Hematopoietic Stem Cell Transplantation for Treatment of Multiple Sclerosis in Sweden

Study Overview
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Brief Summary
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This is an observational cohort study with retrospective analysis of prospectively collected data. The study cohort is constituted of all patients with relapsing-remitting multiple sclerosis (RRMS) treated with autologous stem cell transplantation (AHSCT) in Sweden from 2004 when the first AHSCT was performed until 31 December 2019. The study aims to describe the effectiveness, safety and patient reported outcomes of AHSCT for MS through real world data. Treatment related mortality will be analyzed from start of mobilization until the end of the study. For other adverse events the data collection will end 3 months post-transplantation. A statistical subgroup comparison of efficacy and safety between the conditioning regimens BEAM-ATG and Cy-ATG will be included within the study.

Detailed Description
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All individuals with a diagnosis of MS, who was treated with AHSCT in Sweden until 31 December 2019 can be included in this study. Patients will be identified through the European Bone and Marrow Transplantation register (EBMT) and the Swedish MS register (SMSreg). Baseline data will be collected from the SMSreg. Data concerning AHSCT will be collected from local repositories of the EBMT and supplemented by data obtained by reviewing of medical records. This includes data such as doses and names of drugs used for mobilization and conditioning, dates for administration of these drugs, date of hematopoietic stem cell transplantation, date of hematological milestones, occurrence and grading of adverse events during the first three months after the intervention. Data on clinical outcome after the first three months of the intervention will be collected from SMSreg. Data on vital status will be collected from medical records at the end of study. Any recorded deaths will be analyzed through the medical records to determine if it was treatment-related. The endpoints will be analysed and described for the whole study cohort. A subgroup analysis comparing the outcome of patients treated with different conditioning regimens (e.g. BEAM-ATG and Cy-ATG) will be included in this study.

Official Title
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Hematopoietic Stem Cell Transplantation for Treatment of Multiple Sclerosis in Sweden - a Register-based Retrospective Observational Study

Conditions
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Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Procedure: Autologous hematopoietic stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple sclerosis according to the revised McDonald criteria 2017. Autologous hematopoietic stem cell transplantation performed for treating multiple sclerosis at a Swedish transplantation center until December 31st 2019. Exclusion Criteria: Diagnosis of primary progressive MS or secondary progressive MS according to Lublin et al at the time of transplantation. Patient not accepted reporting of data to the EBMT register. Not fulfilling requirements of the minimal dataset, se below. Definition of minimal dataset Data on disease course of multiple sclerosis at the time of transplantation. Transplantation and the following in-patient care performed in Sweden. Date of transplantation. Data on drugs used in conditioning. At least one follow-up visit performed in Sweden (unless early death before first follow-up visit) including data on: Clinical assessment The Kurtzke Expanded Disability Status Scores (EDSS) Additional note: For a patient to be included in the analysis of treatment effectiveness data on MRI evaluation is needed at least once during follow-up.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: Autologous hematopoietic stem cell transplantation|The therapeutic intervention of AHSCT consists of four parts: the mobilization of hematopoietic stem cells (HSC), the harvest of HSC, the ablation (conditioning) of the immune system and the reinfusion of autologous HSCs. In Sweden, the mobilization of HSCs has been made by a combination of cyclophosphamide (2 g/m2) and granulocyte-colony-stimulating factor. A minimum of 2 × 10^6 CD34+ cells/kg is harvested and cryopreserved. No in vitro manipulation is done to the stem cells. Two conditioning regimens have been used in Sweden for ablation. The BEAM-ATG protocol include carmustine (BCNU) 300 mg/m2, etoposide 800 mg/m2, cytarabine arabinoside (ARA-C) 800 mg/m2 and melphalan 140 mg/m2 + rATG or hATG. The Cy-ATG protocol include cyclophosphamide 200 mg/kg + rATG/hATG with 1000 mg Metylprednisolone given day -5 to -1. After a minimum of 24 hours after the last administration of chemotherapy have passed, the reinfusion of autologous CD34+ cells is performed.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No evidence of disease activity (NEDA) | NEDA is defined as absence of relapses in addition to absence of clinical progression and MRI progression. | 5 years | 
| Treatment related mortality (TRM) | TRM is defined as death due to any transplantation-related cause other than disease progression. | Up to 18 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No evidence of disease activity (NEDA) | NEDA is defined as absence of relapses in addition to absence of clinical progression and MRI progression. | 3 years and 10 years | 
| MRI event free survival | The appearance of any T2 lesion > 3 mm or gadolinium enhancing lesion in the brain or spinal cord not present on the baseline scan measured from the time of AHSCT. | At 3, 5 and 10 years | 
| Relapse free survival | A clinical relapse defined as a period of acute worsening of neurological function lasting ≥ 24 hours not attributable to an external cause such as increased body temperature or acute infection, measured from the time of AHSCT. | At 3, 5 and 10 years | 
| Progression free survival | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS is a composite of disability in eight functional systems. Baseline EDSS ≤ 5 An increase in EDSS score with at least 1 point from baseline that is sustained between two follow-up visits separated in time by no less than six months. Baseline EDSS ≥ 5.5 An increase in EDSS score with at least 0.5 points from baseline that is sustained between two follow-up visits separated in time by no less than six months. | At 3, 5 and 10 years | 
| Annualized relapse rate (ARR) | The number of relapses occurring during a time period divided by the number of years in that time period. E.g. 5 relapses occurring in a time period of 2.5 years equals an ARR of 2 (5/2.5=2), after AHSCT. | Up to 17 years | 
| Proportion of patients with clinical improvement | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS is a composite of disability in eight functional systems. Baseline EDSS ≤ 5.5 A decrease in EDSS score with at least 1 point from baseline that is sustained between two follow-up visits separated in time by no less than six months. Baseline EDSS ≥ 6 A decrease in EDSS score with at least 0.5 points from baseline that is sustained between two follow-up visits separated in time by no less than six months. | Up to 17 years | 
| EDSS change | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS is a composite of disability in eight functional systems. Any change in EDSS from baseline to follow-up. | At 1, 2 and 3 years | 
| Grade 3 serious adverse events the first 100 days | The frequency and of grade 3 serious adverse events within 100 days as defined by the NIH common terminology criteria for adverse events (CTCAE). | 100 days | 
| Grade 4 serious adverse events the first 100 days | The frequency and of grade 3 serious adverse events within 100 days as defined by the NIH common terminology criteria for adverse events (CTCAE). | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous hematopoietic stem cell transplantation, Chemotherapy, Cyclophosphamide, Etoposide, Carmustine, Cytarabine, Melphalan, Antilymphocyte serum