Article Figures & Data
Figures
- Fig 1.
Potential mechanisms of action of aHSCT in autoimmune diseases. In individuals with genetic susceptibility towards autoimmune disease, exposure to multiple environmental factors such as viral infection and toxic or metabolic damage (top), may induce autoimmune disease through aberrant antigen (Ag) mediated activation of T cells (centre). In aHSCT the cytotoxic chemotherapy ablates the lymphoid system including T lymphocyte immunity (as depicted). The leukocyte depletion enables an immune reconstitution that restores the predominance of anti-inflammatory regulating factors (bottom left) over inflammatory effectors (bottom right). These mechanisms may explain induction of long-lasting suppression of some autoimmune diseases by aHSCT.
Tables
Types of HSCT Autologous HSCT (aHSCT) Transplantation of haematopoietic stem cells taken from patients and reinfused after high doses of cytotoxic therapy (usually chemotherapy with immunoablative therapeutic antibodies such as anti-thymocyte globulin [ATG] in patients with severe autoimmune diseases) Allogeneic HSCT Transplantation of haematopoietic stem cells from a donor, either sibling or unrelated, and occasionally cord blood. Allogeneic HSCT is rarely performed for autoimmune diseases given the higher risks, and its use has been largely restricted to paediatrics Sources of haematopoietic stem cells (HSC) Peripheral blood stem cells Stem cells, labelled by the antigen CD34+, are mobilised using granulocyte colony stimulating factor (G-CSF) +/- chemotherapy from the bone marrow into the blood then harvested with apheresis Bone marrow Haematopoietic stem cell source derived by direct aspiration of bone marrow, a stem cell source infrequently used now for autologous HSCT HSCT phases Mobilisation Mobilisation of CD34+ stem cells from the bone marrow into the peripheral blood using granulocyte colony stimulating factor (G-CSF) +/- chemotherapy. Stem cells are then harvested using leukapheresis Conditioning High dose immunoablative or immunosuppressive regimen usually chemotherapy and therapuetic antibodies (for example antithymocyte globulin [ATG]) administered prior to stem cell infusion Harvesting Stem cells are harvested using leukapheresis ‘Transplant’/reinfusion The thawing and reinfusion of the CD34+ cells into the patient Aplastic phase The period when the immune system and haematopoietic system are unable to produce sufficient cells to maintain blood counts and innate immunity. The combination of antibiotic (prophylactic and therapeutic), transfusions, symptomatic care, growth factors and close monitoring required to bring the patient safely through and beyond engraftment, usually around 2 weeks post-transplantation Supportive care The combination of antibiotic (prophylactic and therapeutic), transfusions, symptomatic care, growth factors and monitoring required to bring the patient safely through and beyond engraftment, usually around 2 weeks post-transplantation Engraftment Defined as 3 days of neutrophils rising above 0.5 × 109/L and/or platelets rising above 20 × 109/L unsupported - Table 2.
Registrations in the EBMT Registry for autologous HSCT in autoimmune diseases (n=2515), June 2018*
Multiple sclerosis 1228 Connective tissue 699 Systemic sclerosis 540 SLE 108 Polymyositis-dermatomyositis 17 Sjogren's syndrome 4 Antiphospholipid syndrome 6 Other/unknown 24 Arthritis 166 Rheumatoid arthritis 80 Juvenile chronic arthritis: Systemic JIA 46 Other JIA 18 Polyarticular JIA 12 Psoriatic arthritis 3 Other 7 Inflammatory bowel disease 190 Crohn's disease 171 Ulcerative colitis 2 Other 17 Haematological 51 Immune thrombocytopenia 27 Evans’ syndrome 8 Autoimmune haemolytic anaemia 12 Other 4 Vasculitis 45 Wegener's type 10 Behcet's disease 9 Takayasu 2 Polyarteritis 3 Churg-Strauss 2 HUVSOther/unknown 118 Other neurological 98 Neuromyelitis optica 18 CIDP 47 Myasthenia gravis 8 Other/unknown 24 Type 1 diabetes 20 Other/unknown 18 *EBMT registry accessed 4 June 2018.
CIDP = Chronic inflammatory demyelinating polyneuropathy ; HUVS = hypocomplementemic urticarial vasculitis syndrome; JIA = juvenile idiopathic arthritis
Disease Trial Number of patients Mobilisation regimen Conditioning regimen Comparator arm Results Reference (number) MS ASTIMS 21 Cy 4 g/m2 + G-CSF BEAM + rATG Mitoxantrone + methylprednisolone
monthly for 6 monthsaHSCT significantly superior to mitoxantrone in reducing MRI activity in severe MS (79% reduction in T2 lesions). No difference in disease progression. No TRM 12 MS MIST 110
Interim analysisCy 2 g/m2 + G-CSF Cy 200 mg/kg + rATG Standard of DMT care (interferons, glatiramer acetate, dimethyl fumarate, fingolimod, natalizumab, but not alemtuzumab), aHSCT statistically superior to continued DMTs in terms of disability scores (EDSS) and progression in patients with RRMS with >2 relapses a year. No TRM 13 SSc ASSIST 19 Cy 2g/m2 + G-CSF Cy 200 mg/kg + rATG Cy 1 g/m2 monthly for 6 months All aHSCT (10/10) patients improved in skin score and lung function at 12 months compared to 0/9 in control. No TRM 14 SSc ASTIS 156 Cy 4 g/m2 + G-CSF Cy 200 mg/kg + rATG Cy 750 mg/m2
monthly for 12 monthsEFS and OS favoured aHSCT at 5.8 years. TRM 10% 15 SSc SCOT 75 G-CSF Cy 200 mg/kg + hATG + TBI 800 cGy (with lung and kidney shielding) Cy 500 mg/m2 for 1 month, then 750 mg/m2 for 11 months Superiority of aHSCT for GRCS (at 54 months), and EFS and OS (at 72 months). TRM 3% at 54 months and 6% at 72 months. Three malignancies in aHSCT group (possibly TBI related) compared with one in control group 16 CD ASTIC 45 Cy 4 g/m2 + G-CSF Cy 200 mg/kg + rATG Early versus late aHSCT Failed primary endpoint (sustained clinical remission off medication with no evidence of active disease on endoscopy or imaging). TRM in 1 patient 18 CD ASTIC secondary analysis 38 Cy 4 g/m2 + G-CSF Cy 200 mg/kg + rATG Open label cohort of all patients undergoing aHSCT in ASTIC trial 3 months steroid-free remission at 1 year: 38%, 95% CI 22–55. Complete endoscopic healing: 50%, 95% CI 34–66 19 ASSIST = American Scleroderma Stem Cell versus Immune Suppression Trial; ASTIC = Autologous Stem Cell Transplantation International Crohn's disease; ASTIMS = Autologous Stem Cell Transplantation International MS; ASTIS = Autologous Stem Cell Transplantation International Scleroderma; BEAM = BCNU/Etoposide/ARA-C/Melphalan; Cy = cyclophosphamide; EDSS = expanded disability status scale; EFS = event-free survival; G-CSF = granulocyte colony-stimulating factor; GRCS = global rank composite score; hATG = horse antithymocyte globulin; MIST = Multiple Sclerosis International Stem cell Transplant trial; OS = overall survival; rATG = rabbit antithymocyte globulin; SCOT = Scleroderma: Cyclophosphamide or Transplantation; TBI = total body irradiation; TRM = transplant-related mortality
