deterioration can be expected.9 Therefore, a possible treatment is to eradicate the autoreactive cells with high dose chemotherapy and rescue the patients from the prolonged cytopenias with stem cell reinfusion.10
The present data provide clear evidence that high dose chemotherapy followed by ASCT can produce stable remission or improve neurological status in most patients with progressive MS in the short term. Three post-ASCT clinical outcomes exist. First, the most optimistic outcome is significant neurological improvement as shown by decrease of 1.5－5.0 on EDSS. This may be the clinical benefit by improving the quality of life. The longest remission was 59 months and still continuing. Of the 10 patients followed up for more than 3 years, 4 were still in neurological improvement, 3 in stable status and 3 in relapse. This suggests that the prolonged remission (improvement or stable status) is not reliant on immunosuppression alone because CD4+ and CD8+ lymphocytes have recovered to the normal level at three years after transplantation. A questionable consideration suggests the regeneration of the immune system with restoration of tolerance to selfantigens following ASCT.11-13 The theoretical considerations all suggest that high dose, chemotherapy followed by haematopoietic stem cell rescue could alter immunity.14 The second outcome of ASCT in our trail is that patients can get disease stability. In secondary progressive MS, the insidious accumulation of persistent neurological impairment is thought to be related to axonal degeneration.15 Therefore, secondary progressive MS appears to be both an immune mediated demyelination as well as an axonal degenerative disease.16 Future studies of ASCT for MS should investigate whether the stability status is associated with the interval from diagnosis to transplantation. Earlier intervention with ASCT in progressive patients may be the preferred approach before severe brain injury and irreversible degenerative processes have occurred. The third and worst outcome is failure to respond to ASCT: the patient will relapse again. Both residual autoreactive T lymphocytes in vivo and lymphocytes in the graft are claimed to be responsible for relapses of autoimmune disease in animal models.17,18 Perhaps a more intensive conditioning regimen should be used in patients with highly active symptoms. Antithymocyte globulin is effective for in vivo T cell depletion and may therefore have additional effects in conjunction with the conditioning.19 Therefore, high intensity conditioning regimens have been associated with higher risk of transplant-related mortality. We found the conditioning regimen used in this study is effective because of good lympholytic effect and the possibility of carmustin and cytosine arabinoside exerting their effect across the blood brain barrier. Another consideration would also require elimination of T and B cells in the graft by selecting CD34+cells.20,21
Despite the encouraging clinical results, the outcomes with the same conditional regimen varied. Whether a cure is possible is currently unknown, but longer follow-up and more experience are definitely needed. In addition to clinical observation, risk factors of treatment and immunological reconstitution should be further evaluated.
Acknowledgements: We would like to thank Dr. YU Yue-yi who assisted in the evaluation of patients. We also thank Dr. LI Yao-hua, ZHUANG Guang-yan and HUI Wu-han for their excellent support in preparing this manuscript and data.
1. Hemmer B, Archelos JJ, Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 2002; 3: 291-301.
2. van Bekkum DW. New opportunities for the treatment of severe autoimmune diseases: bone marrow trans- plantation. Clin Immunol Immunopathol 1998; 89: 1-10.
3. Kozak T, Havrdova E, Pit’ha J, Gregora E, Pytlik R, Maaloufova J, et al. High-dose, immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis. Bone Marrow Transplant 2000; 25: 525-531.
4. Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. BMT-MS Study Group. J Neurol 2000; 247: 376-382.
5. Ji BX, Su L, Xu J, Dong HQ, Sun XJ, Liu CY. Autologous peripheral blood stem cell transplantation for progressive multiple sclerosis. Chin J Prac Int Med (Chin) 2005; 25: 884-886.
6. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, Maravilla KR, Park M, et al. High-dose, immuno- suppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 2003; 102: 2364-2372.
7. McCormack PL, Scott LJ. Interferon-beta-1b: a review of its use in relapsing-remitting and secondary progressive multiple sclerosis. CNS Drugs 2004; 18: 521-546.
8. Rovaris M, Filippi M. Interventions for the prevention of brain atrophy in multiple sclerosis: current status. CNS Drugs 2003; 17: 563-575.
9. Mancardi GL, Murialdo A, Rossi P, Gualandi F, Martino G, Marmont A, et al. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler 2005; 11: 367-371.
10. Tyndall A, Koike T. High-dose immunoablative therapy with hematopoietic stem cell support in the treatment of severe autoimmune disease: current status and future direction. Intern Med 2002; 41: 608-612.
11. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 2005; 201: 805-816.
12. Porter DL, June CH. T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ’T’ it up! Bone Marrow Transplant 2005; 35: 935-942.
13. Feng NH, Wu HF, Wu J, Zhang W, Sui YQ, He HG, et al. Transplantation tolerance mediated by regulatory T cells in mice. Chin Med J 2004; 117: 1184-1189.[PubMed]
14. Tyndall A, Matucci-Cerinic M. Haematopoietic stem cell transplantation for the treatment of systemic sclerosis and other autoimmune disorders. Expert Opin Biol Ther 2003; 3: 1041-1049.
15. Pluchino S, Martino G. The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci 2005; 233: 117-119.
16. Hohlfeld R. The prospects for neuroprotection in MS. Int MS J 2003; 10: 103-105.
17. van Bekkum DW. Autologous stem cell therapy for treatment of autoimmune diseases. Exp Hematol 1998; 26: 831-834.
18. Marmont AM, van Lint MT, Occhini D, Lamparelli T, Bacigalupo A. Failure of autologous stem cell transplantation in refractory thrombocytopenic purpura. Bone Marrow Transplant 1998; 22: 827-828.
19. Samijn JP, te Boekhorst PA, Mondria T, van Doorn PA, Flach HZ, van der Meche FG, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006; 77: 46-50.
20. Burt RK, Traynor AE, Cohen B, Karlin KH, Davis FA, Stefoski D, et al. T cell-depleted autologous hemato- poietic stem cell transplantation for multiple sclerosis: report on the first three patients. Bone Marrow Transplant 1998; 21: 537-541.
21. Carreras E, Saiz A, Marin P, Martinez C, Rovira M, Villamor N, et al. CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of followup in 15 patients. Haematologica 2003; 88: 306-314.