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Abstract 3937 Large granular lymphocyte (LGL) leukaemia is a rare lymphoproliferation originating in activated cytotoxic CD8+ T cells or occasionally NK cells. Published series incorporating 40 or more patients are few in number with some differences in diagnostic definitions, making comparisons between studies challenging. Investigators have chiefly relied on peripheral blood for diagnosis; typically defined as a persistent excess (>0.5×109/l) of LGLs, associated with monoclonal T-cell receptor (TCR) gene rearrangements by PCR. However, benign monoclonal CD8+T-cell expansions, phenotypically indistinguishable from T-LGL, are well recognised in both healthy elderly individuals and those with autoimmune disease. To-date, reported response rates to oral Methotrexate (MTX) have been in the order of 40–60%, with MTX-failure reportedly occurring in two-thirds of patients after 1 year of follow-up. We studied 40 patients diagnosed with LGL leukemia at Nottingham University Hospitals NHS Trust, UK, between 1990 and 2011. All patients had a persistent (>6 months) large granular lymphocytosis and, importantly, 97.5% (39/40) patients had undergone a bone marrow (BM) biopsy. In all cases an interstitial infiltrate of cytotoxic T cells and/or NK cells, typically demonstrating characteristic linear arrays, established the diagnosis. A majority of patients had correlative peripheral blood PCR studies confirming clonal TCR gene rearrangements in 80%. Although 5 patients had a polyclonal TCR gene, for all such patients the BM findings (>20% LGLs in some cases) together with clinical context (neutropenia, lymphocytosis and 2 cases of pure red cell aplasia (PRCA)) established the diagnosis of LGL leukemia. The median age at diagnosis was 66 years (21–90 years), with an equal sex distribution. The median total lymphocyte count at clinical presentation was 2.7×109/l (0.7–9.4 x109/l) and a lymphocyte count of ≥2×109/l was seen in 27 patients (68%). Thirty patients (75%) were neutropenic at diagnosis (median neutrophil count 0.9 x109/l (range 0.0–6.5 x109/l). In 13 cases neutropenia was accompanied by anemia, thrombocytopenia or both. Rheumatoid factor was positive in 11 of 27 assessable cases (41%), whilst 11 of 40 (28%) had associated autoimmune clinical disorders, including Rheumatoid arthritis (n=6). With a median follow-up for living patients of 3.2 years (range 1.0–15.1 years), 15 patients (38%) have never required treatment. One further patient was already established on MTX at LGL diagnosis. Treatment was not required in any patients who presented with an isolated, asymptomatic lymphocytosis (n=8, 20%). The median time from diagnosis to treatment was 2.1 months; all treatment-requiring patients needed therapy within 6 months of presentation. Treatment was indicated in 24 patients: neutropenia and recurrent infections (n=8); severe neutropenia (n=6); cytopenias associated with other symptoms (mouth ulcers, skin lesions, organomegaly) (n=8); and PRCA (n=2). MTX (10mg/m2, weekly) was employed as first-line therapy (n=9) and after failure of Prednisolone (0.5–1mg/kg) monotherapy (n=7). Amongst 16 MTX-treated patients, 14 (87.5%) achieved a haematological PR (n=6) or CR (n=8) after a median of 2.5 months (1–9 months). (Improvements in quality of response) Continuing responses (haem-PR to CR) were seen up to 2yrs after starting MTX (of MTX). Notably, for the 14 MTX-responders the median duration of response was 6.5 years (0.3–16), censoring for death and drug-cessation due to patient choice. Neither of the 2 patients with PRCA responded to MTX, but Ciclosporin and Fludarabine were effective salvage therapies for MTX-failures. This is one of the largest single-centre series of LGL leukemia reported to-date. The strengths of our study include robust diagnostic evidence of LGL leukemia including BM biopsy and a long follow-up duration. By contrast to the published data, we describe high rates of response to MTX in both steroid-exposed and naive patients. Time to response exceeded 4 months in some cases and responses were sustained for >5 years in a majority of patients. The role of MTX in LGL leukemia warrants further study. Disclosures: No relevant conflicts of interest to declare.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder leading to hemolytic anemia, which can occur concomitantly with bone marrow disorders (BMD), such as aplastic anemia (AA) and myelodysplastic syndrome (MDS). Accordingly, patients with PNH often require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow failure. After demonstrating a non-inferior efficacy and safety profile in two of the largest clinical trials to date, ravulizumab was approved as a treatment for adults with PNH, including patients with an underlying history of bone marrow disease, who are transfusion dependent or independent. Aims: To assess the efficacy of ravulizumab in patients with PNH with or without an underlying pathology of AA or MDS, and to investigate the impact of ravulizumab on transfusion burden as measured by number of transfusions and total packed RBC (pRBC) units transfused over a 52-week period. Methods: This phase 3 multicenter, randomized, active-controlled, open-label study (study 301, NCT02946463) enrolled complement-inhibitor-naïve patients with PNH. Patients were aged ≥ 18 years with a confirmed diagnosis of PNH by flow cytometry and lactate dehydrogenase (LDH) level ≥ 1.5x the upper limit of normal (ULN; 246 U/L). Patients received either ravulizumab or eculizumab for 26 weeks; after which all patients received ravulizumab from week 26 to week 52. Efficacy outcomes included the proportion of patients achieving transfusion avoidance (TA), number of pRBC units transfused and the number of pRBC or whole blood transfusions (WBT) received from baseline to 26 and 52 weeks of treatment. In this retrospective analysis, outcomes were analysed for the following subgroups: AA, MDS or no BMD (medical history of AA or MDS was determined by the investigator at screening). Descriptive statistics were calculated for continuous (means) and categorical variables (numbers and percentages). Formal hypothesis testing for significance between treatment groups was not performed. Results: Of the 246 patients included in the study, 79 had a history of AA (32.1%) and 13 (5.3%) had a history of MDS. Baseline characteristics were comparable between treatment groups. From baseline to week 26, a comparable proportion of patients with AA achieved TA to those with no BMD; 75.6% for patients with AA and no BMD receiving ravulizumab, and 60.5% and 73.7% for patients with AA and no BMD receiving eculizumab, respectively (Table 1). Importantly, TA was maintained through 52 weeks, with similar proportions of patients with AA (87.1‒91.3%) maintaining TA to patients without BMD (85.7‒91.5%). More specifically, 65.9% of patients with AA and 69.2% of patients without BMD achieved TA through 52 weeks of ravulizumab treatment, and 55.3% and 63.2% of patients with AA and without BMD, respectively, achieved TA on eculizumab followed by ravulizumab. The proportion of patients with MDS who achieved TA appeared numerically lower compared with patients with AA or no BMD, however, this subgroup sample size was small. Furthermore, a lower proportion of patients on ravulizumab with AA or MDS received any transfusion from baseline to weeks 26 and 52 compared with those treated with eculizumab followed by ravulizumab: for week 26, 24.4% and 57.1% for ravulizumab versus 39.5% and 100.0% for eculizumab in patients with AA and MDS, respectively, and for week 52, 29.3% and 57.1% for patients with AA and MDS receiving ravulizumab for 52 weeks versus 44.7% and 100.0% for patients with AA and MDS treated with eculizumab followed by ravulizumab. In addition, ravulizumab-treated patients with AA or MDS had numerally fewer transfusions and units of pRBC/WBT compared with those who received eculizumab followed by ravulizumab. Overall, the exploratory nature of the analysis and small sample size means that interpretation of the data is limited. Conclusions: This analysis demonstrates that majority of patients with PNH and AA who received ravulizumab avoided the need for transfusion up to 52 weeks of treatment. Patients treated with ravulizumab for the 52-week period had numerically fewer transfusions and units of pRBC/WBT transfused compared with patients who received eculizumab followed by ravulizumab. Overall, these findings support the use of ravulizumab in complement-inhibitor-naïve patients with PNH, with or without a history of BMD. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yonemura:Alexion Pharmaceuticals: Honoraria, Research Funding. Munir:Alexion: Honoraria; 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. Pavani:Alexion Pharmaceuticals: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.