Abstract: Previous studies have demonstrated low rates of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with chronic lymphocytic leukemia (CLL). In this national collaboration of 11 cancer centers in the United States, we aimed to further characterize and understand vaccine-induced immune responses, including T-cell responses, and the impact of CLL therapeutics (#NCT04852822). Eligible patients were enrolled in 2 cohorts (1) at the time of initial vaccination and (2) at the time of booster vaccination. The serologic response rates (anti-S) from 210 patients in the initial vaccination cohort and 117 in the booster vaccination cohort were 56% (95% confidence interval [CI], 50-63) and 68% (95% CI, 60-77), respectively. Compared with patients not on therapy, those receiving B-cell-directed therapy were less likely to seroconvert (odds ratio [OR] , 0.27; 95% CI, 0.15-0.49). Persistence of response was observed at 6 months; anti-S titers increased with the administration of booster vaccinations. In the initial vaccination cohort, positive correlations were observed between the quantitative serologic response and CD4 T-cell response for the Wuhan variant and, to a lesser degree, for the Omicron variant (Spearman P = 0.45 Wuhan; P = 0.25 Omicron). In the booster vaccination cohort, positive correlations were observed between serologic responses and CD4 T-cell responses for both variants (P = 0.58 Wuhan; P = 0.57 Omicron) and to a lesser degree for CD8 T-cell responses (P = 0.33 Wuhan; P = 0.22 Omicron). Although no deaths from coronavirus disease 2019 (COVID-19) have been reported after booster vaccinations, patients should use caution as newer variants emerge and escape vaccine-induced immunity. This trial was registered at www.clinicaltrials.gov as #NCT04852822.

Abstract: Background: Ibrutinib (I) and venetoclax (V) have each demonstrated modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Preclinical data have shown synergy with these agents in B-cell cell lines (Kuo H, Mol Cancer Ther 2017). Based on these observations, we proposed the first trial to combine I and V in FL. Results from the phase Ib portion of this multi-institutional investigator-initiated trial are presented here (NCT02956382). Methods: This phase Ib/II trial is open at Georgetown/Lombardi CCC, Hackensack/John Theurer CC, and University of Washington/Fred Hutchinson/Seattle Cancer Care Alliance. Eligibility criteria include WHO grade 1-3a FL, & gt;1 prior systemic therapy, measurable disease warranting therapy by standard criteria or physician discretion, ECOG performance status & lt; 2, adequate marrow, hepatic, renal function. Patients (pts) were enrolled in a standard phase I 3+3 design at a starting dose level (DL) of I 420 mg daily, V 400 mg daily (DL0). The highest initially planned dose level was DL3: I 560 mg daily, V 800 mg daily. There was no dose ramp up of V based on monotherapy experience in FL. Pts at high risk for tumor lysis syndrome (TLS), defined as node ≥ 8 cm and/or significant lymphocytosis, were hospitalized for initial dose. Pts received study drugs until progression or unacceptable toxicity. Response was assessed by PET-CT and bone marrow biopsy (if marrow involvement present at time of enrollment). Results: Sixteen pts were enrolled between November 2017 - May 2020. Median age was 66 years (range 50-87); 75% were male; 75% were Stage III/IV, 94% had WHO grade 1/2 FL (Table 1). FLIPI score at enrollment was 25% low risk, 44% intermediate risk, 31% high risk. Two pts were considered high risk for TLS. Pts received a median of 2 prior therapies (range 1-8); 19% were refractory to last line of therapy. Cohort enrollment was: DL0 (n=3), DL1 (n=6), DL2 (n=6), DL3 (n=1). The protocol was amended to close DL3 based on pharmacokinetic data from DL2 indicating a 1.8-fold higher mean steady-state ibrutinib plasma exposure compared to ibrutinib 560 mg monotherapy and concern for potential toxicity. Grade 3 adverse events (AE) included neutropenia (25%), thrombocytopenia (13%), lung infection (13%), upper respiratory infection (6%), neutropenic fever (6%), atrial fibrillation (6%), ALT/AST elevations (6%), mucositis (6%), failure to thrive in setting of progression (6%), abdominal pain (6%). There were no grade 4/5 AE. Grade 1/2 AE occurring in & gt; 20% of pts included diarrhea (75%), nausea (63%), bruising (38%), rash (31%), headache (31%), constipation (25%), fatigue (25%). There was no evidence of clinical TLS; 19% had grade 1 hyperuricemia. The pt enrolled at DL3 had grade 1 diarrhea, grade 1 neutropenia. One dose limiting toxicity (DLT) occurred at DL1 (I 560 mg, V 400 mg): grade 3 neutropenia with fever and infection. There were no other DLTs. Therefore, DL2 (I 560 mg, V 600 mg) was determined to be the recommended phase 2 dose (RP2D). The ORR was 69% (0.413, 0.890); CR 25% (0.073, 0.524). The ORR at the RP2D was 83% (CR 33%). Responses by dose level are listed in Table 2. The regimen demonstrated activity in the bone marrow; 2 pts had eradication of involvement and 1 had a decrease from 60% to 0.5% by flow cytometry. Response by lines of prior therapy: 1 (86%, 6/7), & gt; 2 (56%, 5/9). Most pts (91%) had a response by time of first assessment (12 weeks). The median progression-free survival (PFS) was 8.3 months (5.6 months, NA) (Figure 1). Of note, 2 responding pts chose to withdraw from study due to travel and were censored in the PFS analysis at time of discontinuation. One remained in a CR at least 9 months after study withdrawal as documented by PET-CT performed off protocol. No pts discontinued due to toxicity. Conclusion: In the first clinical trial to combine a BTK inhibitor and a BCL-2 inhibitor in relapsed/refractory FL, we found the I-V doublet to demonstrate a toxicity profile similar to that seen in mantle cell lymphoma and CLL. While our sample size is small, there was no evidence of clinical TLS, despite omission of the V ramp up. Preliminary results of anti-tumor activity are encouraging and further evaluation at the RP2D (I 560 mg, V 600 mg) is ongoing in the phase II trial. The combination of ibrutinib and venetoclax may provide an effective option for FL, utilizing a targeted approach distinct from other novel agents currently approved for this malignancy. Disclosures Ujjani: Verastem Oncology: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Gilead/Kite: Consultancy, Research Funding. Lai:Agios: Consultancy; Macrogenics: Consultancy; Astellas: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy. Leslie:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Broome:sanofi: Honoraria; argenx: Honoraria; apellis: Honoraria; Alexion: Honoraria. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding. Smith:Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Portola: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy. Till:Mustang: Patents & Royalties, Research Funding. Lynch:Morphosys: Consultancy; Takeda: Research Funding; Bayer: Research Funding; TG therapeutics: Research Funding; Incyte: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Rhizen: Research Funding. Shadman:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Ended employment in the past 24 months; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maloney:Novartis: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Cheson:TG Therapeutics: Speakers Bureau; Symbio: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Trillium: Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Parexel: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: We are presenting data regarding the use of venetoclax and ibrutinib in follicular lymphoma.

Abstract: Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948–2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

Abstract: Introduction. wAIHA is a rare and often serious disease in which red blood cells (RBCs) coated with autoantibodies bind to Fcγ receptor-bearing macrophages, triggering a spleen tyrosine kinase (SYK) dependent signaling pathway that leads to RBC phagocytosis. Fostamatinib is a potent SYK inhibitor administered orally that was approved by the US FDA for the treatment of chronic ITP in adults. A phase 2, multicenter, open-label study (the SOAR study; NCT02612558) evaluated the response to fostamatinib in adult patients with wAIHA. We report the final results of the initial 24-week treatment period and the extension period of the phase 2 study. Methods. The study included adult patients with primary or secondary wAIHA, documented by IgG positive direct antiglobulin test (DAT), who had: failed ≥1 prior treatment for wAIHA, hemoglobin (Hgb) & lt;10 g/dL, haptoglobin & lt;10 mg/dL and lactate dehydrogenase (LDH) & gt;ULN (upper limit of normal). Patients were initiated on fostamatinib at 150mg BID with dose reduction permitted based on tolerability. Patients were seen every 2 weeks for 12 weeks, then every 3 weeks for 12 weeks, and every 6 weeks thereafter. The primary efficacy endpoint was achieving Hgb & gt;10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion. Patients who responded or showed clinical benefit were allowed to enter the extension period as long as they were tolerating the study drug. Results. The study included 25 evaluable patients (15 women) with median age 61 (range 27-88) years, median duration of wAIHA of 2 years ( & lt;1 to 26 years), and median Hgb of 9.0 g/dL (range 6.8-10.6). Most (80%) had primary AIHA; 3 patients had lymphoproliferative disease, 1 had systemic lupus erythematosus, and 1 had other secondary cause. Patients had received a median of 2 unique prior treatments (range 1-9), including corticosteroids (84%), splenectomy (20%) and rituximab (52%), and 52% were on corticosteroids at baseline. As of June 2019, median exposure to fostamatinib was 110.0 days (range, 26-847); median treatment compliance 100%. Eleven of 25 (44%) achieved the primary efficacy endpoint by Week 24 plus 1 late responder at Week 30 (total of 12 responders [48%]). Increases in median Hgb were generally detected at Week 2 (first visit) and sustained over time, with 24% achieving the primary endpoint by Week 2 (Figure). Median Hgb of responders increased by & gt;2.0 g/dL from baseline by Week 4 vs. no change for nonresponders. 13 eligible patients entered the extension period of the study, including 9 of 11 responders, 1 late responder, and 3 patients with a beneficial trend. Seven patients are still on treatment, and 6 discontinued the study, including 3 who withdrew, 1 was lost to follow up, and 2 had a loss of response (1 of whom also had increased alanine aminotransferase). Overall, adverse events (AE) were manageable and consistent with the fostamatinib safety database of & gt;3500 patients across all disease programs. No new safety signals were detected. The most common AEs during the initial treatment period were diarrhea in 9, fatigue in 8, hypertension in 7, and dizziness in 6. AEs were mostly mild to moderate. Seven patients had serious AEs, including anemia, acute myocardial infarction, fall, Hgb decreased, inappropriate secretion of antidiuretic hormone, infection, pneumonia, rhabdomyolysis, sepsis, skin necrosis, and systemic inflammatory response syndrome. Two patients had AEs leading to death: one had infection with skin necrosis and calciphylaxis; the other had pneumonia. Neither were considered related to treatment, and both patients were immunosuppressed due to steroids. Six subjects (24%) received rescue therapy, including RBC transfusion, prednisone and/or immunoglobulins. Conclusions. In this phase 2, multicenter, open-label study, fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA. Adverse events were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure Disclosures Rogers: Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Boxer:Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Arnold:Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy; Bristol-Myers Squibb: Research Funding. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Incyte: Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Rigel: Research Funding. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Murakhovskaya:Momenta: Membership on an entity's Board of Directors or advisory committees. Chow:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Zheng:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Kuter:Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Kezar: Research Funding; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.

Abstract: Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26] ) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P & lt; .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Abstract: BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments. AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%. The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with 〈 0.01% by both methods, 1 sample with 0.03% CLL by HTS and 〈 0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log). CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to 〉 95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with 〈 0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. Disclosures Rawstron: Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

Abstract: Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) 〈 10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb 〉 10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B‐cell lymphoma, COVID‐19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double‐blind, phase 3 study is nearing completion.