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Autologous Stem Cell Transplant in Adult Multiple Sclerosis Patients: A Study from North India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.284385
Keywords: ASCT, ATG, lymphoablative, multiple sclerosis, MS, RRMS, SPMSKey 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.
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.
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.
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].
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.
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.
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.
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.
[Table 1], [Table 2]
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