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1 Supplementary Online Content van Laar JM, Farge D, Sont JK, et al; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. doi: /jama efigure 1. Post hoc Subgroup Analysis etable 1A. Transplant Group: Treatment Details etable 1B. Control Group: Treatment Details etable 2A. Causes of Death etable 2B. Major Organ Failure etable 3. Sensitivity Analysis: Treatment Responses in Clinical Outcome Variables, Change in the Area Under the Time Response Curve From Baseline to 2 Years Follow-up etable 4. Immunosuppressive Drugs Used Between 12 and 24 Months etable 5. Transplant Group: Treatment-Related Deaths etable 6. Viral Infections and Reactivations After Randomization eappendix. Analysis of the Time-varying Hazard Ratios This supplementary material has been provided by the authors to give readers additional information about their work.

2 efigure 1. Post hoc Subgroup Analysis Odds ratios for event Subgroup Age, y <=45 >45 Sex Female Male Disease duration,y a <=2 >2 Smoking status Never smoked Ever smoked Pre-trial cyclophosphamide Yes No Weight <=66 5 kg >66 5 kg No of Events/ No of Patients 13/84 15/72 15/92 13/64 22/128 6/28 11/72 17/84 4/34 24/122 12/78 16/78 Odds Ratio (95% CI) 0.88 ( ) 1.03 ( ) 0.72 ( ) 1.31 ( ) 0.92 ( ) 1.14 ( ) 0.28 ( ) 2.26 ( ) 0.29 ( ) 1.18 ( ) 0.81 ( ) 1.06 ( ) P Value for Heterogeneity Favors transplant Favors control Odds ratios for event (death or a persistent major organ failure) at 2 years follow-up according to subgroups. a Disease duration was defined as time in year since the development of the first sign of skin thickening until randomisation.

3 etable 1A. Transplant Group: Treatment Details Time, days Randomization to mobilization 31 (21-44) Harvest to conditioning a 41 (31-55) Randomization to transplantation 93 (78-119) Transplantation to engraftment b 13 (11-15) Data are medians (IQR). Seventy-nine patients were allocated to the transplant group, 75 of whom started the transplant treatment. a Data were available for 68 patients. b Data were available for 66 patients. No (%) of Patients a Mobilization started 75 (100) Mobilization failure 2 (2.7) Remobilization 2 (2.7) Mobilization/remobilization completed 75 (100) Leukapheresis started 74 (98.6) Leukapheresis completed 74 (98.6) Conditioning started 72 (96.0) Conditioning completed 71 (94.7) Transplant received 71 (94.7) a Seventy-five patients started the transplant treatment. Grafts Characteristics No (%) of Patients a CD34 + cells actually infused >2 X 10 6 cells/kg b 62 (92.5) CD34 + /nucleated cells infused >90% c 23 (37.7) Residual T cell content <1 X 10 5 cells/kg d 47 (88.7) a Seventy-one patients were transplanted. b Data were available for 67 patients. c Data were available for 61 patients. The percentage median (IQR) of CD34 + to nucleated cells infused was 84 5 (58-98). d Data were available for 53 patients. Engraftment: Supportive Care No (%) of Patients a Red blood cells transfusion b 58 (85.3) Platelet transfusion c 54 (79.4) Use of cytokines in the immediate post-transplant period d 21 (33.9) a Seventy-one patients were transplanted. b Data were available for 68 patients. c Data were available for 68 patients. d Data were available for 62 patients Engraftment: Complications No (%) of Patients a Infections b 50 (75.7) Bleeding c 9 (13.4) a Seventy-one patients were transplanted. b Data were available for 66 patients. c Data were available for 67 patients.

4 etable 1B. Control Group: Treatment Details Time, days Randomisation to 1 st cyclophosphamide infusion 14 (7-26) Randomisation to 12 th cyclophosphamide infusion 338 ( ) Data are medians (IQR). Seventy-seven patients were allocated to the control group. Seventy-five (97.4) patients started the treatment. Fifty-seven (76.0) patients completed the treatment.

5 etable 2A. Causes of Death Cause of Death Transplant Group (n=19) a Control Group (n=30) Disease progression 9 (47.4) 19 (63.3) Treatment- 8 (42.1) 0 Cardiovascular 0 4 (13.3) Cerebrovascular 1 (5.3) 0 Hemato-oncological malignancy 1 (5.3) 5 (16.7) Other b 0 2 (6.7) Values are No (%) of patients. a Percentages do not add up to 100% because of rounding. b One patient died because of acute renal failure, and one patient committed suicide. etable 2B. Major Organ Failure Type of Major Organ Failure a Transplant Group (n=3) Control Group (n=8) b Lung c 1 (33.3) 3 (37.5) Heart d 0 2 (25.0) Renal e 2 (66.7) 3 (37.5) Values are No (%) of patients. a Major organ failure was defined as involvement of lung, heart, or kidney. b Seven patients who developed a major organ failure died subsequently. c Lung (respiratory) failure was defined by the study protocol as resting arterial oxygen tension (PaO2) < 8 kpa (< 60 mmhg) and/or resting arterial carbon dioxide tension (PaCO2) > 6.7 kpa (> 50 mmhg) without oxygen supply. d Heart failure was defined as left ventricular ejection fraction < 30% by multiple gated acquisition scan (MUGA) or cardiac echo. e Renal failure was defined as need for renal replacement therapy.

6 etable 3. Sensitivity Analysis: Treatment Responses in Clinical Outcome Variables, Change in the Area under the Time Response Curve from Baseline to 2 Years Follow-up AUC (with imputation, n=156) a Mean P Difference (95% Value CI) d AUC (with imputation, n=131) b Mean Difference (95% P CI) d Value AUC (complete case analysis) c Mean Difference (95% CI) d P Value Weight (kg) 3.3 (-4.1 to 10.7) (-3.5 to 3.1) (-3.7 to 3.3 ) e.90 Modified Rodnan skin 7.6 (0.7 to 14.5) (7.3 to < (7.2 to score 15.0) 17.0) f <.001 Creatinine clearance, 15.1 (0.1 to (1.5 to (1.3 to ml/min g 30.1) h 20.3) h 24.1) i.03 LVEF (%) by cardiac 1.4 (-8.1 to 11.0) (-4.7 to 5.2).91 echo -2.8 (-8.0 to 2.4) j.29 VC (% predicted) -4.1 (-14.2 to (-14.7 to (-14.2 to 5.9) 2.5) 1.4) k.11 TLC (% predicted) -3.3 (-11.7 to (-11.9 to (-14.1 to 5.2) 0.9) 1.7) l.12 RV (% predicted) 2.9 (-12.2 to (-7.9 to 13.2) (-10.6 to 17.9) 21.3) m.51 DLCO (% predicted) 1.8 (-6.1 to 9.7) (-4.9 to 6.0) (-5.1 to 7.0) n.75 HAQ-DI 0.25 (-0.16 to (0.51 to (-0.27 to 0.61) 0.73) 1.05) o.24 SF-36 score Physical component Mental component EQ-5D Index-based utility score VAS score -4.7 ( to 1.11) 0.9 (-6.85 to 8.72) (-0.38 to ) -3.4 ( to 11.09) (-10.9 to - 1.4) (-5.41 to 6.07) (-0.45 to ) ( to 7.87) ( to 0.32) p (-2.18 to 18.35) q.12 < (-0.69 to ) r ( to 25.73) s.87 Abbreviations: AUC, area under the curve; LVEF, left ventricular ejection fraction; VC,(forced) vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, diffusion capacity of the lung for carbon monoxide; HAQ-DI, health assessment questionnaire disability index; SF- 36, 36-item short form general health survey; VAS, visual analogue scale. a Seventy-nine and 77 patients were randomised to the transplant and control groups respectively and were included in the analysis on the intention to treat principle. If a clinical outcome value was missing, the nearest available observation (in time, previous or next observation) was used to impute the missing value. In addition, when data were missing because of death, the poorest observed values in the whole cohort for those outcome variables or the poorest possible validated outcome values (in the case of the quality of life questionnaires) were used to impute the missing data. b Sixty-seven patients in the transplant group and 64 patients in the control group were still alive at 2 years after randomization and were included in the analysis on the intention to treat principle. If a clinical outcome value was missing, the nearest available observation (in time, previous or next observation) was used to impute the missing value. c Only patients with a complete set of data were included in the analysis (complete case analysis). Patients with missing values were excluded by listwise deletion. d Mean difference values are mean AUC for the control group minus mean AUC for the transplant group. Increase in the modified Rodnan skin score and HAQ-DI indicates worsening. Increase in all other variables indicates improvement. e Weight values were available for 41 and 34 patients in the transplant and control groups respectively. f Modified Rodnan skin score values were available for 41 and 37 patients in the transplant and control groups respectively. g Creatinine clearance was estimated by using the Cockroft-Gault formula. h Two patients in the transplant group and one patient in the control group, all with renal failure, were excluded from the analysis. i Creatinine clearance values were available for 40 and 31 patients in the transplant and control groups respectively. j LVEF values were available for 41 and 32 patients in the transplant and control groups respectively.

7 k VC values were available for 49 and 46 patients in the transplant and control groups respectively. l TLC values were available for 42 and 41 patients in the transplant and control groups respectively. m RV values were available for 40 and 37 patients in the transplant and control groups respectively. n DLCO values were available for 50 and 44 patients in the transplant and control groups respectively. o HAQ-DI values were available for 28 and 21 patients in the transplant and control groups respectively. p Values were available for 15 and 19 patients in the transplant and control groups respectively. q Values were available for 15 and 19 patients in the transplant and control groups respectively. r Values were available for 20 and 21 patients in the transplant and control groups respectively. s Values were available for 22 and 21 patients in the transplant and control groups respectively. etable 3. Clinical Outcomes: Poorest Possible Validated and Observed Values Poorest possible validated value Poorest (worst) value observed in the cohort Weight (kg) 32 Modified Rodnan skin score Creatinine clearance, ml/min g 5.1 LVEF (%) by cardiac echo 35 VC (% predicted) 35 TLC (% predicted) 43 RV (% predicted) 17 DLCO (% predicted) 20 HAQ-DI 3 3 SF-36 score Physical component Mental component EQ-5D Index-based utility score VAS score 0 0

8 etable 4. Immunosuppressive Drugs Used Between 12 and 24 Months Drug Name Transplant Group (n=67) Control Group (n=64) Glucocorticoids 12 (17.9) 12 (18.7) Mycophenolate 4 (6.0) 10 (15.6) Azathioprine 0 9 (14.1) Cyclophosphamide a 0 3 ( 4.7) Methotrexate 0 2 ( 3.1) Infliximab 0 1 ( 1.6) Docetaxel b 0 1 (1.6) Adriamycine c 0 1 (1.6) Rabbit anti-thymocyte globulin d 0 1 (1.6) Values are No (%) of patients. Sixty-seven patients in the transplant group and 64 patients in the control group were still alive at two years after randomization and were included in the analysis. Fifteen and 28 patients in the HSCT and control groups respectively received at least one immunosuppressive drug between 12 and 24 months (P=.02). Some patients received more than one immunosuppressive drug during this period. a Cyclophosphamide received after the completion (or withdrawal) of the trial treatment. One patient in the control group received cyclophosphamide as part of the rescue transplant treatment. Another patient in the control group received cyclophosphamide as part of a chemotherapy regimen for breast cancer. b Docetaxel received as part of a chemotherapy regimen for breast cancer. c Adriamycine received as part of a chemotherapy regimen for breast cancer. d Rabbit anti-thymocyte globulin received as part of rescue transplant treatment.

9 etable 5. Transplant Group: Treatment-Related Deaths Se x Age, y Disease Duratio n, y Organ Involveme nt Smokin g Status a Conditioni ng Surviva Survival l, days b after Transpla nt, days Cause of Death M 42 3 L, C ES Y progressive heart failure after HSCT, to underlying SSc and treatment M 61 <1 L ES Y hemodyna mic shock during ATG administrati on followed by ARDS, mesenteric ischemia, ATN and subsequentl y MOF F 46 2 L, PAH, R ES Y 87 5 shock and subsequentl y ARDS M 55 1 L, PAH ES Y hemodyna mic shock, EBV reactivation, PTLD, ATN, ARDS and subsequentl y MOF Autopsy not done extensive fibrosis and pleural thickening, dilated cardiomyopat hy, peripheral (but not coronary) atherosclerosi s and ATN not done malignant lymphoma in spleen and lymph nodes Relationsh ip to Treatment c probably definitely definitely definitely

10 etable 5. Transplant Group: Treatment-Related Deaths (continued) Disease Duratio n, y Organ Involveme nt Smokin g Status b Survival after Transplan t, days Se x Age, y Conditionin g Surviva l, days c Cause of Death M 61 1 L, O ES Y pulmonary hemorrhag e followed by pulmonary emboli and septicaemi a leading to ARDS; progressiv e renal failure followed by MOF M 19 1 L, O NS Y 94 0 d acute dyspnea, tachycardi a, respiratory distress, pulmonary edema, aspiration e F 45 1 L ES N 47 f respiratory failure during treatment with G- CSF leading to right heart failure M 50 1 L, O CS Y fever, alveolitis leading to liver and kidney failure, and ARDS Autopsy myocardial infarction not done NSIP and haemorrhag ic alveolitis (neutrophilgranulocytic ), ARDS, DIC and hypoxic myocardial damage not done Relationshi p to Treatment d probably possibly definitely definitely

11 etable 5. Transplant Group: Treatment-Related Deaths (continued) Abbreviations: M, male; F, female; L, lung; C, cardiac; PAH, pulmonary arterial hypertension; R, renal; O, esophagus; ES, ex-smoker; NS, never smoked; CS, current smoker; Y, yes; N, no; HSCT, hematopoietic stem cell transplant; SSc, systemic sclerosis; ATG, anti-thymocyte globulin; ARDS, Acute respiratory distress syndrome; ATN, acute tubular necrosis; MOF, multiple organ failure; EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disease; G-CSF, granulocyte-colony stimulating factor; NSIP, non-specific interstitial pneumonia; DIC, disseminated intravascular coagulation; ATG, anti-thymocyte globulin. Eight deaths in the transplant group were deemed treatment- by the independent data monitoring committee (IDMC). a All ex-smokers had stopped smoking less than 10 years before the day of randomization. b Survival is time in days from the day of randomization until the occurrence of death. c The causal relationship between death and treatment was established by the IDMC. d Patient died before being transplanted. e Pulmonary edema was first diagnosed by a chest x-ray prior to administration of ATG (four days before death). As a result, echocardiography was performed which showed a pericardial effusion of 1 cm, no pulsus paradoxus, and normal left ventricular function. Although, the exact cause of the pulmonary edema was never established the local investigators attributed the pulmonary oedema to either ATG or cardiac arrhythmia. f Patient died during mobilization. etable 6. Viral Infections and Reactivations After Randomization Transplant Group Patients, No/Total Patients, No (%) Control Group Patients, No/Total Patients, No (%) Viral infection/reactivation Cytomegalovirus (CMV) Primary infection a 2/40 (5.0) 0 Recurrent CMV infection b 7/37 (18.7) 0 Symptomatic CMV infection c 3/7 (42.9) 0 CMV disease 0 0 Epstein-Barr virus (EBV) Primary infection 0 0 Reactivation d 6/48 (12.5) 0 EBV- PTLD e 2/6 (33.3) 0 Herpes simplex virus (HSV) Primary infection f 2/29 (6.9) 1/35 (2.9) Reactivation g 9/41 (22.0) 0 CMV/ HSV co-infection 3/79 (3.8) 0 Varicella zoster virus (VZV) Primary infection 0 0 Reactivation h 3/50 (6.0) 0 Hepatitis B virus (HBV) Chronic infection i 1/1 (100.0) 0 Abbreviations: PTLD, post-transplant lymphoproliferative disease. Twenty-two and one patients in the HSCT and control groups respectively had at least one viral infection episode after randomization (P<.001). Some patients experienced more than one viral infection episode. a Primary CMV infection was defined as detection of CMV in a previously seronegative patient. One patient had a CMV/HSV co-infection and was treated with aciclovir. b Recurrent CMV infection was defined as detection of CMV in a previously seropositive patient. Two patients were treated with ganciclovir, one patient with ganciclovir and valganciclovir, and one patient with valganciclovir. c Three patients had symptomatic CMV infection: one had diarrhea with a normal colonoscopy, one patient had pulmonary symptoms, and one patient had CMV- pancytopenia and was treated with ganciclovir and, because of lack of efficacy, subsequently with foscarnet. d One patient with asymptomatic EBV reactivation was treated with rituximab. e Two patients presented with EBV lymphoma; one patient was successfully treated with rituximab, one patient died (treatment- mortality). f In the transplant group, 1 patient was treated with aciclovir and 1 patient with valaciclovir. g Six patients were treated with aciclovir, and one patient with aciclovir and valaciclovir. h Two patients were treated with aciclovir. i Patient was treated with entecavir.

12 eappendix. Analysis of the Time-Varying Hazard Ratios As a standard check of the proportional hazards assumption we assessed whether event-free survival and overall survival were time-varying by inclusion of logtime and an interaction term treatmentxlogtime in the model. The functional form of this interaction term is given in Figure A. This analysis revealed that the curves differed between the treatment groups since the hazard ratio varied with time. The time-varying hazard ratios were explored to build a more appropriate model given the data. We observed that the hazard in the control group was more or less constant, but that the hazard (slope of the survival curve) in the transplant group is initially high, due to TRM, but gradually improves and that after 2 years of FU the proportional hazard is met. The treatment-time interaction was therefore modelled allowing a more gradual change of the hazard of the transplant group crossing the hazard of the control group at 0.5 years and ending up as a constant after 2 years of FU. The functional form of this interaction term is given in Figure B. Figure A. Functional form of interaction term [treatmentxln(time)] against time trtxlntime _t Figure B. Functional form of interaction term [treatmentxmodel_time] against time trtxmodel_time _t