Fostamatinib, a Spleen Tyrosine Kinase Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia: Initial Results of the Multicenter, Open-Label Extension Period of the Soar Phase 2 Study
Bibliographic record
Abstract
Abstract Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease characterized by antibody-mediated destruction of red blood cells (RBCs). Activation of Fc receptors on macrophages in turn activates spleen tyrosine kinase (SYK), which triggers a signaling cascade leading to phagocytosis of the antibody-bearing cells. Fostamatinib, a SYK inhibitor, markedly improved Hgb levels in 9 of 17 (53%) patients with wAIHA during a phase 2, open-label, multicenter study. This abstract reports the results of ongoing fostamatinib treatment as of 2 July 2018 in patients who completed the 24-week treatment period and rolled over into the extension period of the study. Methods: Eligible adult patients had primary or secondary wAIHA and had failed more than one prior treatment for wAIHA. Patients had to have hemoglobin (Hgb) <10 g/dL, an IgG-positive direct antiglobulin test, haptoglobin <10 mg/dL, and lactate dehydrogenase (LDH) >ULN. In order to enter the extension period of the study, patients had to have [1] met the primary efficacy endpoint (Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion) OR have shown a beneficial trend during the 24-week treatment period and [2] tolerated study drug. Fostamatinib 150mg BID (or the dose taken at the end of the 24-week treatment period, if a dose reduction had occurred) was taken orally with no food restriction, and patients were seen every 6 weeks during the extension period. Results: Six patients have entered the extension period including 5 who had met the primary efficacy endpoint and 1 who showed a beneficial trend at Week 24 (and had a response at Week 30). One patient had lymphoproliferative disease. Prior AIHA treatment included splenectomy (1), steroids (6), and rituximab (2). The median duration of disease was 1.9 years (range 0.4-15.7). The mean age was 58.7 years (range 30-86), 5 were female, all were white, and 4 were Hispanic or Latino. At baseline the median Hgb was 9.1 g/dL (range: 8.6-9.5); the median lactate dehydrogenase was 273 U/L (range 233-781); the median reticulocyte count was 252.2 x109/L (range 7.8-350.0); and the median haptoglobin was 7.0 mg/dL (range 7.0-9.0). The direct antiglobulin test was positive for IgG in 5 patients at screening. Median Hgb levels increased over the course of the study. See figure. Four of 6 patients had an ongoing response as of the data cutoff date, and none has had rescue therapy or an RBC transfusion. All 6 patients had ≥1 adverse event (AE) during the study, including noninfectious diarrhea in 1 (treatment-related), hepatic disorders in 3 (treatment-related in 2; treatment interrupted in 1), and hypertension in 1 (not related). One patient had a serious AE (inappropriate antidiuretic hormone secretion), which was not related to fostamatinib. To date, no new safety signals have been detected. Summary/Conclusion: Patients with wAIHA continued to display markedly improved Hgb levels during the extension period of the study. Side effects were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure. Figure. Disclosures Kuter: ONO: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen Inc.: Consultancy; Principia: Research Funding; Bioverativ: Consultancy, Research Funding; Argenx: Consultancy; Syntimmune: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arnold:Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boxer:Incyte: Speakers Bureau; Rigel: Speakers Bureau; AbbVie: Speakers Bureau. Broome:Bioverativ: Honoraria; Alexion: Honoraria. Field:Prolong: Research Funding; Ironwood: Consultancy, Research Funding; Incyte: Research Funding. Lowe:Rigel: Consultancy. Tong:Rigel: Employment, Equity Ownership. Zayed:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".