The thing I learnt from the CCSVI saga was to light the touch paper and retreat, so make the post and say nothing. CCSVI has had its day and no we are frequented by the HSCT Brigade. This post will bring them out like abit of catnip.
You can all read and have your opinion. I think targeting NEDA-3 is a more difficult ask, as progressive disability is a composite of two pieces of biology only one of these is going to respond well. However HSCT is not one thing and the protocols are not the same and so this has to be born in mind. Secondard autoimmunity rears its head and I think this is because of common biology with alemtuzumab. In addition, in this study amenorrhea is the problem. This is where you say amen to your ovaries, as you stop menstruation. This is because of the agents used in the immune ablation processes and this is obviously an issue for people considering this procedure.
Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway.Kvistad SAS, Lehmann AK, Trovik LH, Kristoffersen EK, Bø L, Myhr KM, Torkildsen Ø. Mult Scler. 2019 Dec 13:1352458519893926. doi: 10.1177/1352458519893926. [Epub ahead of print]
BACKGROUND: Haematopoietic stem cell treatment (HSCT) is a promising treatment option for multiple sclerosis (MS), but detailed safety and efficacy measures are still scarce.
METHODS: Retrospective single-center observational study of all MS patients that underwent HSCT in Norway during January 2015 to January 2018. The primary outcome was no evidence of disease activity (NEDA-3) status.
RESULTS: A total of 30 patients with a median follow-up time of 26 months (range: 11-48) were evaluated. In total, 25 (83%) achieved NEDA-3 status, and none received disease-modifying treatment after HSCT. For 13 (43%) of the patients, there were sustained improvement in Expanded Disability Status Scale (EDSS) score, and 10 (33%) were working full time after the treatment, compared to only 1 (3%) before treatment. There were no serious treatment-related complications and was no mortality. Five patients (17%) were diagnosed with an autoimmune thyroid disease after the procedure, and 10 (43%) of the women had amenorrhea lasting >12 months and symptoms of ovarian failure.
CONCLUSION: HSCT in MS is an effective and relatively safe treatment option, with few serious complications and no mortality in Norway, so far. However, long-term adverse event with amenorrhea is a common problem.
Study population and design: This was a single-center retrospective observational study of all Norwegian patients (n = 30) that received HSCT from January 2015 to January 2018. All patients were evaluated and treated at Haukeland University Hospital in Bergen, Norway. The selection criteria for HSCT treatment were as follows: (1) RRMS according to the McDonald criteria, (2) at least two clinical relapses the last year during immunomodulatory treatment, (3) at least one Gadolinium-lesion and/or new T2-lesions on MRI at two following MRI examinations the last year, and (4) a baseline Kurtzke Expanded Disability Status Scale (EDSS) score ⩽6.0. Relative criteria were disease duration less than 6 years and an age ⩽45 years. Patients with comorbidities that precluded HSCT were excluded. There were no restrictions regarding previous immunomodulatory treatment before HSCT treatment. The study was approved by the Regional Ethical Committee (REK 2018/377) and based on written consent. Medical records of all patients were assembled from the time they were first assigned to HSCT treatment until the most recent clinical control, and evaluated.
Procedure: All patients underwent screening prior to therapy, including chest X-ray, spirometry, echocardiography, and dental visit to exclude any medical contradictions for stem cell treatment. All patients were screened for concurrent or chronic infections, hematological-, and thyroid function. All men and women below 35 years were offered fertility-preserving treatment. A total of five women had cryopreservation of ovarian tissue, one had cryopreservation of embryos, and one had mature oocyte cryopreservation. Five of the men had sperm cryopreservation.The treatment protocol was uniform for all patients. Peripheral hematopoietic stem cells were mobilized by cyclophosphamide (2 g/m2) in 1 day followed by daily granulocyte colony-stimulating factor (G-CSF), 5 μg/kg × 1 per day for 5 days. A minimal amount of 3 × 106 CD34+ cells/kg per planned procedure was requested. The conditioning regimen was started 4–5 weeks later consisting of high-dose cyclophosphamide 50 mg/kg i.v. for 4 days, defined as low-intensity chemotherapy regimen according to the EBMT classification. Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5-mg/kg body was added i.v. on the first day, 1.0-mg ATG-rabbit/kg was added i.v. on the second day, and 1.5-mg ATG-rabbit/kg was given i.v. on the next 3 days over 10 hours in 500 mL of normal saline (NaCl: 0.9%). The stem cells, median 4.05 × 106 (3.4 – 5.1) CD34+ cells/kg, were reinfused after 18–54 days without any graft manipulation. All patients received prophylactic regimen with ciproxin, valaciclovir, and fluconazole. The study protocol was adopted from Burman et al.
The mean age was 30.8 years, and 76% were women. All patients had a history of a highly active disease with at least two clinical attacks the past year, and 73% of the patients had new Gd-enhancing MRI lesions the year before inclusion. The mean disease duration before HSCT was 5.2 years. All patients had a history of sub-optimal treatment response on other medications due to side effects and clinical relapses. The median number of medications prior to HSCT was two, but 6 (20%) had failed more than four different therapies. Previous treatments were fingolimod (n = 21), interferon-β (n = 20), natalizumab (n = 12), dimethyl fumarate (n = 10), glatiramer acetate (n = 6), teriflunomide (n = 4), alemtuzumab (n = 3), and rituximab (n = 2). At the time of inclusion, the patients were using fingolimod (n = 14), natalizumab (n = 5), dimethyl fumarate (n = 3), alemtuzumab (n = 3), rituximab (n = 2), glatiramer acetate (n = 1), teriflunomide (n = 1), and interferon-β (n = 1). The mean follow-up time was 26.5 months, and median follow-up time was 26 months (range: 11–48).
Treatment response: Clinical relapses: Three patients (10%) had clinical relapses post-HSCT. One had symptoms of an optic neuritis 12 months after HSCT confirmed by visual evoked potential (VEP), but with no findings on MRI. The second patient had two episodes of optic neuritis, the first being 12-month post-HSCT and there was also a new lesion on MRI at the 1-year follow-up. A third patient had a clinical relapse, but no MRI finding 29-month post-HSCT. All patients were treated with high-dose corticosteroids during the relapses. None of these patients have started with immunomodulatory treatment after the relapses. One of the patients was planned for rituximab treatment, but the infusion was stopped after a few minutes due to side effects. This patient has been followed for 16 months without any new disease activity, and it has been decided to await further immunomodulatory therapy.
EDSS. A total of 13 (43%) patients had sustained improvement in EDSS score compared to the last EDSS score set before treatment, with a median decrease in 1.0 point and a maximal decrease in 5.0 points. In 15 (50%) of the patients, there was a stabilization of EDSS score post-HSCT. Two patients (7%) had a progression of 1.0 point of the EDSS score, in which one of them also had a clinical relapse post-HSCT.
MRI. Three patients (10%) had new T2-lesions on MRI post-HSCT of which two (7%) of the patients also had clinical relapses. The third patients had only one new T2-lesion on MRI and did not have any clinical symptoms.
NEDA-3. Overall, 25 (83%) of the patients achieved NEDA-3 status. The mean follow-up time was 26.5 months. At 24-month follow-up, 13 out of 17 patients (76%) had achieved NEDA-3 status
Follow-up: Patients underwent clinical follow-up at Haukeland University Hospital approximately 3-month, 6-month, and 1-year post-HSCT and thereafter mostly annually in addition to controls at their local neurologist.
There was no MRI re-baselining in this study, and the time between MRI and HSCT varied among patients. For patients with the last MRI >4 months prior to HSCT, new lesions on 6 months control were considered to have occurred before treatment and not registered as new MRI activity.
HSCT treatment and early adverse events (<100-day post-HSCT): Most patients experienced mild side effects with back pain and headache during mobilization by peripheral stem cell apheresis with cyclophosphamide and G-CSF, but one patient was admitted to hospital due to strong back pain, and six patients (20%) were treated with antibiotics due to neutropenic fever or infections
The patients were good mobilizers, and sufficient amount of stem cells for potentially two HSCT treatments were harvested by one apheresis for all but two, who therefore were harvested 2 days. A total of 23 (77%) of the patients were treated with antibiotics during the conditioning regimen and isolation period due to different infections or neutropenic fever. Nine patients (30%) experienced neutropenic fever with negative blood cultures, and six patients (20%) had bacteremia One patient suffered from influenza. Altogether, 23 patients (77%) received platelet transfusions and 14 patients (47%) received red blood cell transfusions.Some common side effects associated with HSCT were reported. Half of the patients had diarrhea, and five patients had mucositis (17%). Two patients had oropharyngeal candidiasis (7%). The mean isolation period lasted 10.4 days, and no patient was isolated longer than 12 days. No patient required treatment in the intensive care unit, and there was no treatment-related mortality. All patients were discharged from the hospital within 21 days.
HSCT treatment and late adverse events (>100-day post-HSCT): In the period after HSCT, five patients (17%) were diagnosed with autoimmune thyroid diseases, three with Mb. Graves, and two with hypothyreosis.
There were 23 women in the study, and 12 (52%) experienced amenorrhea and heat flashes in the period after HSCT. Two of them got normal menstrual cycles after about 1 year. For the remaining 10 (43%), the symptoms of ovarian failure persisted. The mean age of these women were 35 years, with the oldest being 44 years and the youngest being 25 years old.