Abstract 3075
Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course ...evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS.
A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27–53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52–232) weeks. Patients were infused with a median of 4.58(2.95–9.73) × 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9–15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/−0.637), 3.78(+/−0.951) and 4.13(+/−0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI :73.9, 99.4)% and 76.7(90% CI :41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.Table 1:Brain MRI: Changes in first year after transplant.Baseline n=24Month 2 n=24Month 6 n=24Month 12 n=23Total Gd+ lesions n (%)014 (58%)19 (90%)22 (96%)22 (100%)14 (17%)0 (0%)1 (4%)0 (0%)2+6 (25%)2 (10%)0 (0%)0 (0%)T2 lesion volume change (cc)*n202320Median(min, max)-0.13 (-6.51,1.26)-0.60 (-6.46,1.73)-0.58 (-5.14,0.97)1T1 lesion volume change (cc)*n202320Median (min, max)-0.002 (-1.10, 0.87)0.02 (-0.87, 0.99)0.11 (-0.40,1.74)2Brain volume change (%)*n202419Mean (SD)-0.91 (0.73)3-1.19 (0.86)-1.28 (1.01)Wilcoxon signed rank test: 1) p=0.0014; 2) p=0.0186 3) t-test: p<0.0001Conducted by the Immune Tolerance Network, sponsored by NIAID, National Institutes of Health, Bethesda, MD.*Change from baseline
High-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses.
Stuve:Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Consultancy, Honoraria; Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Honoraria; Teva Neruoscience: Research Funding. Arnold:NeuroRx Research: Equity Ownership. Wundes:Biogen Idec: Consultancy, Research Funding, Speakers Bureau; Teva pharmaceutics: Consultancy.
Abstract ▪962▪This icon denotes a clinically relevant abstract
Most patients with relapsing-remitting multiple sclerosis (RRMS) do not achieve a sustained remission after disease-modifying therapy. A ...phase II clinical trial of high-dose immunochemotherapy (HDIT; BCNU, etoposide, ara-C, melphalan and antithymocyte globulin) and autologous hematopoietic cell transplantation (HCT) was conducted in patients with highly active RRMS who had failed conventional therapy to assess if a high rate of sustained remission could be induced. Eligibility required an EDSS of 3.0 (moderate disability, fully ambulatory) to 5.5(severe disability, ambulatory only 100 meters without aids) and >2 relapses on treatment in previous 18 months. Treatment-failure was defined as a composite endpoint including 1) mortality 2) relapse 3) new MRI lesions or 4) disability increase >0.5 EDSS points. Adverse events (AE) were recorded according to NCI-CTCAE v3.0.
25 patients at a median age of 38(27-53) years were treated with G-CSF to mobilize the autograft; prednisone was given at the same time to prevent MS flares. The autograft was CD34-selected (Baxter, Isolex). One patient withdrew after mobilization secondary to HIT/pulmonary embolus. 24 patients had HDIT/HCT according to protocol. Median follow-up was 131 (52, 282) weeks. After initially stabilizing, one patient died from progressive loss of neurological function at 32 months. No patient had delayed recovery of blood counts. In the 1st year after HDIT, there were 42 grade 3 and 6 grade 4 non-hematopoietic AE. Grade 4 AE included: one suicide attempt (with 3 grade 4 AE); hyperuricemia; hypokalemia; and elevated ALT. In the 2ndyear, there were 13 grade 3 and 1 grade 4 non-hematopoietic AE. The 1-year and 2-year probabilities of event-free survival (i.e. without treatment-failure) were 95.8% (90% CI: 80.2%-99.2%) and 82.8% (90% CI: 65.0%-92.0%), respectively. Progression-free and relapse-free survival at 1 year were 100% (90% CI: 100%-100%) and 95.8% (90% CI: 80.2%-99.2%) and at 2 years were 91.7% (90% CI: 75.7%-97.3%) and 91.7% (90% CI: 75.7%-97.3%), respectively. The probability of freedom from disease activity detected by brain MRI was 95.8% (90% CI: 80.2%-99.2%) at both year 1 and 2. In comparison, a randomized clinical trial of placebo vs natalizumab (Havrdova E et al, Lancet Neurology, 2009) showed that 7% and 37% of RRMS patients were free of disease activity (i.e. progression, relapse and MRI) at 2 years, respectively.
T2-weighted MRI scans measure disease burden from MS. T2 lesion volume was significantly reduced by 6 months and was sustained at 2 years (Table 1). T1 lesion volume was increased at 1 year. There was a significant loss of brain volume at 6 months but stabilized after this time point.
Flow cytometry of peripheral blood was done at baseline and at 1, 2, 6 and 12 months. There was near complete depletion of naïve CD4 and CD8 T cells (CD45RA+) at 1 month. Memory CD4 and CD8 T cells (CD45RO+) were not completely eliminated from the blood after in vivo depletion from HDIT. Within 2 months of transplant, there was rapid expansion of memory CD8 T cells. The numbers of CD4 naïve and memory T cells were not recovered at 1 year. CD4 and CD8 recent thymic emigrants (CD45RA+, CD31+) were increased at 1 year compared to the nadir at 1 month but did not completely recover. Recovery of naïve and memory B cells was complete between months 6 and 12.
HDIT/HCT for highly active RRMS resulted in profound immunosuppression and induced a high rate of sustained remissions at 2 years. The small increase in T1-weighted lesion volume in the absence of persistent brain inflammation may have resulted from damage due to previous brain injury. No further loss in brain volume was observed after 6 months. Follow-up is planned through 5 years.
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No relevant conflicts of interest to declare.
Abstract Background The treatment of worsening Multiple Sclerosis (MS) remains challenging. Mitoxantrone, an anthracyclines, is approved as a treatment for worsening MS. However, systematic analyses ...of its tolerability and effectiveness outside of controlled trials are few. Certain advantages, including easy application and simple monitoring, need to be balanced against its toxicity. Objective To study efficacy, tolerability and feasibility of mitoxantrone treatment in a regular clinical setting. Methods Retrospective analysis of data from 96 MS patients with worsening MS before, during, and after mitoxantrone. Specifically, we addressed adherence and reasons for deviations from the intended treatment schedule regarding tolerability and safety, and consequences of deviations on clinical efficacy. Results Schedule deviations were frequent. Only a third of patients received the intended cumulative dose. Hematological toxicity was generally mild and transient. In 7 patients, treatment was withheld because of impact on ventricular ejection fraction, in the absence of clinical symptoms of cardiac failure. No malignancies were observed. With respect to clinical benefit, most patients remained stable and the relapse rate decreased with mitoxantrone initiation in both relapsing and secondary MS patients ( p < 0.0001). A possible modest non-significant dose-effect on annualized relapse rates was observed. Conclusion Mitoxantrone may be considered for treatment of refractory MS. Poor tolerability impacted adherence but dose-limiting safety events were rare. Mitoxantrone needs to be carefully assessed in light of recent data on risk of cardiotoxicity and leukemia.
Blockade of CD49d-mediated lymphocyte trafficking has been used therapeutically for certain autoimmune diseases. In addition to effects on mature lymphocytes, in mice and monkeys CD49d blockade also ...mobilizes immature hematopoietic cells from bone marrow (BM), capable of complete long-term engraftment despite a partial BM seeding defect. The aim of these studies was to ascertain effects on the biology of HSPC mobilization of single or chronic CD49d blockade in Multiple Sclerosis (MS) patients receiving disease-modifying treatment with the anti-functional anti-CD49d antibody, Natalizumab. These studies represent the first observations on HSPC mobilization by anti-CD49d antibodies in humans and on chronic exposure to a mobilizing agent. Circulating CD34+ cells (1.8±0.4/μL) and CFU-C (638±128/mL) were normal in MS patients (n=9) prior to the first Natalizumab infusion (normal controls: 1.3±0.1/μL CD34+ cells, 608±129/mL CFU-C). In chronically treated patients (i.e patients who had received ≥5 prior doses of Natalizumab) HSPC numbers were significantly elevated 30 days after the last infusion (CD34+ cells 9.0±1.2/μL, CFU-C 3243±332/mL, n=10, p<0.005). The blood of chronically Natalizumab-treated subjects also contained SCID-repopulating cells (n=3). After the first Natalizumab infusion, peripheral blood CD34+ cells and CFU-C were significantly increased over pre-treatment values (CD34+ cells 1.6±0.2/μL vs. 8.0±2.1/μL, CFU-C 414±161/mL vs. 2560±726/mL, n=7, p<0.005), indicating that a single dose of Natalizumab was sufficient to elicit similar mobilization levels as in chronic recipients. Renewed Natalizumab infusion in “chronic” Natalizumab-recipients did not result in additional mobilization, compared to values from just before that infusion (CD34+ cells 7.9±1.7/μL vs. 7.9±0.9/μL, CFU-C 3133±335/mL vs. 3525±305/mL, n=4). These data indicate that in the absence of CD49d-mediated BM retention a new equilibrium is established between HSPC in BM and in circulation. In long-term Natalizumab recipients a total of ca. 50x10E6 CD34+ cells (8 CD34+ cells/μL * 6L of blood) are in circulation at any given time. Considering the documented short half-life of circulating HSPC, (100 min in the mouse) this implies that approximately 700x10E6 CD34+ cells/day are trafficking in the average Natalizumab recipient. Whether the elevated numbers of circulating HSPC play a clinically relevant role for Natalizumab-treated MS patients is currently unclear. Given reports of MS flares under G-CSF, we propose that “steady-state” apheresis without additional mobilizing agents may be a safe and effective alternative to G-CSF if MS patients on Natalizumab are considered for autologous HSPC transplantation, an emerging treatment for refractory MS. The usefulness of Natalizumab as a mobilizing agent is likely restricted to the autologous setting, given the risk of immunization against Natalizumab and its prolonged effects. Instead, short-acting small-molecule inhibitors of CD49d could be developed as a mobilizing strategy for patient groups intolerant or unresponsive to G-CSF, alone or in combination with other novel mobilizing agents.
Ocrelizumab is an intravenous disease modifying therapy for primary progressive and relapsing-remitting multiple sclerosis (RRMS). In the clinical trials (OPERA 1, OPERA 2, ORATORIO) and post ...marketing studies, gastrointestinal (GI) adverse events prompting discontinuation occurred in 0.2% of patients. There have been two cases of colitis related to ocrelizumab and several cases of rituximab related GI adverse events, including colitis, diverticulitis, and colon perforation.
To report the first case of severe diverticulitis 48 hours after ocrelizumab infusion that progressed to perforation requiring surgical intervention.
Case report
35-year-old man with a past medical history of obesity but no GI history was diagnosed with RRMS eleven months earlier by 2017 McDonald criteria. His initial DMT, dimethyl fumarate, was stopped for severe nausea. Due to an aggressive disease course and imaging instability, ocrelizumab was started. Two days after his third infusion, he presented with bilateral lower quadrant abdominal pain and a fever of 101.4 F. CT scans showed a perforated sigmoid diverticulitis with loculated extraluminal air in the sigmoid mesocolon. Conservative medical management was unsuccessful. The patient underwent laparoscopic resection of a portion of the sigmoid colon.
GI adverse events requiring ocrelizumab discontinuation are extremely rare, but clinicians should remain vigilant of this potential complication of anti-CD20 therapy.
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