ProfK and his pharma mates did a trial called MAGNIFY and reported what happens after 24 months of cladribine but that is is essentially only 12 months after the last dose. So it is no different than looking 12 months after the first dose. This looks at three years so that is two years after the last dose. it shows that what happens to B cells after cladribine is essentially the same after CD20 and CD52 depletion, /Naive and transitional cells return quickly and other cells stay depleted for years. You don’t need to give cladribine every year you don’t need to give alemtuzumab every year and it also suggests that perhaps the dosing with anti-CD20 depleting antibody is overkill. There are a number of presentations on this subject this year. But it says already that what comes back is not the same as was there before treatment started and so a short term treatment may have a longer-term action.
Abstract Number: 2379/P1374 Breaking inflammatory cycles: cladribine targets pathogenic B cell subsets in Multiple Sclerosis Breaking inflammatory cycles: cladribine targets pathogenic B cell subsets in Multiple Sclerosis
Marta Pirronello et al.
Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease in which B cells play a central pathogenic role by presenting autoantigens and secreting proinflammatory cytokines. Cladribine, an oral purine analog, shows durable efficacy in MS and is hypothesized to act via selective depletion of pathogenic B-cell subsets.
Objectives/Aims: Here, we aimed to characterize cladribine’s selective effects on peripheral B-cell subsets in MS. In a longitudinal cohort of 40 relapsing MS patients, we used multicolor flow cytometry to track the frequencies of B-cell subsets (transitional, naive, classical memory, marginal zone-like (MZ-like) memory, and double-negative (DN) memory B cells) over 36 months of cladribine treatment. We also assessed B-cell cytokine production and measured serum neurofilament light chain (NfL) as a biomarker of neuroaxonal damage.
Methods: Peripheral immune cells were profiled by flow cytometry immunophenotyping. Serum neurofilament light chain (sNfL) was quantified by SIMOA (Quanterix). B-cell cytokine production was evaluated by multicolor flow cytometric intracellular staining.
Results: Cladribine induced rapid depletion of circulating B cells followed by differential reconstitution: transitional and naive B cells predominated early, whereas memory B cells (classical, MZ-like, and DN) were nearly absent. Memory reconstitution was uneven: DN memory B cells re-emerged partially by 2–3 years and classical memory B cells recovered only minimally, whereas MZ-like B cells remained profoundly depleted long-term. MZ-like B cells were uniquely proinflammatory and polyfunctional, producing granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) simultaneously, and expressing high levels of the lipid antigen-presenting molecules CD1c and CD1d. During sustained MZ-like B-cell depletion, serum NfL levels decreased and remained low, indicating reduced axonal damage.
Conclusion: Long-lasting depletion of proinflammatory MZ-like B cells may underlie cladribine’s durable efficacy in MS. Notably, cladribine was originally developed for hairy cell leukemia (HCL), a B-cell malignancy, and its efficacy in MS may reflect the shared immunophenotype between HCL cells and MZ-like or DN memory B cells.
Abstract Number: 1657/P582
Postpartum disease activity after cladribine, ocrelizumab/rituximab, or natalizumab therapy in women with highly active MS Postpartum disease activity after cladribine, ocrelizumab/rituximab, or natalizumab therapy in women with highly active MS
Kaya Bayer et al.
Introduction: Women with MS face an increased relapse risk, especially within three months postpartum. Whether this can be mitigated remains unclear, particularly in highly active MS. Studies suggest that starting/resuming fingolimod or natalizumab in the first month postpartum may be not sufficient. The potential of other prepartum treatment strategies to reduce postpartum relapse risk is not fully elucidated.
Objectives/Aims: Objectives/Aims: To compare the 6-month postpartum relapse risk (number, annualized relapse rate, time to first relapse) in women with highly active MS following different prepartum treatments: (1) cladribine anytime before pregnancy, (2) ocrelizumab/rituximab within one year before pregnancy….
Methods: Data from the German MS and Pregnancy Registry (DMSKW) were analysed. Cohorts were stratified by treatment discontinuation: (1) cladribine (a) > 365 days before pregnancy, (b) > 180 to ≤ 365 days before pregnancy, (c) ≤ 180 days before pregnancy; (2) ocrelizumab/rituximab (a) > 180 to ≤ 365 days before pregnancy, (b) > 90 to ≤ 180 days before pregnancy, (c) > 0 to ≤ 90 days before pregnancy, (d) during pregnancy;
Results: Among 637 women with at least 6 months postpartum follow-up (cladribine: 67, ocrelizumab/rituximab: 282…..), corticosteroid-treated relapses during pregnancy were rare (1.88%)…Within six months postpartum 47/63 (7.38%, median 0 [0-2]) women experienced a relapse (cladribine: 2.99%; ocrelizumab/rituximab: 6.74%). Women receiving cladribine ≤ 180 days before pregnancy or ocrelizumab/rituximab during pregnancy remained relapse-free.
Conclusion: Postpartum relapse risk was low across all three strategy-groups, with numerically lowest rates in those treated prepartum with cladribine…These findings should be considered during pregnancy planning for women with highly active MS.
Source: multiple-sclerosis-research.org