Hematopoietic Stem Cell Transplantation for Treatment of Multiple Sclerosis in Sweden

Multiple Sclerosis Clinical Trial

— AutoMS-Swe  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05029206
• Other study ID #: EPM 2021-01530
• Status: Completed
• Start date: May 5, 2021
• Est. completion date: September 30, 2022

Study information

• Verified date: November 2023
• Source: Uppsala University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 174
• Est. completion date: September 30, 2022
• Est. primary completion date: September 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

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.

Locations

Country	Name	City	State
Sweden	Sahlgrenska University Hospital	Gothenburg
Sweden	Linköping University Hospital	Linköping
Sweden	Skåne University Hospital	Lund
Sweden	Örebro University Hospital	Örebro
Sweden	Danderyd Hospital	Stockholm
Sweden	Karolinska University Hospital	Stockholm
Sweden	Umeå University Hospital	Umeå
Sweden	Uppsala University Hospital	Uppsala

Sponsors (8)

Lead Sponsor	Collaborator
Uppsala University	Karolinska University Hospital, Region Örebro County, Sahlgrenska University Hospital, Sweden, Skane University Hospital, University Hospital, Linkoeping, University Hospital, Umeå, Uppsala University Hospital

Country where clinical trial is conducted

Sweden, 

References & Publications (26)

Alping P, Burman J, Lycke J, Frisell T, Piehl F. Safety of Alemtuzumab and Autologous Hematopoietic Stem Cell Transplantation Compared to Noninduction Therapies for Multiple Sclerosis. Neurology. 2021 Mar 16;96(11):e1574-e1584. doi: 10.1212/WNL.0000000000011545. Epub 2021 Jan 29. — View Citation

Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, Bence-Bruckler I, Birch P, Bredeson C, Chen J, Fergusson D, Halpenny M, Hamelin L, Huebsch L, Hutton B, Laneuville P, Lapierre Y, Lee H, Martin L, McDiarmid S, O'Connor P, Ramsay T, Sabloff M, Walker L, Freedman MS. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85. doi: 10.1016/S0140-6736(16)30169-6. Epub 2016 Jun 9. — View Citation

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Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelson F, Barreira AA, Carlson K, Han X, Moraes D, Morgan A, Quigley K, Yaung K, Buckley R, Alldredge C, Clendenan A, Calvario MA, Henry J, Jovanovic B, Helenowski IB. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/jama.2018.18743. — View Citation

Burt RK, Cohen BA, Russell E, Spero K, Joshi A, Oyama Y, Karpus WJ, Luo K, Jovanovic B, Traynor A, Karlin K, Stefoski D, Burns WH. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003 Oct 1;102(7):2373-8. doi: 10.1182/blood-2003-03-0877. Epub 2003 Jul 3. — View Citation

Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, Oyama Y, Russell EJ, Stern J, Muraro P, Rose J, Testori A, Bucha J, Jovanovic B, Milanetti F, Storek J, Voltarelli JC, Burns WH. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009 Mar;8(3):244-53. doi: 10.1016/S1474-4422(09)70017-1. Epub 2009 Jan 29. Erratum In: Lancet Neurol. 2009 Apr;8(4):309. Stefosky, Dusan [corrected to Stefoski, Dusan]. — View Citation

Compston A, Coles A. Multiple sclerosis. Lancet. 2002 Apr 6;359(9313):1221-31. doi: 10.1016/S0140-6736(02)08220-X. Erratum In: Lancet 2002 Aug 24;360(9333):648. — View Citation

Daumer M, Griffith LM, Meister W, Nash RA, Wolinsky JS. Survival, and time to an advanced disease state or progression, of untreated patients with moderately severe multiple sclerosis in a multicenter observational database: relevance for design of a clinical trial for high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation. Mult Scler. 2006 Apr;12(2):174-9. doi: 10.1191/135248506ms1256oa. — View Citation

Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler. 2009 Feb;15(2):229-37. doi: 10.1177/1352458508096875. Epub 2008 Sep 19. — View Citation

Hader WJ. Disability and survival of multiple sclerosis in Saskatoon, Saskatchewan. Can J Neurol Sci. 2010 Jan;37(1):28-35. doi: 10.1017/s0317167100009616. — View Citation

Hamerschlak N, Rodrigues M, Moraes DA, Oliveira MC, Stracieri AB, Pieroni F, Barros GM, Madeira MI, Simoes BP, Barreira AA, Brum DG, Ribeiro AA, Kutner JM, Tylberi CP, Porto PP, Santana CL, Neto JZ, Barros JC, Paes AT, Burt RK, Oliveira EA, Mastropietro AP, Santos AC, Voltarelli JC. Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Bone Marrow Transplant. 2010 Feb;45(2):239-48. doi: 10.1038/bmt.2009.127. Epub 2009 Jul 6. — View Citation

Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001 May;124(Pt 5):962-73. doi: 10.1093/brain/124.5.962. — View Citation

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86. doi: 10.1212/WNL.0000000000000560. Epub 2014 May 28. — View Citation

McFarland W, Granville NB, Dameshek W. Autologous bone marrow infusion as an adjunct in therapy of malignant disease. Blood. 1959;14(5):503-521. Blood. 2016 Apr 14;127(15):1839. doi: 10.1182/blood-2016-01-696450. — View Citation

Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, Freedman MS, Georges GE, Gualandi F, Hamerschlak N, Havrdova E, Kimiskidis VK, Kozak T, Mancardi GL, Massacesi L, Moraes DA, Nash RA, Pavletic S, Ouyang J, Rovira M, Saiz A, Simoes B, Trneny M, Zhu L, Badoglio M, Zhong X, Sormani MP, Saccardi R; Multiple Sclerosis-Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. doi: 10.1001/jamaneurol.2016.5867. — View Citation

Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler. 2009 Dec;15(12):1509-17. doi: 10.1177/1352458509348519. Epub 2009 Dec 7. — View Citation

Philip T, Armitage JO, Spitzer G, Chauvin F, Jagannath S, Cahn JY, Colombat P, Goldstone AH, Gorin NC, Flesh M, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987 Jun 11;316(24):1493-8. doi: 10.1056/NEJM198706113162401. — View Citation

Reiffers J, Trouette R, Marit G, Montastruc M, Faberes C, Cony-Makhoul P, David B, Bourdeau MJ, Bilhou-Nabera C, Lacombe F, et al. Autologous blood stem cell transplantation for chronic granulocytic leukaemia in transformation: a report of 47 cases. Br J Haematol. 1991 Mar;77(3):339-45. doi: 10.1111/j.1365-2141.1991.tb08581.x. — View Citation

Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015 Feb;72(2):152-8. doi: 10.1001/jamaneurol.2014.3537. — View Citation

Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D, Greco R, Jessop H, Kazmi M, Kirgizov K, Labopin M, Mancardi G, Martin R, Moore J, Muraro PA, Rovira M, Sormani MP, Snowden JA; European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE). Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020 Feb;55(2):283-306. doi: 10.1038/s41409-019-0684-0. Epub 2019 Sep 26. — View Citation

Skoog B, Runmarker B, Winblad S, Ekholm S, Andersen O. A representative cohort of patients with non-progressive multiple sclerosis at the age of normal life expectancy. Brain. 2012 Mar;135(Pt 3):900-11. doi: 10.1093/brain/awr336. — View Citation

Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017 Feb;23(2):201-204. doi: 10.1177/1352458516645670. Epub 2016 Jul 11. — View Citation

Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, Mancardi GL. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. 2017 May 30;88(22):2115-2122. doi: 10.1212/WNL.0000000000003987. Epub 2017 Apr 28. Erratum In: Neurology. 2017 Jul 11;89(2):215. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in cognitive function	Explorative outcome. Measured by Symbol Digit Modalities Test (SDMT) is a test of cognitive function in MS-patients.	At 1, 2 and 3 years
Other	Changes in quality of life	Explorative outcome. Changes in quality of life, measured by the Multiple Sclerosis Impact Scale (MSIS-29) from the patient's perspective.	At 1, 2 and 3 years
Other	Changes in MS-related fatigue	Explorative outcome. As measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC), a 20-item scale for evaluating MS-related cognitive and motor fatigue.	At 1, 2 and 3 years
Primary	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
Primary	Treatment related mortality (TRM)	TRM is defined as death due to any transplantation-related cause other than disease progression.	Up to 18 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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