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Background: Sickle cell disease, a debilitating, inherited haemolytic anaemia with premature morbidity and mortality, affects millions globally. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease., Methods: We report results from the phase 2, 12-week, double-blind period of RISE UP, a global, phase 2/3, double-blind, randomised, placebo-controlled trial. The phase 2 part of the study was conducted at 32 clinical study sites across 13 countries. Patients aged 16 years or older with a confirmed diagnosis of sickle cell disease (any genotype), baseline haemoglobin of 5·5-10·5 g/dL (inclusive), and two to ten sickle cell pain crises within 12 months before providing informed consent, were randomly assigned 1:1:1 to receive oral mitapivat 50 mg, 100 mg, or placebo twice daily, in this portion of the study which is now complete. Randomisation was performed using a permuted-block method and concealed with an interactive response system; patients, investigators, and individuals assessing outcomes were masked to treatment assignment. Primary efficacy and safety endpoints were haemoglobin response (≥1·0 g/dL increase from baseline in average haemoglobin concentration from week 10 through week 12), and type, severity, and relationship to study drug of adverse and serious adverse events. Efficacy and safety endpoints were evaluated in the full analysis set (all randomly assigned patients) and safety analysis set (all patients who received at least one dose of study drug), respectively. This study is registered with ClinicalTrials.gov as part of an ongoing phase 2/3 study (NCT05031780)., Findings: Between Jan 19, 2022, and April 25, 2023, 79 patients were randomly assigned (51 [65%] female, 28 [35%] male; 46 [58%] Black or African American, 26 [33%] White, five [6%] multiracial, two [3%] Asian); 26 received mitapivat 50 mg, 26 received mitapivat 100 mg, and 27 received placebo, twice daily. Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 mg group and 13 [50%] of 26 patients in the mitapivat 100 mg group, versus one [4%] of 27 patients in the placebo group; two-sided p=0·0003 and p=0·0001, respectively). Mitapivat was generally well tolerated. Serious adverse events were reported in two (8%) of 26 patients in the mitapivat 50 mg group, four (15%) of 26 patients in the mitapivat 100 mg group, and three (11%) of 27 patients in the placebo group; grade 3 or worse adverse events occurred in three (12%), five (19%), and two (7%) patients, respectively. No serious or grade 3 or worse adverse events were considered treatment related and there were no treatment-related deaths. The most common grade 3 or worse adverse events were infections and infestations, and included one patient in the placebo group with an infected skin ulcer, one patient in the mitapivat 50 mg group with meningitis and one with pelvic inflammatory disease, and one patient each with malaria, pneumonia, and tonsillitis in the mitapivat 100 mg group., Interpretation: Mitapivat, through its dual effect of increasing ATP and decreasing 2,3-diphosphoglycerate, could provide clinical benefit to patients with sickle cell disease. These results support continued evaluation of mitapivat in the phase 3 portion of the study., Funding: Agios Pharmaceuticals., Competing Interests: Declaration of interests MI reports receiving grants from Pfizer, Global Blood Therapeutics, Novartis, Agios, Novo Nordisk, Forma and Alexion; consulting fees from Novo Nordisk, Global Blood Therapeutics, Novartis, Vertex, and bluebird bio; honoraria from Global Blood Therapeutics; and is on an advisory board for Global Blood Therapeutics. BA reports receiving research grants from Afimmune, Global Blood Therapeutics, Forma Therapeutics, Hemanext, Novartis, and Pfizer; receiving honoraria from Agios Pharmaceuticals, bluebird bio, Pfizer, and Vertex; being on an advisory board for Agios Pharmaceuticals, Afimmune, Aruvant, bluebird bio, CVS/Accordant, Editas, Emmaus, Forma Therapeutics, Fulcrum, Global Blood Therapeutics, Hemanext, Merck, Novartis, Novo Nordisk, Pfizer, and Vertex; receiving meeting travel support from Agios Pharmaceuticals and Pfizer; and having a leadership role at Sickle Cell Disease Association of America. AI reports receiving research grants from Agios Pharmaceuticals, Bausch, Forma Therapeutics, Global Blood Therapeutics, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Roche, and Vifor; being a steering committee member for Global Blood Therapeutics and Novartis; and being on an advisory board for Forma Therapeutics and Roche. AKG reports receiving clinical grants from The Children's Foundation; receiving honoraria from Pfizer; and being on an advisory or data safety monitoring board for Bausch, bluebird bio, and Global Blood Therapeutics. PB reports receiving consulting fees and honoraria from Agios Pharmaceuticals; and being a co-founder of INNOVHEM. RC reports receiving grants from bluebird bio and Global Blood Therapeutics; and receiving honoraria from Addmedica, Agios Pharmaceuticals, Forma Therapeutics, Global Blood Therapeutics, Novo Nordisk, Pfizer, and Vertex. ATT reports being a consultant for and receiving research funding from Agios Pharmaceuticals, Bristol-Myers Squibb (Celgene), Novo Nordisk, Pharmacosmos, and Vifor. MRA reports receiving research funding from Agios Pharmaceuticals, Global Blood Therapeutics/Pfizer, Novartis, and Novo Nordisk; being on an advisory board for Agios Pharmaceuticals, Global Blood Therapeutics/Pfizer, and Novartis; and being on a data safety committee for Vertex Pharmaceuticals. DD reports being on an advisory committee for Agios Pharmaceuticals. KIA reports receiving grants from the National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Takeda, and the US Food and Drug Administration; being a consultant for Agios Pharmaceuticals, Biomarin, Fulcrum Therapeutics, Hillhurst Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi; receiving honoraria from Novartis; and participating in a data safety monitoring or advisory board for Vertex Pharmaceuticals. ABA reports being a consultant for Novo Nordisk, Pfizer, and Takeda; receiving honoraria from Novo Nordisk, Pfizer and Takeda Turkey. KHMK reports receiving grants from Agios Pharmaceuticals and Pfizer; receiving consultancy fees for Biossil; being on an advisory board for Alexion, Agios Pharmaceuticals, Bristol-Myers Squibb, Forma, Pfizer, Novo Nordisk, and Vertex; receiving honoraria from Agios and Bristol-Myers Squibb; and being on the data safety monitoring board or advisory committee for Sangamo. AO, SM, HS, SP, RU, AUZ, and SG are employees of Agios Pharmaceuticals and own stock. AMY is an employee of Agios Pharmaceuticals and reports receiving consulting fees from Novartis; receiving honoraria from Agios Pharmaceuticals, Global Blood Therapeutics, and Hemostasis and Thrombosis Research Symposium; receiving meeting support from American Academy of Pediatrics and American Society of Hematology; being in a leadership role for American Academy of Pediatrics and Hematology-Oncology; and owns Agios Pharmaceuticals stock. VI is a former employee of Agios Pharmaceuticals and owns stock, as well as shares from Novartis. WRS reports being a consultant for Agios Pharmaceuticals, Alexion, bluebird bio, Fulcrum Therapeutics, Novartis, Pfizer, and Vertex Pharmaceuticals; being an investigator for Agios Pharmaceuticals, Alexion, bluebird bio, Fulcrum Therapeutics, Novartis, and Pfizer; receiving honoraria and meeting support from Agios Pharmaceuticals; and participating in a data safety monitoring board for Novo Nordisk. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL., Methods: We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5 × 10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials.gov, number NCT00345345., Findings: From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders., Interpretation: This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression., Funding: National Heart, Lung, and Blood Institute., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report a case of t(8;21) acute myeloid leukemia presenting as severe aplastic anemia. While initial bone marrow biopsy lacked any cytogenetic abnormalities in 20 analyzed metaphases, repeat bone marrow biopsy eight days later demonstrated this translocation. Initial cytogenetic analysis of 20 metaphases was therefore insufficient to make the diagnosis of hypocellular acute myeloid leukemia. We discuss that further complementary molecular tests, such as CGH, would likely provide a more robust diagnosis of hematopoietic diseases.