Evidence Table Clinical Area:

Transcription

1 Evidence Table Clinical Area: Stem cell transplant for autoimmune disease. Reference: Gratwohl A, BocelliTyndall C, Fassa A, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplantation 2005;35: Study Type: Case Series. Study Aim: To report on the safety and efficacy of autologous stem cell transplantation in arresting the progression of severe autoimmune diseases. Outcomes Primary: Patient survival, transplant related mortality, treatment response, and disease progression. Design: Number of subjects: N=473. Description of study population: These were patients who received autologous hematopoietic stem cell transplantation (HSCT) for the treatment of an autoimmune disease (AD), in 0 institutions from 2 countries in Europe and Australia through October Their ages ranged from 2 to 69 years, with a median of 34.4 years. 64% were females. 60% had rheumatologial disorders (mainly systemic sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, and systemic lupus), 33% had neurological disorders mainly multiple sclerosis, 6% had hematological immunocytopenias, and % had inflammatory bowel disease. Method of subject selection (inclusion/exclusion criteria): Data were obtained from the European Bone Marrow Transplant (EBMT) database. This included patients with a prognosis severe enough to justify the risk of transplantation, but not with a condition that is beyond salvage. Patients with a second transplant were included and those were mobilization data only were excluded. Consecutive patients? All consecutive transplants were recorded in the registries. Exposure/Intervention: All patients received an autologous transplant. The source of the stem cells was peripheral blood in 89% of cases, and bone marrow in %. Mobilization was performed by a growth factor combined with cyclophosphamide or other chemotherapy in 69% of cases, or by a growth factor (granulocyte colonystimulating factor {GCSF} or granulocytemacrophage colony stimulating factor {GMCSF}) in 2% of cases. In the remaining 0% mobilization was done by other factors or data were missing. The conditioning regimens varied according to the disease, and were of high, intermediate or low intensity, and mainly cyclophosphamide based. The transplant techniques also varied between disease categories. Source of outcome data (e.g. patient selfreport, doctor report, lab results): Data were obtained from registries. Patients underwent clinical evaluation to assess response to therapy, and activity level. Length of followup: 8 months with a median of 20 months. Completeness of followup: Data were obtained from records. patients with incomplete followup were not included in the analysis.

2 2 Validity: Is the study type appropriate for the question(s) being asked? No, a randomized controlled study would be more appropriate. Were patients similar with respect to baseline characteristics? No, it was a heterogeneous group of patients. Were the intervention and other aspects of patient care similar for all patients (or for all patients in a defined subgroup)? Basically all patients received either a marrow or peripheral blood autologous transplant. The mobilization and conditioning regimens, as well as the technique of the transplants varied between patients, diseases, and centers. Was the process of observation likely to affect the outcome? Probably. Did an objective observer assess outcomes and were outcome measurements consistent? Not discussed. Was followup duration appropriate? Probably not. Conclusions regarding validity of methods: This study was an analysis of data obtained from registries and pooled data from 0 centers. There were several differences in eligibility criteria, patient ages, disease categories, regimens received, protocol and transplant techniques. Moreover, there were no controls or comparison groups who received an alternative or no therapy. Results: At the time of analysis (median 20 months of followup), 420 (89%) of the patients were alive, and 53 (%) had died. Mortality (N=53) No % % Of all mortalities Of total patients Transplant related* progression * 50% due to infections, 2.5% due to hemorrhage, and the rest due to other cause as cardiac toxicity, venoocclusive disease, suicide, liver failure or others.

3 3 Survival and mortality in patients after HSCT for autoimmune diseases MS SSc RA JIA SLE ITP Age < >40 Conditioning intensity Stem cell source BM PB Total No of patients Probability of survival % Probability of TRM %* Probability of dying from disease %* MS=multiple sclerosis, SSc systemic sclerosis, RA=rheumatoid arthritis, JIA= juvenile idiopathic arthritis, SLE=systemic lupus erythematosus, ITP= immune thrombocytopenia, BM=bone marrow, PB= peripheral blood. * treatment related mortality at 3 years after HSCT There were no significant differences between men and women, or manipulation. Response** to transplant: 299/370* (8%) showed response. This was sustained in 7% of the responders 7/370 (9%) failed to respond. * Evaluable patients ** Differed between disease categories (p<0.000) progression at 3 years Overall % intensity conditioning 3 + 7% intensity conditioning %

4 4 Factors associated* with outcome and their relative risk Outcomes Survival Transplant related mortality Conditioning intensity Year of transplant <2000 >2000 Response Priming Growth factor alone Growth factor + Cy Bone marrow Age <20 years 2040 years >40 years Progression Conditioning intensity RR (95% CI).89 ( ) 4.77 (.0222.) 0.56 ( ) 3.28 ( ) 0.92 ( ) 0.45 (0.7.20) 0.29 (0.0.82) 2.34 (.0745.).8 ( ) * According to a multivariate analysis ** cyclophosphamide <0.005 <0. <0.000 <0.000 Intensity of conditioning was directly related to treatment related mortality and inversely related to disease progression Authors Conclusions: The authors concluded that analysis of data from the European Bone Marrow Transplant registry suggest that highdose chemotherapy and autologous HSCT can alter disease progression in a large proportion of patients with severe autoimmune diseases. Reviewer s Conclusions: This analysis was based on data pooled from 0 transplant centers in 2 countries. This has the advantage of studying the efficacy and safety of the procedure in a larger series of patients, but has several limitations including the variations between these centers in the eligibility criteria, patient characteristics, autoimmune disorders and stage of the disease, protocol and techniques of the transplant, and experience in performing the procedure as

5 5 well as others. Moreover the analysis did not include a control or comparison group that received an alternative or no treatment. The results of the analysis show that the overall treatment related mortality was 7% and significantly varied between the different autoimmune diseases (ADs). The extremes being 20% for immune thrombocytopenia and 2% for rheumatoid arthritis. There were also significant variations between the ADs in the disease related mortality and probability of survival after a HSCT. The results also show that a more aggressive conditioning regimen is statistically associated with slowing down of the disease progression, but was is also associated with a significantly higher treatment related mortality. The results of this analysis should be interpreted cautiously due to the study design, potential selection and observation biases, and lack of control or comparison groups.