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Novik et al.

Cellular Therapy and Transplantation (CTT), Vol. 1, No. 3

Please cite this article as follows: Novik AA, Kuznetsov AN, Melnichenko VY, Fedorenko DA, Ionova TI, Kruglina RV, Kartashov AV, Kurbatova KA, Gorodokin GI. High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis: Case report. Cell Ther Transplant. 2009;1:e.000030.01. doi:10.3205/ctt-2009-en-000030.01

© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported
Submitted: 26 December 2008, accepted: 4 September 2009, published: 22 September 2009

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High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis: Case report

 

A.A. Novik1, A.N. Kuznetsov1, V.Y. Melnichenko1, D.A. Fedorenko1, T.I. Ionova1, R.V. Kruglina1, A.V. Kartashov1, K.A. Kurbatova1, G.I. Gorodokin2

1Pirogov National Medical Surgical Center, the Department of Hematology and Cellular Therapy and the Department of Neurology, Pirogov National Medical Surgical Center, Moscow, Russia; 2New Jersey Center for Quality of Life and Health Outcome Research, USA

Correspondence: Andrey A. Novik, MD, PhD, Russian Cooperative Group for Cellular Therapy, Nizhnaya Pervomaiskaya str. 70, 105207 Moscow, Russian Federation, Tel.: +7 095 464 10 54, Fax: +7 095 464 10 54, E-mail: nqolc@spam is badyandex.ru

Summary

During the last several years high dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-HSCT) has been established as a therapeutic option for multiple sclerosis (MS) patients. We report clinical and patient-reported outcomes of HDCT + auto-HSCT in a male patient affected by secondary progressive MS (EDSS 5.0 at base-line). Reduced BEAM conditioning regimen was used. As a result, clinical response in terms of reduction of disability and disease activity was achieved along with quality of life (QoL) treatment response and symptom treatment response. The patient was off immunosuppressive or immunomodulating therapy throughout the post-transplant period. Our findings demonstrate that HDCT+auto-HSCT might be considered as an effective treatment for MS patients with high disease activity and relatively low disability rate. Reduction of dose intensity seems to have no influence on treatment outcome. QoL and symptom measurement appears to be an effective approach to assessment of treatment outcomes in patients with MS.

Keywords: multiple sclerosis, high dose chemotherapy, autologous stem cell transplantation, quality of life treatment response, symptom treatment response

Introduction

Bone marrow transplantation has contributed significantly to the treatment of life-threatening hematological and non-hematological disorders. Recently, high dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-HSCT) was proposed as a new and promising therapy for multiple sclerosis (MS) patients [2,5,6,11]. MS is a chronic inflammatory disorder of central nervous system (CNS), caused by autoimmune reactivity of T cells towards CNS myelin components. Although MS is a non-life-threatening disorder, its progression inevitably leads to impairment of motor function, sensitive disturbances and cognitive impairment in MS patients due to the immune-mediated demyelination and axon degeneration [10]. The clinical course of the disease is very heterogeneous; however, most of the patients experience “relapsing-remitting” disease initially, which is characterized by intermittent exacerbations followed by neurological recovery. This disease stage is usually followed by gradual neurological impairment, known as secondary progressive disease [12]. The neurological disability in MS patients is quantified according to the Expanded Disability Status Scale (EDSS) [9]. EDSS ranges from zero (no disability) to 10 (death related to neurological progression) with 0.5-step increments. EDSS steps from 1.0 to 4.5 refer to fully ambulatory MS patients, while patients with EDSS 7.0 are essentially restricted to a wheelchair.Conventional therapies do not provide satisfactory control of MS. Although results of preclinical studies suggest that allogenic transplantation may lead to the decreased incidence of relapses of autoimmune disease, in a clinical situation the toxicity of allogenic SCT results in the unacceptable rate of transplant-related mortality. Therefore, HDCT+auto-HSCT has been established as a therapeutic option for MS patients. Since 1995, several clinical studies have addressed the issue of feasibility and efficacy of HDCT+auto-HSCT in MS and a certain clinical benefit was shown [2,8,10,11,13-17,19]. The majority of patients included in the above-mentioned studies were severely disabled with an average EDSS score of 6.5. The BEAM conditioning regimen is considered to be the most effective although it is accompanied with the risk of transplant-related mortality [4]. At the same time taking into account the information about the risk of transplant-related mortality and side effects of myeloablative conditioning regimens, the rationale to use non-myeloablative regimens sounds reasonable [1]. In this connection different centers have initiated studies comparing mуеlоаblаtivе and nоn-mуеlоаblаtivе approaches. Our preliminary data shows that a non-myeloablative regimen based on reduced intensity BEAM is both effective and safe [14,15,21].

We report the clinical and patient-reported outcomes of HDCT+auto-HSCT with reduced dose conditioning regimen (nоn-mуеlоаblаtivе approach) in an MS patient with secondary progressive disease.

Patient Characteristics

The patient S., a 35-year-old male, was diagnosed with MS at the age of 32 in 2004 when he presented with retrobulbar right eye neuritis, decreased vision of the right eye and unsteadiness. MRI examination revealed multiple widespread lesions in the periventricular, subepindimar and subcortical area, and corpus callosum. The extended disability status score (EDSS) was 3.0. After the second relapse the diagnosis of relapsing-remitting type MS was made (2004). The patient was treated with steroids and plasmapheresis. Complete regression of symptoms was achieved. From 2004 to 2006, the patient developed progressive deterioration of neurological function; relapses were registered twice a year. From 2006 to 2007 steady disease progression with no evident relapses and the increase of disability (by 2 EDSS points) was observed. Steroids and plasmapheresis were ineffective. Results of an MRI revealed 48 lesions in the brain and 3 in the cervical section of the spinal cord; among them there were 22 Gd+ lesions in the brain and 1 in the spinal cord (Figure 1, (a)). The EDSS was upgraded to 5.0. Due to disease progression without relapses within a year and the increase of disability the diagnosis of secondary progressive type MS was made.

The patient was enrolled in the study, which was approved by the local IRB and the Ethical Committee.

Figure 1. MRI scans of patient S. before (a) and 3 months after HDCT+auto-HSCT (b).
a - Multiple Gd+ lesions in periventricular  area and Gd + ring lesion in cerebellum


Treatment outcomes


Clinical and patient-reported outcomes were assessed at baseline, at discharge, and at 3, 6, 9, 12, and 18 months after transplantation. Neurological assessment included measuring the EDSS score and MRI examinations. Patient-reported outcomes included QoL and symptom assessment. QoL was assessed by generic QoL questionnaire SF-36 [7]. The integral QoL index (IQLI) was calculated as described previously [18]. QoL treatment response was evaluated by comparison of IQLI before and after treatment. The following grades of response were used: improvement, stabilization and worsening. Symptoms were assessed using Comprehensive Symptom Profile-MS-SF. Comprehensive Symptom Profile-MS-SF is a new symptom assessment tool developed to assess the severity of 22 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from “0” (no symptom) to “10” (most expressed symptom). Applicability and satisfactory psychometric properties of the instrument have been tested in MS patients’ population. Symptom treatment response was evaluated by comparison of symptom severity before and after treatment. The following grades of response were used: improvement, stabilization and worsening.

Stem Cell Mobilization and Transplant Procedure


Mobilization of hematopoietic stem cells was conducted according to EBMT/EULAR guidelines [22]. Stem cells were mobilized with G-CSF at 10 µg/kg.b.wt. The “Hemonetics MCS” system was used for autologous stem cell apheresis. The grafts were not manipulated. Reduced BEAM conditioning regimen included: BCNU (300 mg/m2) on day -6, etoposide (75 mg/m2) from day -5 to day -2, cytarabine (100 mg/m2 bd) from day -5 to day -2, and melphalan (30 mg/m2) on day -1. It was followed by autologous hematopoietic stem cell transplantation (day 0). In vivo T-cell depletion was achieved through infusion of 30 mg/kg of horse anti-thymocyte globulin (ATGAM, PHARMACIA & UPJOHN COMPANY) on days 1 and 2. Five µg/kg s.c. of G-CSF were administered from day 3 post-infusion until granulocyte recovery. For infection prophylaxis oral ciprofloxacin, fluconazole, and acyclovir were given.

Results

Adverse events

Transplantation procedure was well tolerated by the patient. Mobilization was successful: 2.3 x106/kg CD34+ cells were 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. Neutropenia (grade IV) with PMN 0.09x109 was registered from D+4 to D+9; and thrombocytopenia with Plt 10x109 from D+4 to D+11. Neutropenic fever without infection was observed at D+7.

Clinical and patient reported outcomes

As a result of HDCT+auto-HSCT, disease improvement was registered. EDSS score dropped by 1.0 point (from 5.0 to 4.0) by 3 months post-transplant and remained stable throughout the time of follow-up (18 months) (Figure 2). The results of MRI scans 3 months after HDCT+auto-HSCT revealed a decrease in the number and the size of lesions. All 23 Gd+ lesions (22 brain and 1 spinal cord) turned to an inactive status (Figure 1, (b)). The MRI scans remained inactive at the end of follow-up (18 months post-transplant).

Figure 1. MRI scans of patient S. before (a) and 3 months after HDCT+auto-HSCT (b). 
b - No Gd+ lesion


Significant QoL improvement was observed after HDCT+auto-HSCT. The IQLI increased from 0.33 at base-line to 0.50 at discharge. Further improvement of QoL parameters took place during follow-up: IQLI achieved 0.70 at 18 months post-transplant (Figure 2). It is worth mentioning that before transplantation IQLI was much lower than the corresponding value of the population norm adjusted to age and gender (IQLI mean in the sample of 35–39 year old males from general population is 0.49). After transplantation IQLI of patient S. achieved and then exceeded the corresponding value of the population norm. Thus, QoL treatment response is considered as improvement.

Figure 2. EDSS and Integral Quality of Life Index dynamics in patient S. before and after HDCT+auto-HSC


Exceptional decrease of symptom severity after HDCT+auto-HSCT was registered. Before HDCT+auto-HSCT patient S. experienced 14 symptoms. The majority of these symptoms (9 out of 14) were moderate-to-severe (5–10 on numerical rating scale): fatigue, unsteadiness, vision disturbances, urination disturbances, speech disturbances, memory loss, decrease of attention concentration, poor heat tolerance and chill. Other symptoms: coordination problems, tremor, movement disturbances, and sexual problems were mild (1–4 on the numerical rating scale). The severity of moderate-to-severe symptoms of patient S. before transplantation and at different time-points post-transplant is presented in figure 3. In a year after transplantation the severity of these symptoms decreased significantly. Among the symptoms which were moderate-to-severe at base-line it is worth mentioning the decrease of severity of the following symptoms: fatigue (5 vs 0), unsteadiness (8 vs 1), vision disturbances (8 vs 4), urination disturbances (5 vs 2), speech disturbances (5 vs 2), memory loss (8 vs 1), decrease of attention concentration (8 vs 1), poor heat tolerance (10 vs 1), and chill (7 vs 1). Thus, symptom treatment response was achieved.

The patient received no treatment during the follow-up period post HDCT+ auto-HSCT.

Figure 3. Symptom severity in patient S. at different time-points after HDCT+auto-HSCT

Please click on the image to view a larger version.
Discussion

During the last decade HDCT+autoHSCT has been used as a therapeutic option for MS patients. It is important to emphasize that there are two goals of treatment in MS patients. The first one is pathogenetic, which is to stop the disease progression and prevent the appearance of new lesions in the nervous tissue. The second, which is considered to be the final goal of a patient’s treatment, is to improve or maintain his QoL. Another important consideration is the necessity to search for optimal conditioning regimen, myeloablative or non-myeloablative, for HDCT+autoHSCT in MS. Taking into account the toxicity of myeloablative conditioning regimens, the rationale of using the non-myeloablative approach sounds reasonable. Therefore, auto-HSCT with reduced dose intensity BEAM was performed for this secondary progressive MS patient. In this case study we report effects of reduced dose intensity BEAM with auto-HSCT on the clinical course of the disease and patient-reported outcomes.

To our knowledge, this is the first case report to analyze clinical response, QoL treatment response and symptom treatment response in a MS patient after HDCT+auto-HSCT. Notably, the patient had a relatively low EDSS score as compared with patients included in the previous studies [4,17]. As a result, clinical response was achieved both in terms of reduction of disability and disease activity. After transplantation EDSS decreased and all Gd+ lesions turned to an inactive status. HDCT+autoHSCT resulted in a QoL treatment response and symptom treatment response. The patient was off all therapy throughout the post transplant period.

Notably, his good response to this therapy might be explained by a relatively low EDSS score at base-line. Considering the pivotal role of autoreactive T-cells in MS pathogenesis, their eradication has to be a primary objective of MS treatment. This is achieved through ablation of the patient’s immune system with HDCT. HDCT is followed by auto-HSCT to restore an immune system that is expected to become tolerant to autoantigens. However, such “resetting” of the immune system is effective at early stages of MS only. Later in the clinical course of the disease, processes of axonal degeneration are prevailing and the damage to CNS tissue is too significant to expect a neurological recovery after HDCT+auto-HSCT. Indeed, failure of HDCT+auto-HSCT to prevent progression of the disease when performed on its late stages was shown in both animal models [3] and in recent clinical studies [11,14]. Our findings corroborate these data, since patients who benefited from HDCT+auto-HSCT had had a low disability score.

Finally, this case demonstrates that HDCT+auto-HSCT may be an effective treatment for MS in terms of clinical and patient-reported outcomes. Use of a reduced dose intensity conditioning regimen resulted in clinical treatment response along with QoL treatment response and symptom treatment response. Complex evaluation of QoL treatment response and symptom treatment response along with neurological and MRI data is a convenient method of assessment of treatment outcomes in such heterogeneous group as MS patient population. Further studies should be done to investigate long-term effects of HDCT+auto-HSCT in MS patients for better definition of a treatment success.

References

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21. Shevchenko Y, Novik A, Kuznetsov A, et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-929. doi: 10.1016/j.exphem.2008.03.001.

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© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported

Please cite this article as follows: Novik AA, Kuznetsov AN, Melnichenko VY, Fedorenko DA, Ionova TI, Kruglina RV, Kartashov AV, Kurbatova KA, Gorodokin GI. High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis: Case report. Cell Ther Transplant. 2009;1:e.000030.01. doi:10.3205/ctt-2009-en-000030.01

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