ABSTRACT
Introduction: Cases of de novo immune thrombocytopenia (ITP), including a fatality following SARS-CoV-2 vaccination in a previously healthy recipient, led to studying its impact in pre-existing ITP. Published reports are limited but suggest that most patients with ITP tolerate the COVID-19 vaccines well without frequent ITP exacerbations (Kuter, BJH, 2021). Data regarding risk factors for exacerbation and relationship of response to first dose to that of second dose are limited. Methods: Data for patients with pre-existing ITP were obtained via 3 sources. First, via a ten-center retrospective study of adults with ITP who received a SARS-CoV-2 vaccine between December 2020 and March 2021 and had a post-vaccination platelet count (n=117);9 centers were in the United States. Eighty-nine percent of patients received mRNA-based vaccines. The second and third sources of data were surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom ITP Support Association. A 'stable platelet count' was defined as a post-vaccination platelet count within 20% of the pre-vaccination level. ITP exacerbation was defined as any one or more of: platelet decrease ≥ 50% compared to pre-vaccination baseline, platelet decrease by >20% compared to prevaccination baseline with platelet nadir < 30x10 9/L, receipt of rescue therapy for ITP. Continuous variables were described as mean ±SD or median [interquartile range];categorical variables were described as n (%). Relative risks and 95% confidence interval were calculated to estimate strength of association. Results: Among 117 patients with pre-existing ITP from 10 centers who received a SARS-CoV-2 vaccine, mean age was 63±17 years, 62% were female, with median 12 [4-23] years since diagnosis of ITP;patients had received a median of 3 [2-4] prior medical treatments. Sixtynine patients were on ITP treatment at the time of vaccination (Table 1). There was an almost even distribution of platelet count response following each vaccine dose. In 109 patients with data for dose 1, platelet counts increased in 32 (29%), were stable in 43 (39%), and decreased in 34 (31%);in 70 patients following dose 2, platelet counts increased in 24 (34%), were stable in 25 (36%), and decreased in 21 (30%) (Figure 1). Nineteen (17%) patients experienced an ITP exacerbation following the first dose and 14 (20%) of 70 after a second dose. In total, fifteen patients received and responded to rescue treatments (n = 6 after dose 1, n = 8 after dose 2, n = 1 after both doses). Of 7 patients who received rescue treatment after dose 1, 5 received dose 2 and only 1/5 received rescue treatment again. Rescue consisted of increased dose of ongoing medication, steroids, IVIG, and rituximab. Splenectomized persons and those who received 5 or more prior lines of medical therapy were at highest risk of ITP exacerbation. Only 1 of 47 patients who had neither undergone splenectomy nor received 5 or more lines of therapy developed ITP exacerbation after dose 1. There were 14 patients offtreatment at the time of dose 1 and 7 patients at time of dose 2;1 patient in each group developed ITP exacerbation with both these having had normal counts prior to vaccination and having undergone splenectomy. In 43 patients whose platelet counts were stable or increased after dose 1 and received dose 2, only 6 (14%) had platelet decreases to <50 x10 9/L after dose 2. Age, gender, vaccine type, and concurrent autoimmune disease did not impact post-vaccine platelet counts. In surveys of 57 PDSA and 43 U.K. ITP patients, similar rates of platelet change were seen (33% of participants reported decreased platelet count in both surveys) and prior splenectomy was significantly associated with worsened thrombocytopenia in each. Conclusions: Thrombocytopenia may worsen in pre-existing ITP post-SARS-CoV2-vaccination but when ITP exacerbation occurred, it responded well to rescue treatment. No serious bleeding events were noted. Rescue treatment was needed in 13% of patients. Proactive vaccination surveillance of patien s with known ITP, especially those post-splenectomy and with more refractory disease, is indicated. These findings should encourage patients with ITP to not only be vaccinated, but to receive the second dose when applicable to ensure optimal immunization. Rituximab interferes with vaccination response and ideally would be held until a minimum of 2 weeks after completion of vaccination.
ABSTRACT
Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: • Age ≥18;• Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);• failure of ≥1 prior treatment for wAIHA;• Haptoglobin <LLN (lower limit of normal) or total bilirubin >ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;• Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: • Presence of other forms of AIHA;• Uncontrolled or insufficiently controlled hypertension;• Neutrophil count <1,000/µL, • Platelet count <30,000/μL (unless patient has Evans syndrome);• Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy;duration of hemoglobin response;and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patien s have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. [Formula presented] Disclosures: Cooper: Amgen: Honoraria, Speakers Bureau;Novartis: Honoraria, Speakers Bureau. Numerof: Rigel: Current Employment, Current equity holder in publicly-traded company. Tong: Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter: Incyte: Consultancy, Honoraria;Genzyme: Consultancy, Honoraria;Immunovant: Consultancy, Honoraria;Momenta: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Dova: Consultancy, Honoraria;Merck Sharp Dohme: Consultancy, Honoraria;UCB: Consultancy, Honoraria;Up-To-Date: Consultancy, Honoraria, Patents & Royalties;Zafgen: Consultancy, Honoraria;Sanofi (Genzyme): Consultancy, Honoraria;Shionogi: Consultancy, Honoraria;Shire: Consultancy, Honoraria;Principia: Consultancy, Research Funding;Protalix Biotherapeutics: Consultancy;Shionogi: Consultancy;Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Daiichi Sankyo: Consultancy, Honoraria;Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Immunovant: Other: Travel Expenses, Research Funding;Caremark: Consultancy, Honoraria;CRICO: Consultancy, Honoraria;Kezar Life Sciences, Inc: Other, Research Funding;Principia Biopharma: Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Other, Research Funding;Rigel: Consultancy, Honoraria, Other, Research Funding;Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Research Funding;Kyowa-Kirin: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Platelet Disorder Support Association: Consultancy, Honoraria.