Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used in the treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183 multiple sclerosis (MS) patients, recorded in the database of the European Blood and Marrow Transplantation Group (EBMT). Transplant data were available from 178 patients who received an autologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to the period 1995-2000, with no further TRM reported since then. Busulphan-based regimens were significantly associated with TRM. Clinical status at the time of transplant and transplant techniques showed some correlations with toxicity. No toxic deaths were reported among the 53 patients treated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyte globulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months, and was not associated with the intensity of the conditioning regimen. In this large series, HSCT was shown as a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS; the safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.

CTI BioPharma Corp.

Extended matching for selected antigens reduced the alloimmunization risk by 64% in surgical patients. Extended matching seems successful only if the patient did not receive accompanying nonmatched PLT transfusions.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. Our aims were to investigate the effects of COVID-19 vaccination in ITP patients on platelet count, bleeding complications and ITP exacerbation (any of: ≥50% decline in platelet count; or nadir platelet count <30x109/L with >20% decrease from baseline; or use of rescue therapy). Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after first and second vaccination. Linear mixed-effects modelling was applied to analyze platelet counts over time. We included 218 ITP patients (50.9% female, mean age 55 years and median platelet count of 106x109/L) and 200 healthy controls (60.0% female, mean age 58 years and median platelet count of 256x109/L). Platelet counts decreased by 6.3% after vaccination. We observed no difference in decrease between the groups. Thirty ITP patients (13.8%, 95%CI 9.5%-19.1%) had an exacerbation and 5 (2.2%, 95%CI 0.7%-5.3%) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count <50x109/L (OR 5.3, 95%CI 2.1-13.7), ITP treatment at time of vaccination (OR 3.4, 95%CI 1.5-8.0) and age (OR 0.96 per year, 95%CI 0.94-0.99). Our study highlights safety of COVID-19 vaccination in ITP patients and importance of close monitoring platelet counts in a subgroup of ITP patients. ITP patients with exacerbation responded well on therapy.

BACKGROUND AND PURPOSE:In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS.

The overall short-term treatment efficacy of rituximab (R) in immune thrombocytopenia (ITP) is reported to be approximately 58%.1,2 With four once-weekly 375 mg/m 2 doses, responses of 31% after two years, 2 and 21% after five years 2 can be expected with a median clinical improvement time of 10.5 1 months, and up to 49 months in other studies. 3 Since lower doses have comparable efficacy, 4 R remains an attractive second-line therapy especially in patients where splenectomy is contraindicated or should be delayed. 1,3,[5][6][7][8] However, there are no known response-modifying factors that can provide an optimal basis for choosing R and its dosing. Moreover, while numbers of ITP patients are limited, knowledge on these issues is mainly derived from (clustered) often small-sized and non-randomized studies. [1][2][3]5,9 Therefore, in order to, firstly, delineate the efficacy and safety of two alternative dosing strategies, and secondly, to study the R-response-modifying factors (RMF), the Dutch Hemato-Oncology Cooperative Group (HOVON) randomized 156 immune thrombocytopenia (ITP) patients between four once-weekly standard 375 mg/m 2 doses (arm A), a 2-weekly 375 mg/m 2 in early responding patients (arm B), and a 2-weekly 750 mg/m 2 regimen (arm C). In more detail, in arm B, when no early (at day 15) response was present or when response was lost within six weeks, another two once-weekly 375 mg/m 2 rituximab infusions were given.Eligible patients needed to be 18 years of age or older and with an ITP relapse or refractoriness (at least 2 platelet counts less than 30x10 9 /L) and at least three weeks after high-dose corticosteroids (≥ 1mg/kg) before start of R (R start); further study details are available in the Online Supplementary Appendix. Complete (CR) good/partial (PR) and moderate (MR) response were defined as platelet counts of 150x10 9 /L or more and 50x10 9 /L or more on 2 consecutive occasions and a platelet count over 30x10 9 /L with at least twice the base-line count, respectively. Retrospectively, responses were also analyzed according to the International Working Group (IWG) ITP trial guidelines. 10 Relapse was defined as a further fall in platelet count to below 30x10 9 /L or below the 2-fold increase of base-line platelet count. Relapse-free survival (RFS), defined as time from response until relapse, emergency treatment, or death, was analyzed using the actuarial Kaplan-Meier method. Patients still alive at the date of last contact were censored. The primary objective of this study was to evaluate the individual treatment arms as sufficiently promising (CR+ PR + MR > 50%) strategies 11 but not to compare the results between the treatment arms. All analyses were performed according to the intention-to-treat principle, irrespective of patients' compliance. Ineligible patients were excluded from all analyses. With 15 patients considered ineligible, and 3 patients who did not start with their assigned R treatment, 138 patients were evaluated for response as primary end point (Table 1).Twelve patients (...

The aim of this randomized, controlled trial is to determine whether anti-SARS-CoV-2 hyperimmune globulin protects against severe COVID-19 in severely immunocompromised, hospitalized, COVID-19 patients. Patients were randomly assigned to receive anti-SARS-CoV-2 hyperimmune globulin (COVIG) or intravenous immunoglobulin without SARS-CoV-2 antibodies. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven out of eight (88%) in the IVIG control group (p = 0.015, Fisher’s exact test). COVIG may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available. The trial was registered at www.trialregister.nl (#NL9436).

BACKGROUND RUX, a potent oral JAK1/JAK2 inhibitor, has shown superiority over standard therapies in MF. RUX was approved for the treatment of MF on the basis of the phase 3 COMFORT trials, in which RUX led to sustained improvements in splenomegaly and symptom burden as well as longer survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). The starting dose (prescribing information) is based on PLT count: > 200 × 109/L, 20 mg bid; 100-200 × 109/L, 15 mg bid. Due to limited data available at the time, the recommended starting dose in pts with PLT counts of 50 to < 100 × 109/L was determined to be 5 mg bid. However, findings from COMFORT-I and Study 258 (phase 2 study of RUX in pts with MF with low PLT count) demonstrated that final titrated doses of ≥ 10 mg bid were safe and resulted in larger improvements in spleen volume and MF-related symptoms compared with titrated doses of ≤ 5 mg bid. The EXPAND study established a maximum safe starting dose (MSSD) in pts with low baseline PLT count (50 to < 100 × 109/L) and evaluated the safety and tolerability of RUX in this population. The 24-wk (Vannucchi AM, et al. ASH 2015 #2817) and 48-wk (Vannucchi AM, et al. Haematologica. 2019) analyses determined the MSSD to be 10 mg bid for pts with baseline PLT count of 50 to < 100 × 109/L. We present the final results from the study, confirming 10 mg bid as a safe starting dose for pts with low PLT count. METHODS EXPAND is a phase 1b, dose-finding study (NCT01317875) in pts with MF and baseline PLT count of 50 to < 100 × 109/L (Stratum [S] 1, 75 to < 100 × 109/L; S2, 50 to < 75 × 109/L). The study had a core period (up to wk 24) consisting of 2 phases (dose escalation and safety expansion) followed by an extension period (up to 3 years total). The primary objective was determination of the MSSD for both strata; safety and efficacy were secondary objectives. RESULTS Of 69 enrolled pts, 38 received RUX at the MSSD of 10 mg bid (S1, n = 20; S2, n = 18) and are the focus of this analysis. Baseline characteristics were indicative of advanced disease in both strata. Overall, 50% of pts in S1 and 83% of pts in S2 discontinued study treatment. Primary reasons for discontinuation were progressive disease (15%), adverse events (AEs; 10%), and other (10%) in S1 and AEs (33%), death (17%), and physician decision (17%) in S2. Median (range) duration of exposure was 155 (4-210) wk in S1 and 83 (4-161) wk in S2; 17/20 pts (85%) in S1 and 11/18 (61%) in S2 received RUX for ≥ 48 wk. AEs were consistent with the known safety profile of RUX (Table). The most common AEs were thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%); other common (> 30% all grade) AEs included diarrhea, ecchymosis, PLT decrease, and pyrexia (each 30%) in S1, and cough (33%) in S2. A total of 85% of pts in S1 and 89% in S2 had grade ≥ 3 AEs; thrombocytopenia (S1, 40%; S2, 78%) and anemia (25%; 17%) were most common. Overall, 20% and 50% of pts in S1 and S2 had AEs leading to study drug discontinuation, most commonly thrombocytopenia (S1, 5%; S2, 20%); other AEs led to discontinuation in 1 pt each. On-treatment deaths included 1 cardiac arrest (S1), 1 AML (S1), 1 multiorgan failure (S2), and 1 sepsis (S2). The death due to cardiac arrest was assessed as related to study drug; the others were unrelated. Overall, 40% (6/15) and 38% (3/8) of evaluable pts in S1 and S2 achieved a spleen response (≥ 50% reduction in spleen length from baseline) at wk 24; 33% (5/15) and 30% (3/10) of evaluable pts in S1 and S2 achieved a spleen response at wk 48; 55% (11/20) and 67% (12/18) of pts achieved a response at any time. A symptom response (≥ 50% reduction in MF-SAF TSS from baseline to wk 24) was achieved by 31% (4/13) of evaluable pts in S1 and 40% (4/10) in S2; at wk 24, there was a mean (SD) decrease (improvement) in total daily score from baseline by 7.7 (9.7) in S1 and 3.9 (11.4) in S2. There was no significant difference in the PK of RUX among pts with low PLT counts in this study compared with that in pts with PLT ≥ 100 × 109/L. CONCLUSIONS A starting dose of RUX 10 mg bid was manageable in this previously unstudied MF pt population with low PLT counts (50 to < 75 × 109/L and 75 to < 100 × 109/L). AEs were consistent with the known safety profile of RUX, with no new or unexpected adverse findings. This was supported by the PK/PD results as well. RUX treatment at a starting dose of 10 mg bid provided the benefit of spleen length reductions and clinical symptom improvements. EXPAND results confirm that a starting dose of RUX 10 mg bid is suitable for pts with MF and low PLT counts. Disclosures Kiladjian: AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Verstovsek:ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Boyer-Perrard:Novartis (RUMYCUP study only): Consultancy. Niederwieser:Novartis: Speakers Bureau; Amgen: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding. Liberati:Janssen: Honoraria, Research Funding; Onconova: Research Funding; Verastem: Research Funding; Oncopeptides: Research Funding; Incyte: Honoraria; GSK: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding. Harrison:AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Promedior: Honoraria; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau. Roussou:Novartis: Current Employment, Other: I have Novartis shares. Wroclawska:Novartis Pharma AG: Current Employment. Majidi:Novartis: Current Employment. Gisslinger:Janssen-Cilag: Honoraria; Roche: Honoraria; Celgene: Honoraria; AOP Orphan Pharmaceuticals AG: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MyeloPro Diagnostics and Research: Honoraria; PharmaEssentia: Honoraria. OffLabel Disclosure: Label dose in this patient population is 5 mg bid starting dose. EXPAND presents data for a 10 mg bid starting dose.