Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used ...reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications.
DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant.
We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications.
The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.
(ClinicalTrials.gov, NCT01570348)
The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in ...advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.
More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous ...CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, −22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, −1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.
Abstract Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of ...disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.
Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may ...benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.
To determine if sustained responses could be achieved after HDIT and rescue with autologous CD34-selected hematopoietic cells, we assessed the 4-yr outcome in patients (pts) with severe SSc. ...Thirty-four early (≤4 years), diffuse mod. Rodnan skin score (mRSS) ≥16 SSc pts with predefined visceral organ dysfunction (primarily lung) were included. G-CSF was used for mobilization of peripheral blood stem cells and the autologous graft was CD34-selected. HDIT included cyclophosphamide (120 mg/kg), antithymocyte globulin (90 mg/kg) and total body irradiation (800 Gy) (with lung shielding of the last 26 pts). Neutrophil and platelet counts recovered by 9 (7–13) and 11 (7–25) days, respectively. There was a significant improvement in skin (−73%, p<0.0001) and in overall function (HAQ-DI: −56%, p<0.0001) at 4 (1–8) years in evaluable pts compared to baseline (Table). Lung, heart and kidney function, in general, remained clinically stable. Importantly, biopsies confirmed a response in skin associated with resolution or a significant decrease of dermal fibrosis. Seventeen (63%) of 27 evaluable patients surviving at least 1 year after HDIT continued to have sustained responses at 4 (1–8) yrs and required no DMARD (drug-modifying antirheumatic drug) treatment. Twelve patients died (transplant-related=8 23%; SSc-related=4 12%). Two transplant-related deaths were secondary to renal crisis events that occurred within 3 months of HDIT. The other 6 transplant-related deaths were cardiac or pulmonary toxicities (n=4), EBV-PTLD (n=1) and a myelodysplastic syndrome (n=1). The estimated overall survival was 64% at 5 yrs. In conclusion, sustained responses were observed in 63% of evaluable patients after HDIT (median: 4 yrs) and marked improvement in skin and overall function was observed in high-risk SSc pts. A decrease in skin score was associated with skin remodeling.
Assess-mentsMean Baseline (BL) (n=34)Year 1–2 Difference from BL*Year 3–4 Difference from BL*Year 5–8 Difference from BL*Difference at 4 (1–8) Yrs from BL*mRSS (skin score)30.12−17.56, p<0.0001 (n=25)−21.24, p<0.0001 (n=21)−21.82, p<0.0001 (n=11)−22.08, p<0.0001 (n=25)mHAQ (disability score)1.85−1.26, p<0.0001 (n=23)−1.08, p<0.0001 (n=20)−1.50, p<0.0001 (n=11)−1.03, p<0.0001 (n=26)FVC (%)71.534.48, p=0.06 (n=27)2.09, p=0.56 (n=23)10.36, p=0.007 (n=11)2.11, p=0.50 (n=27)DLCO (%)60.09−1.37, p=0.60 (n=27)−3.70, p=0.31 (n=23)−2.27, p=0.51 (n=11)−7.07, p=0.02 (n=27)Creatinine (mg/dL)0.780.26, p=0.02 (n=26)0.25, p=0.009 (n=23)0.13, p=0.008 (n=11)0.25, p=0.003 (n=27)Ejection Fraction (%)63.24−0.21, p=0.90 (n=24)−2.84, p=0.06 (n=19)−3.85, p=0.03 (n=11)−2.37, p=0.06 (n=27)* Difference between last measurement in that time period from baseline.
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