None listed
Conditions
Brief summary
Patients with severe systemic sclerosis with cardiac complications requiring a stem cell transplant after their disorder progressing after standard treatment not deemed suitable for standard dose cyclophosphamide can be enrolled into an available cohort group to receive one of 3 different LOW doses of cyclophosphamide This study aims to reduce Treatment related side effects by reducing the intensity of conditioning, in particular cyclophosphamide dosage, in order to offer the potential benefits of stem cell transplant to patients normally excluded from HSCT whilst potentially maintaining efficacy. It is hypothesised that a lower dose cyclophosphamide stem cell transplant regimen of 12.5-35mg/kg/day in 3 cohorts will be tolerated with less toxicity than an historical cohort of 50mg/kg/day in patients with severe systemic sclerosis
Interventions
Eligible Patients with severe systemic sclerosis not deemed suitable for standard dose cyclophosphamide will be enrolled in the study . Dose finding study whereby 5 patients will be enrolled in cohort 1. Next cohort will be enrolled after 12 months re safety and efficacy. cohort 3 will start 12 moths after cohort 2 reviewed re safety and efficacy reviewed .
Cohort 1: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for th
Eligible Patients with severe systemic sclerosis not deemed suitable for standard dose cyclophosphamide will be enrolled in the study . Dose finding study whereby 5 patients will be enrolled in cohort 1. Next cohort will be enrolled after 12 months re safety and efficacy. cohort 3 will start 12 moths after cohort 2 reviewed re safety and efficacy reviewed . Cohort 1: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on hospital admission. Cyclophosphamide 12.5mg/kg is administered intravenously daily for 2 doses on Day -3, and Day-2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously daily for 4 doses from Day -6 to day -3. A test dose of ATG 0.001mg given intradermal will be administered several hours before first dose on Day -6. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the days of ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months. Cohort 2: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on hospital admission. Cyclophosphamide 25mg/kg is administered intravenously daily for 2 doses on Day -3 and Day -2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously once daily for 4 doses from Day -6 to Day -3. A test dose of ATG 0.001mg will be given intradermal on Day -6 several hours before the first dose.. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the same days as ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months. Cohort 3: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on Hospital admission. Cyclophosphamide 35mg/kg is administered intravenously daily for 2 doses on Day -3and Day-2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously daily for 4 doses from Day -6 to Day-3. A test dose of ATG 0.001mg will be given intradermal several hours pro to first dose. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the days of ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months. Patient's regardless of the cohort have a blood test to evaluate any below normal blood results and physical assessment /reviewed by their treating physician weekly for 1 month, then fortnightly then monthly. Assessment using Rodnan skin score. Patient will also complete questionnaires ( VAS, HAQ and SF-36) at the following timepoints; pre HSCT, 3 months, 6 months, 12 months then yearly
Sponsors
St Vincent's Hospital Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
16 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Able to provide informed written consent Severe SSc either de novo or unresponsive to previous therapies requiring HSCT (in the opinion of the referring physician) Age 16-65 ECOG 0,1,2,3. Negative serology for HIV. If hepatitis B positive– willing to take entacavir for 1 year If hepatitis C positive – must be cleared by anti-viral therapy prior to HSCT Negative pregnancy test. Absence of severe chronic infection. Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age. Ineligible for HDCy using 200mg/kg due to pre-existing cardio-respiratory disease due to Age greater than 60yrs Cardiac LV Ejection Fraction less than 50% Total Lung Capacity less than 50% Resting mean pulmonary artery pressure (mPAP) greater than 25mmHg mPAP greater than 30mm/hg after 500mls bolus DLCO/VA less than 50%. Abnormal Cardiac MRI Cardiac event (eg: arrhythmia, episode of chest pain or dysopnoea) whilst harvesting haemopoietic stem cells using the conventional protocol of HDCy 2g/m2 (these patient would be withdrawn from the standard protocol and consented to the low dose cohorts). Known stable coronary artery disease ( equal to 30% stenosis of a major coronary artery or previous therapy for coronary disease).
Exclusion criteria
Karnofsky 40% or less Cardiac Ejection fraction less than 40% mPAP greater than 50mmHg DLCO/VA less than 30% Unstable coronary artery disease Prior history of malignancy or other current medical condition which in the opinion of the investigators would restrict the ability of the patient to tolerate the procedure. Unable to provide informed consent and/or the diagnosis of mental and cognitive deficits which can interfere with the capability of providing the informed consent. Major bone marrow failure or condition which results in significant neutropenia (less than 1000/ul) or thrombocytopenia (less than 100,000/ul). Severe renal (serum creatinine greater than 200hmol/l) or liver disease (Bilirubin greater than 50umol/l or known cirrhosis) Uncontrolled infection.
Outcome results
None listed