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ORIGINAL ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 2  |  Page : 454-457

Autologous Stem Cell Transplant in Adult Multiple Sclerosis Patients: A Study from North India


Department of Hematology and BMT, Fortis Memorial Research Institute, Gurgaon, Haryana, India

Date of Web Publication15-May-2020

Correspondence Address:
Aniruddha Dayama
Department of Hematology and BMT, Fortis Memorial Research Institute, Gurgaon - 120 002, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.284385

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 » Abstract 


Introduction: Autologous Stem Cell Transplant (ASCT) provides long periods of progression-free-survival in multiple sclerosis (MS). This is an observational study to demonstrate the safety of ASCT in MS patients at a transplant center in North India using a lymphoablative regimen.
Materials and Methods: MS patients > 18 years referred by a neurologist or who came of their own volition were evaluated. Kurtzke Expanded Disability Status Scale (EDSS) score was calculated and those with a score of >7 were excluded. Informed written consent was taken. Mobilization was done with G-CSF with prednisolone to prevent disease flare-up. A minimum of 2 × 106 CD34 cells/kg was collected. Conditioning regimen consisted of rabbit ATG and cyclophosphamide. Rituximab 375 mg/m2 was given to prevent EBV reactivation and disease relapse. Antibiotic prophylaxis was given with levofloxacin, fluconazole, and valacyclovir. Any persistent change in EDSS scores ≥0.5 was considered significant.
Results: Twenty patients were included. Seven patients had positive urine cultures prior to transplant and were treated before starting any chemotherapy. Majority patients were women (13/20). All patients developed febrile neutropenia, which was managed as per department policy. There was no mortality. Subjective symptoms improved in all patients. EDSS score improved in 6/19 patients (5/6 with RRMS) with no disease progression in any patient at a median follow-up duration of 242 days.
Conclusion: ASCT can be done safely for patients with relatively high EDSS scores with additional precautions for screening for infections. RRMS patients with the active disease show most improvement. SPMS patients may not show significant improvement in the short term.


Keywords: ASCT, ATG, lymphoablative, multiple sclerosis, MS, RRMS, SPMS
Key Message: Autologous stem cell transplant can be performed safely in selected patients of Multiple Sclerosis at specialized centers with adequate pre-transplant infection screening to prevent mortality.


How to cite this article:
Dayama A, Bhargava R, Kurmi SR, Jain S, Dua V. Autologous Stem Cell Transplant in Adult Multiple Sclerosis Patients: A Study from North India. Neurol India 2020;68:454-7

How to cite this URL:
Dayama A, Bhargava R, Kurmi SR, Jain S, Dua V. Autologous Stem Cell Transplant in Adult Multiple Sclerosis Patients: A Study from North India. Neurol India [serial online] 2020 [cited 2020 Jun 1];68:454-7. Available from: http://www.neurologyindia.com/text.asp?2020/68/2/454/284385




Multiple sclerosis (MS) is a devastating demyelinating disorder affecting people in the prime of their lives. It has two components, namely, inflammatory and degenerative. Most patients present with a relapsing and remitting (RRMS) course characterized by inflammation caused by autoreactive lymphocytes. This leads to axonal degeneration causing disease progression over a period of time and patients accumulate neurological deficits. RRMS then progresses into secondary progressive MS (SPMS).[1]

Majority of the drugs used for the treatment are immunomodulatory in nature and try to halt the inflammation-causing neuronal damage. However, this does not lead to a reversal of degeneration caused by axonal damage. Autologous hematopoietic cell transplant (AHCT) was started as an experimental therapy with the rationale of destruction of autoreactive lymphocytes by chemotherapy and “resetting” the immune system.[2] Over the past many years, many groups have done the procedure in various groups of patients with different types of MS and using different conditioning regimens.

The incidence of MS is highest in European countries. The approximate incidence rate of MS is 8.35/100000 population in India, derived from a hospital-based study.[3] The treatment options have increased with the availability of many newer agents but the cost-benefit ratio has placed them out of reach of many patients in India. The data from India regarding the outcome and safety of AHCT is unknown. Only a single case report has been published highlighting the hesitation in the minds of neurologists regarding the efficacy of AHCT in MS patients.[4]

The aim of the current study was to prove the safety and efficacy of AHCT in Indian patients with MS.


 » Materials and Methods Top


All patients of MS who presented to the Hematology center of a tertiary care hospital in North India between January 2017 and January 2018 were included. These patients had either been referred by a neurologist or came of their own volition. These patients underwent evaluation for assessment of feasibility of AHCT. Kurtzke Expanded Disability Status Scale (EDSS) score was calculated for all patients and those with a score of >7 were excluded. Patients <18 years were excluded. Informed written consent was taken from all patients for performing AHCT. The patients were counseled for expected outcomes based on the trials done earlier using similar conditioning protocols.

Pre-AHCT workup

All patients underwent screening for urinary tract infections by urine culture. Those who were positive were treated with antibiotics as per the results of the sensitivity patterns and AHCT was deferred till they became culture negative. In addition, they underwent testing for hepatitis B, hepatitis C, HIV, CMV, biochemistry, and specialized tests such as DTPA-GFR, echocardiography, and pulmonary function test.

Mobilization and stem cell collection

Patients were mobilized with G-CSF (biosimilar) 10 μg/day for 5 days with prednisolone 1 mg/day to prevent disease flare-up. Patients underwent femoral vein catheterization for stem cell harvest and were harvested on Spectra Optia apheresis machine (TerumoBCT, Colorado, USA). Pre-harvest and post-harvest CD34 counts were done on BD FACS Canto II (BD Biosciences, San Jose, CA, USA) in all patients to get a minimum yield of 2 × 106 cells/kg.

Conditioning regimen

The conditioning regimen was a lymphoablative regime with rabbit anti-thymocyte globulin (ATG) [Sanofi] 0.5 mg/kg on day-6 and then 1 mg/kg on day-5 to day-2. Cyclophosphamide was given at a dose of 50 mg/kg on day-5 to day-2 with mesna. Antiemetics were used as per department protocol. Rituximab (biosimilar) was given on day-7 and day +30 at a dose of 375 mg/m2 to prevent Epstein Barr virus reactivation secondary to ATG use.

Prophylaxis for infections

All patients received levofloxacin, fluconazole, co-trimoxazole, and valacyclovir as part of prophylaxis during and post-transplant period till day +30. Co-trimoxazole and valacyclovir were continued till day +90. Febrile neutropenia was managed as per departmental policy for transplant patients.

Follow-up

Patients continued their routine follow-up with a neurologist to assess any persistent change in EDSS scores ≥0.5 points, which was considered significant. MRI scan was planned in case of any acute change and at 1-year post-transplant to assess disease activity.


 » Results Top


A total of 20 patients were included in this study. One patient out of twenty was from the United Kingdom and has been lost to follow-up with no response to repeated communication attempts. Most of the patients were from North India with one each from east, west, and southern part of India.

The patient demographics and details of their transplant are recorded in [Table 1].
Table 1: Details of 20 patients of MS who underwent ASCT

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The majority of the patients were female (13/20, M:F: 1.8:1). The median age of the study population was 31.5 years (range 22–65 years). More than half of the patients had SPMS (11/20) with no active lesion on their MRI. Only six out of 9 (66%) of RRMS patients had active disease on MRI contrast scans. All except one RRMS patient were refractory to ≥2 lines of therapy.

Pretransplant urine culture was positive in 7 patients (Sr. No. 3, 4, 6, 7, 9, 11, 18) which was treated prior to mobilization. The median CD34 count was 6.07 × 106 CD 34 cells/kg (range 2.69–13.19 × 106/kg). Nineteen (95%) patients developed febrile neutropenia with only two (10%) positive blood cultures. There was no immediate and day +100 mortality. The median follow-up duration was 242.5 days (110–380). The median EDSS score was 5.5 (range 1–7).

Progression-free survival (PFS) was measurable in 19/20 patients as one patient was lost to follow-up after 110 days. Seven out of nineteen patients (36.8%) have shown improvement in EDSS score during the short-term follow-up of the study and these include six patients of RRMS (66.6%) and one patient of SPMS (10%). However, none of the patients have shown any disease progression clinically. The short-term PFS was 100% at one year. However, this may not hold true in long term. All of the patients had a subjective improvement such as fatigue or stiffness. However, this was not measured on any scoring scale.


 » Discussion Top


AHCT for multiple sclerosis has evolved over the past two decades. According to a recent European Bone Marrow Transplant registry article, more than 800 autologous transplants have been done for MS.[5] There is no data from India regarding the outcome of ASCT in patients with MS except a single case report of a patient with SPMS by Pandit et al.[4] In our study similar to the study by Muraro et al., majority of the patients were SPMS.[6] Their study, which described long-term outcomes of autologous transplant in various centers across the world, consisted of 66% of patients with SPMS. Our study had 55% SPMS patients in the patient cohort. Other studies like those done by Atkins et al.[7] and Shevchenko et al.[8] also had a similar percentage of SPMS patients. Some studies such as the open label HALT-MS by Nash et al.[9] and the other one by Currò et al.[10] have included only RRMS patients. These two studies have shown impressive response rates in RRMS patients although the patient numbers are small.[9],[10]

A comparison between the above-mentioned studies is tabulated in [Table 2] highlighting the inferior outcome in SPMS patients. Our data has also shown similar trends with 4/6 (66%) RRMS patients with active lesions showing improvement. None of the study patients have shown any worsening in the EDSS score. The PFS in the short term is 100%. One patient with SPMS showed improved in EDSS score. As the median follow-up is very short, it is naïve to expect that such a high PFS will be maintained when the patients are followed up for longer periods.
Table 2: Comparison of patient data with other studies

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It is imperative to prevent mortality and published studies have shown very little mortality with rates less than 1%. In order to prevent mortality and morbidity, screening for infections was done with urine culture and HRCT chest. There was a high rate of positive urine culture (7/20, 35%) in patients emphasizing the need for screening as many have bladder dysfunction which can lead to post-void residual volume and urinary tract infection. There was no mortality in the study group.

The median EDSS score in our study was similar to those by Muraro et al.[6] and Atkins et al.[7] However, it was higher than that of Shevchenko et al.[8] and Nash et al.[9] This highlights the advanced stage of presentation of most of the patients in our study group. This may lead to inferior outcomes in the long term.


 » Conclusion Top


The study shows that ASCT can be done safely for patients with relatively high EDSS scores with additional precautions for screening for infections. RRMS patients with the active disease on MRI show the most improvement. SPMS patients may not show significant improvement in the short term. None of our patients has progressed in short-term follow-up and AHCT has not impacted any patient adversely. The study has its limitations with its small patient size and short-term follow-up. A long-term follow-up is required to assess the eventual impact of AHCT in this subgroup. Better selection of patients may lead to further improvement in outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: Prospects for disease therapy, repair, and restoration of function. Lancet 2017;389:1357-66.  Back to cited text no. 1
    
2.
Fassas A, Kimiskidis VK. Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: Rationale and clinical experience. J Neurol Sci 2004;223:53-8.  Back to cited text no. 2
    
3.
Singhal BS. Multiple sclerosis. Neurol India 1999;47:1-2.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Pandit AK, Prasad K, Seth T. Autologous hematopoietic stem cell transplantation in progressive severe multiple sclerosis. Ann Indian Acad Neurol 2015;18:459-63.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Marjanovic Z, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv 2017;1:2742-55.  Back to cited text no. 5
    
6.
Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for Multiple Sclerosis. JAMA Neurol 2017;74:459-69.  Back to cited text no. 6
    
7.
Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: A multicentre single-group phase 2 trial. Lancet 2016;388:576-85.  Back to cited text no. 7
    
8.
Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kurbatova KA, et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: Physician's and patient's perspectives. Ann Hematol 2015;94:1149-57.  Back to cited text no. 8
    
9.
Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT fo relapsing-remitting MS. Neurology 2017;88:842-52.  Back to cited text no. 9
    
10.
Currò D, Vuolo L, Gualandi F, Bacigalupo A, Roccatagliata L, Capello E, et al. Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study. Mult Scler 2015;21:1423-30.  Back to cited text no. 10
    



 
 
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