No Evidence Of Disease Activity After Autologous Haematopoietic Stem Cell Transplantation In Aggressive Multiple Sclerosis

Prior treatment

• Receipt of live or live-attenuated vaccines within 6 weeks of randomization.
• Treatment with natalizumab, fingolimod and dimethyl-fumarate within the last 4 weeks to allow for proper wash-out. For previously natalizumab-treated patients with a positive John Cunningham virus antibody index, a negative CSF JCV-PCR is required.
• Prior history of solid organ transplantation.
• Prior history of AHSCT.
• Prior exposure to mitoxantrone.
• Prior exposure to cyclophosphamide.
• Treatment with teriflunomide within the last 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal).
• Treatment with ocrelizumab, ofatumumab, ublituximab, alemtuzumab and cladribine within the last 3 months.

Other illness

• Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection.
• Serological positivity to HCV or HIV
• Presence or history of Child-Pugh score B and C hepatic cirrhosis.
• Presence or history of clinically significant cardiac disease (including coronary artery disease, moderate to severe valve stenosis or insufficiency, symptomatic mitral valve prolapse, presence of prosthetic mitral or aortic valve).
• Known untreated or unregulated thyroid disease.
• Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy.
• Any condition that precludes the participant from undergoing MRI with gadolinium administration.
• Presence or history of genetically inherited progressive central nervous system disorder, or central nervous system tumors.
• Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose steroids and rabbit anti-thymocyte globulin.
• In case of unexplained cytopenia, polycythemia, thrombocythemia diagnosis of myelodysplastic syndrome must be ruled out before including patient in the protocol.
• History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix.

Lab values

• Hepatic disease with the presence at two consecutive assessments 15 days apart of either of the following: total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin ≥ 3.0 times the ULN in the presence of Gilbert's syndrome, or alanine aminotransferase or aspartate aminotransferase ≥ 3.0 times the ULN.
• Left ventricular ejection fraction (LVEF) < 50%.
• eGFR < 60 mL/min/1.73m2
• If white blood cells < 1,5 x 109/L and/or lymphocytes CD4+ < 200/mm3 because of a reversible effect of documented ongoing medication, the WBC count must be ≥ 1,5 x 109/L and lymphocytes CD4+ ≥ 200/mm3 before start of study treatment.

Other

• Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria
• Patients who are unwilling to practice pharmacological prophylaxis in case of HBsAg or HBcAb positivity
• Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator).
• Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted
• Positive pregnancy test or breast-feeding.
• Patients who are unwilling to practice adequate contraception during the duration of the study. Female participants of child-bearing potential should use highly effective contraception for 12 months after AHSCT, 4 months after the last infusion of alemtuzumab and for the entire time of natalizumab, ocrelizumab, ofatumumab and ublituximab treatment. Female highly effective contraception methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable implantable); Intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomised partner; sexual abstinence. Male participants with female partners of child-bearing potential must be willing to use highly effective contraception if they are randomized to the AHSCT arm for 12 months after treatment. Male highly effective contraception methods include: vasectomy, sexual abstinence or the use of male condom with or without spermicide plus one highly effective contraception method for the female partner.
• Inability to understand the contents of the Informed Consent form.
• Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML).

• Diagnosis of relapsing remitting MS according to the 2017 Mc Donald’s criteria.
• Treatment-resistant MS, defined as the occurrence of disease activity following ≥ 6 months of treatment with an oral agent or a monoclonal antibody in the 12 months prior to the screening visit (≥ 1 relapse AND the occurrence of MRI evidence of disease activity, defined as ≥ 1 gadolinium-enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 18 months prior to the screening visit). OR aggressive-highly active MS, characterized by the presence of at least one disabling relapse in the 6 months prior to the screening visit AND the evidence at MRI of ≥ 1 gadolinium enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 6 months prior to the screening visit. For aggressive-highly active MS, the following additional inclusion criteria must be present: high brain lesion load or the presence of spinal cord lesions.
• Age ≥ 18 and ≤ 55.
• Expanded Disability Status Scale (EDSS) ≥ 2.0 and ≤ 6.0.
• Candidacy for treatment with at least one of the following diseases modifying treatments (DMT): natalizumab, alemtuzumab, ocrelizumab and/or ublituximab. Candidacy must include no prior treatment failure with the candidate DMT and no contraindication to the candidate DMT.