HSCT protocols for people with MS

A. A. Maximov; aHSCT protocol for autoimmune diseases (Russia)

• More than 2 x 10⁶/kg CD 34+ hematopoietic stem cells are harvested (multiple apheresis days might be necessary
• Ex-vivo T-cell depletion is done with a “CliniMACS^® reagent system” 
• Cyclophosphamide 50 mg/kg (per block)
• Rituximab 500 mg/m²
• In rare, pre-discussed cases, a Top-up is performed after one year with Rituximab of Mitoxantrone
• Source: booklet – Pirogov national medical surgical center, A. A. Maximov department of hematology and cellular therapy autologous Hematopoietic Stem Cell Transplantation (aHSCT) for autoimmune diseases (aid); General Information

Clínica Ruiz, The Mexican Method; aHSCT for MS patients (Mexico)

• Treatment is done on an outpatient basis
• The harvested CD 34+ hematopoietic stem cells (> 1 × 10⁶ cells/kg) are not frozen
• Cyclophosphamide 50 mg/kg (per block)
• Rituximab 1000 mg
• Source: clinical trials description

Artemis Hospital; aHSCT for MS patients (India)

• Cyclophosphamide 50 mg/kg (per block)
• rATG amount as of yet unknown
• Source: document – InfoPack.HSCT.Artemis.Hospitals.India.pdf 

Raffles Cancer Centre; aHSCT for autoimmune diseases (Singapore)

• Apheresis follows 10 days after the first Cyclophosphamide (2 g/m²)
• Following the apheresis, a minimum 2-week period of rest is required, to allow the body to recover. 
• CD34 selection of the harvested stem cells is done using a “CliniMACS® system” 
• Fudarabine 30 mg/m² (per block)
• Cyclophosphamide 50 mg/kg (per block)
• Patients are given preventative antibiotics and antiviral medications for up to 12 months after the transplant
• Source: article “Successful Autologous Hematopoietic Stem Cell Transplantations for Severe Multiple Sclerosis with Fludarabine and Cyclophosphamide Conditioning” & website

This protocol is also being used in:

• Singapore General Hospital

Non-myeloablative, low-intensity protocol

• Cyclophosphamide 50 mg/kg (per block)
• rATG 0.5 mg/kg on day −5, 1.0 mg/kg on day −4, and 1.5 mg/kg on days −3, −2 and −1
• Between 3 and 5 x 10⁶/kg CD 34+ hematopoietic stem cells are harvested
• Source: article “A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis”

This protocol is being used (in roughly the same form) in i.a.:

• University Hospital of Antwerp (Belgium)
• Karonlinska University Hospital, Stockholm (Sweden)
• Heidelberg University Hospital (Germany)
• The RAM-MS study
• Note: This protocol is similar to the protocol used in the MIST study. In that protocol, however, a higher dose of methylprednisolone (1000 mg) is given before administering ATG (Source: doi:10.1001/jama.2018.18743)
• Northwestern University, Chicago (USA)
• Uppsala University (Sweden)
• Sheffield Teaching Hospitals NHS Foundation Trust (UK)
• University of Sao Paulo (Brasil)

Myeloablative intermediate intensity protocol

• BCNU (carmustine) 300 mg/m²
• Cytarabine (Ara-C) twice daily 100 mg/m² (per block)
• Etoposide twice daily 100 mg/m² (per block)
• Melphalan 140 mg/m²  
• rATG 3.75 mg/kg in 6-8 hours (per block)
• Source: http://hsct4ms.com/protocol/

This protocol is being used (in roughly the same form) in i.a.:

• Shares Tzedek medical center, Jerusalem (Israel)
• University Hospital of Navarra (Spain)
• Careggi University Hospital, Florence, (Italy)

MakatiMed aHSCT for MS patients (Philippines)

• After the apheresis there is a rest period of 5-10 days
• BCNU (carmustine) 150 mg/m² (per block)
• Etoposide 100 mg/m²
• Cytarabine (Ara-C) 100 mg/m²
• Melphalan 100 mg/m² 
• hATG 30 mg/kg (per block) -note: this is horse derived ATG unlike the rabbit variant used in all other centers. There is no evidence for a difference in the effectiveness for treatment of MS. (MakatiMed’s choice for hATG is due to availability)-
• Source: patient information 2017

Myeloablative high intensity protocol

• Cyclophosphamide 50 mg/kg (per block)
• There is an undefined period between the apheresis and the conditioning regimen
• The amounts of Busulfan and rATG used are unspecified
• Ex-vivo T cell depletion is being done with a “CliniMACS® system” 
• Source: article “Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis”

Note that low, intermediate and high intensity protocols are terms used by the EBMT. The protocols of Singapore and India would qualify as “low intensity”, non-myeloablative. The protocols of Russia and Mexico are even lower in intensity than what the EBMT refers to as “low intensity” protocols.