Thiamine Deficiency

Researchers have discovered vitamin B1 produced by microbes in rivers, findings that may offer hope for vitamin-deficient salmon populations. Oregon State University researchers have discovered vitamin B1 produced by microbes in rivers, findings that may offer hope for vitamin-deficient salmon populations. Findings were published in Applied and Environmental Microbiology. The authors say the study in California's Central Valley represents a novel piece of an important physiological puzzle involving Chinook salmon, a keystone species that holds significant cultural, ecological and economic importance in the Pacific Northwest and Alaska. Christopher Suffridge, senior research associate in the Department of Microbiology in the OSU College of Science, and doctoral student Kelly Shannon examined concentrations of thiamine and the microbial communities in rivers of the Sacramento River watershed. Thiamine is the compound commonly referred to as vitamin B1 and is critical to cellular function in all living organisms. "This study is the first-ever report of thiamine compounds in salmon spawning rivers and the associated gravels where salmon spawn," Suffridge said. "This source of thiamine has potential implications for reducing health impacts on naturally spawning salmon that are suffering from thiamine deficiency complex." TDC, an emerging threat to the stability of West Coast salmon populations, has affected salmon and trout in lake systems in northeastern North America and Atlantic salmon in the Baltic Sea. Chinook salmon in the Central Valley have recently been diagnosed with TDC, the researchers note. Afflicted female salmon that return to rivers and streams to spawn can pass the deficiency on to their hatchlings, which have problems swimming and experience high mortality rates. "In California, most hatchery-spawning Chinook salmon are treated with thiamine to prevent TDC," Suffridge said. "However, it was previously unknown if there was a source of thiamine in the environment that could potentially rescue naturally spawning salmon afflicted with TDC. We have now identified microbially produced thiamine in natural salmon spawning habitats." "It's a complicated issue," Shannon added. "The broader context is that Central Valley Chinook salmon, as well as some populations of salmon in other places, are becoming thiamine deficient because of shifts in their diet in their feeding grounds." Historically, Shannon said, Central Valley Chinook salmon ate a diverse, healthy diet consisting of many different species of prey fish. But in recent years, shifts in the ocean ecosystem have caused northern anchovy populations to explode, meaning they've become the primary dietary component for salmon. This change in diet is the likely cause of TDC, he said. "Northern anchovies are high in an enzyme called thiaminase that degrades thiamine," Shannon said. "So by the time many California Central Valley Chinook salmon are ready to spawn they have been feeding on so many anchovies that they have become deficient in thiamine from the activity of the thiaminase enzyme in anchovies." The results of the new study implicate river sediments as likely sources of microbial thiamine, which could supplement early life stages of Chinook salmon that experience TDC, he said. Future studies will examine to what degree environmental thiamine acquisition by adult Chinook salmon, their incubating eggs and hatched fry could alleviate the negative health outcomes caused by TDC. "It was unknown if the vitamin could even be measured in rivers in the first place, and the thiamine concentrations we measured were much lower -- more than a million times lower -- than a hatchery thiamine bath," Shannon added. "The data have implications for salmon health but are not concrete enough to say anything definitive. More research is needed to determine what role the environmental thiamine might play, but obviously learning that it's there is an important first step." The collaboration included Rick Colwell, a professor in the OSU College of Earth, Ocean, and Atmospheric Sciences, and Hailey Matthews, who graduated from the Oregon State Honors College in June 2023. Also taking part in the study were scientists from the National Oceanic and Atmospheric Administration, the University of California, Davis, Bronx Community College and the California Department of Water Resources. The California Department of Fish and Wildlife was the primary funder of this research. Additional support was provided by the National Science Foundation.

New data from our multiple myeloma portfolio across targets and molecular approaches show significant progress toward our goal of transforming the treatment paradigm and improving outcomes for patients Multiple first disclosures including preliminary Phase 1 data for subcutaneous administration of bispecific T cell engager alnuctamab in heavily pretreated multiple myeloma, preliminary Phase 1 results for GPRC5D CAR T in relapsed/refractory multiple myeloma and first results from the Phase 2 KarMMa-2 trial evaluating Abecma in high-risk multiple myeloma New data for CD19-directed CAR T cell therapy Breyanzi, including longer-term follow up from pivotal Phase 3 TRANSFORM study in second-line relapsed or refractory large B-cell lymphoma PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol-Myers Squibb (NYSE: BMY) today announced the presentation of research across its hematology portfolio at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, which will take place in New Orleans, Louisiana, and virtually, from December 10 to 13, 2022. Data from more than 100 company-sponsored studies will be featured, including 34 oral presentations, highlighting the range of modalities, targets and research platforms the company is advancing and showcasing our commitment to scientific progress across hematologic diseases. “Our presence at ASH underscores the transformational potential of our diverse pipeline, poised to deliver the next wave of advances in hematology,” said Samit Hirawat, M.D., executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb. “These exciting data, spanning a variety of modalities and targets, demonstrate significant progress toward our goals of improving long-term outcomes across patient populations and finding solutions in important areas of remaining need.” Key data being presented by Bristol Myers Squibb and its partners at the 2022 ASH Annual Meeting and Exposition include: Cell Therapy Updated data including longer-term follow up from the primary analysis of the Phase 3 TRANSFORM study evaluating Breyanzi® (lisocabtagene maraleucel) versus the standard of care as a second-line treatment in relapsed or refractory large B-cell lymphoma (LBCL) Updated data from the primary analysis of the Phase 2 OUTREACH study evaluating Breyanzi as a third-line plus treatment in relapsed or refractory LBCL in the community setting Safety and efficacy results of the match-adjusted indirect comparison of the TRANSFORM versus ZUMA-7 studies evaluating Breyanzi versus axicabtagene ciloleucel in the second-line setting in relapsed or refractory LBCL Two first disclosures of results from cohorts 2a and 2c of the Phase 2 KarMMa-2 trial evaluating Abecma in high-risk multiple myeloma First disclosure of preliminary Phase 1 results for GPRC5D chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory (R/R) multiple myeloma, including patients previously treated with a B-cell maturation antigen (BCMA)-directed CAR T cell therapy Hematology Multiple analyses of Reblozyl® (luspatercept-aamt), including overall survival data from the Phase 3 MEDALIST study in lower-risk myelodysplastic syndromes and real-world, longer-term results from the Phase 2 BEYOND study in beta thalassemia Multiple analyses of Inrebic® (fedratinib), including the primary analysis of safety and efficacy from the Phase 3b FREEDOM trial in intermediate- or high-risk myelofibrosis Longitudinal analyses of acute myeloid leukemia gene mutations with Onureg® (azacitidine tablets) from the Phase 3 QUAZAR® AML-001 study Early Pipeline First disclosure of preliminary results from the dose escalation and expansion components of the Phase 1 CC-93269 MM-001 study, evaluating subcutaneous bispecific T cell engager alnuctamab in heavily pretreated multiple myeloma First results from dose expansion cohort of the CC-92480 Phase 1/2 MM-001 study, evaluating CELMoDTM agent mezigdomide with dexamethasone in patients with R/R multiple myeloma Results from post-BCMA cohort of the CC-220 Phase 1/2 MM-001 study, evaluating CELMoD agent iberdomide with dexamethasone in patients with R/R multiple myeloma previously treated with a BCMA-directed therapy First results from a Phase 1/2 study evaluating BMS-986158, a potent Bromodomain and Extraterminal (BET) inhibitor, as monotherapy and in combination with ruxolitinib or Inrebic in intermediate- or high-risk myelofibrosis To learn more about our science and commitment in hematology, check out the BMS at ASH 2022 content hub. You can find additional information about BMS’ presence at the meeting on the ASH website. Selected Bristol Myers Squibb studies at the 64th ASH Annual Meeting and Exposition include: Abstract Title Author Presentation Type/# Session Title Session Date/Time (CST) Beta Thalassemia Erythroid Response in Patients with Non-Transfusion-Dependent ß-Thalassemia Treated with Luspatercept: Long-Term Data from the BEYOND Trial Ali Taher Poster Presentation #3669 112. Thalassemia and Globin Gene Regulation: Poster III Monday, December 12, 6:00 – 8:00 PM Lymphoma Five-Year Results From the Phase 3 Randomized Study AUGMENT: Lenalidomide Plus Rituximab (R2) vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma John Leonard Oral Presentation #230 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological III Saturday, December 10, 2:15 PM Iberdomide (CC-220) Monotherapy or in Combination with an Anti-CD20 Monoclonal Antibody as Effective Therapy in Patients with Relapsed/Refractory Lymphoma: Early Results from a Phase 1/2 Study Catherine Thieblemont Oral Presentation #233 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological III Saturday, December 10, 3:00 PM Lisocabtagene Maraleucel (liso-cel) versus Standard of Care (SOC) with Salvage Chemotherapy Followed by Autologous Stem Cell Transplantation (ASCT) as Second-line (2L) Treatment in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL): Primary Analysis of the Randomized, Phase 3 TRANSFORM Study Jeremy Abramson Oral Presentation #655 705. Cellular Immunotherapies: Results from CD19-Directed CAR T in treating Aggressive B-cell Lymphomas Sunday, December 11, 4:30 PM Matching-Adjusted Indirect Comparison (MAIC) of Lisocabtagene Maraleucel (Liso-cel) Versus Axicabtagene Ciloleucel (Axi-cel) for Second-line (2L) Treatment of Patients with Refractory/Early Relapsed (R/R) Large B-Cell Lymphoma (LBCL) Jeremy Abramson Poster Presentation #2031 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster I Saturday December 10, 5:30 – 7:30 PM Real-World Treatment Patterns and Costs of Chimeric Antigen Receptor (CAR) T Cell Therapies (CAR T), Polatuzumab Vedotin-piiq (pola), and Tafasitamab-cxix (tafa) in Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Fei Fei Liu Oral Presentation #999 905. Outcomes Research—Lymphoid Malignancies: Health Outcomes in CAR T and Stem Cell Transplantation Monday, December 12, 5:00 PM Results from OUTREACH: A Phase 2 Study of Lisocabtagene Maraleucel (Liso-cel) Administered as Outpatient (Outpt) or Inpatient (Inpt) Treatment in the Community/Nonuniversity Setting in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL) Yuliya Linhares Poster Presentation #4673 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster III Monday, December 12, 6:00 – 8:00 PM Multiple Myeloma Alnuctamab (BMS-986349; CC-93269), a B-cell Maturation Antigen (BCMA) x CD3 2+1 T cell Engager (TCE), in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from a Phase 1 First-in-Human Clinical Study Sandy W. Wong Oral Presentation #162 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Bispecific Monoclonal Antibodies in Myeloma Saturday, December 10, 1:15 PM KarMMa-2 Cohort 2a: Efficacy and Safety of Idecabtagene Vicleucel in Clinical High-risk Multiple Myeloma Patients with Early Relapse After Frontline Autologous Stem Cell Transplantation Saad Usmani Oral Presentation #361 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR T in Multiple Myeloma and T-cell Therapies After Allo-HCT Saturday, December 10, 4:00 PM Clinical Activity of BMS-986393 (CC-95266), a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)–Targeted Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients With Relapsed and/or Refractory (R/R) Multiple Myeloma (MM): First Results From a Phase 1, Multicenter, Open-Label Study Susan Bal Oral Presentation #364 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR T in Multiple Myeloma and T-cell Therapies After Allo-HCT Saturday, December 10, 4:45 PM Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Anti-B-Cell Maturation Antigen (BCMA)-Exposed Cohort of the CC-220-MM-001 Trial Sagar Lonial Poster Presentation #1918 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster I Saturday, December 10, 5:30 – 7:30 PM Results From the First Phase 1 Clinical Study of the B-cell Maturation Antigen (BCMA) NEX-T Chimeric Antigen Receptor (CAR) T Cell Therapy CC-98633/BMS-986354 in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) Luciano Megala Costa Oral Presentation #566 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Novel Drugs and Optimized Approaches in Myeloma Sunday, December 11, 12:15 PM Mezigdomide (CC-92480), a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD), Combined with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Dose-Expansion Phase of the CC-92480-MM-001 Trial Paul Richardson Oral Presentation #568 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Novel Drugs and Optimized Approaches in Myeloma Sunday, December 11, 12:45 PM KarMMa-2 Cohort 2c: Efficacy and Safety of Idecabtagene Vicleucel in Patients with Clinical High-risk Multiple Myeloma due to Inadequate Response to Frontline Autologous Stem Cell Transplantation Madhav Dhodapkar Poster Presentation #3314 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II Sunday, December 11, 6:00 – 8:00 PM Myelodysplastic Syndromes Real-World Outcomes of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated with Luspatercept: an Evaluation of US Clinical Practice Utilization and Treatment Patterns Sudipto Mukherjee Oral Presentation #389 906. Outcomes Research—Myeloid Malignancies I Saturday, December 10, 5:00 PM Multiple Episodes of Transfusion Independence with Luspatercept Treatment and the Impact of Dose Escalation in Patients with Lower-Risk Myelodysplastic Syndromes from the MEDALIST Study Uwe Platzbecker Poster Presentation #3098 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II Sunday, December 11, 6:00 – 8:00 PM Overall Survival and Progression-Free Survival of Patients Following Luspatercept Treatment in the MEDALIST Trial Valeria Santini Poster Presentation #1174 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster I Sunday, December 11, 5:30 – 7:30 PM Myelofibrosis Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial Vikas Gupta Poster Presentation #1711 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I Saturday, December 10, 5:30 – 7:30 PM BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study Rosa Ayala Poster Presentation #4346 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III Monday, December 12, 6:00 – 8:00 PM Bristol Myers Squibb: Creating a Better Future for Cancer Patients Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. BREYANZI U.S. INDICATION Breyanzi is a CD-19 directed chimeric antigen receptor (CAR) T cell therapy, administered as a defined composition to reduce variability of the CD8 and CD4 component dose. Breyanzi has a 4-1BB costimulatory domain which enhances the expansion and persistence of the CAR T cells. Breyanzi was previously approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. Breyanzi is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. Breyanzi is also approved in Europe, Switzerland, Canada and Japan for relapsed and refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphoma. For more information, visit clinicaltrials.gov. IMPORTANT SAFETY INFORMATION BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed. BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. Cytokine Release Syndrome Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Among patients receiving BREYANZI for LBCL (N=418), CRS occur in 46% (190/418) of patients, including ≥ Grade 3 CRS (Lee grading system) in 3.1% of patients. In patients receiving BREYANZI after two or more lines of therapy for LBCL, CRS occurred in 46% (122/268), including ≥ Grade 3 CRS in 4.1% of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 98% with a median duration of 5 days (range: 1 to 17 days). In patients receiving BREYANZI after one line of therapy for LBCL, CRS occurred in 45% (68/150), including Grade 3 CRS in 1.3% of patients. The median time to onset was 4 days (range: 1 to 63 days). CRS resolved in all patients with a median duration of 4 days (range: 1 to 16 days). The most common manifestations of CRS (≥10%) included fever (94%), hypotension (42%), tachycardia (28%), chills (23%), hypoxia (16%), and headache (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Of the 418 patients who received BREYANZI for LBCL, 23% received tocilizumab and/or a corticosteroid for CRS, including 10% who received tocilizumab only and 2.2% who received corticosteroids only. Neurologic Toxicities Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred. In patients receiving BREYANZI after two or more lines of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 35% (95/268), including ≥ Grade 3 in 12% of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of neurotoxicity was 8 days (range: 1 to 46 days). Neurologic toxicities resolved in 85% with a median duration of 12 days (range: 1 to 87 days). In patients receiving BREYANZI after one line of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 27% (41/150) of patients, including Grade 3 cases in 7% of patients. The median time to onset of neurologic toxicities was 8 days (range: 1 to 63 days). The median duration of neurologic toxicity was 6 days (range: 1 to 119 days). In all patients combined receiving BREYANZI for LBCL, neurologic toxicities occurred in 33% (136/418), including ≥ Grade 3 cases in 10% of patients. The median time to onset was 8 days (range: 1 to 63), with 87% of cases developing by 16 days. Neurologic toxicities resolved in 85% of patients with a median duration of 11 days (range: 1 to 119 days). Of patients developing neurotoxicity, 77% (105/136) also developed CRS. The most common neurologic toxicities (≥ 5%) included encephalopathy (20%), tremor (13%), aphasia (8%), headache (6%), dizziness (6%), and delirium (5%). CRS and Neurologic Toxicities Monitoring Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. BREYANZI REMS Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are: Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities. Further information is available at or contact Bristol-Myers Squibb at 1-888-423-5436. Hypersensitivity Reactions Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO). Serious Infections Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In patients receiving BREYANZI for LBCL, infections of any grade occurred in 36% with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections occurred in 4.3%, viral infections in 1.9% and fungal infections in 0.5%. Febrile neutropenia developed after BREYANZI infusion in 8% of patients with LBCL. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant active systemic infections. Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In patients who received BREYANZI for LBCL, 15 of the 16 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines. Prolonged Cytopenias Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 36% of patients with LBCL, and included thrombocytopenia in 28%, neutropenia in 21%, and anemia in 6%. Monitor complete blood counts prior to and after BREYANZI administration. Hypogammaglobulinemia B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. In patients receiving BREYANZI for LBCL, hypogammaglobulinemia was reported as an adverse reaction in 11% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 28% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated. Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI. Secondary Malignancies Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing. Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks. Adverse Reactions The most common nonlaboratory adverse reactions (incidence ≥ 30%) are fever, CRS, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, hemoglobin decrease. Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide. ABECMA U.S. INDICATION ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. IMPORTANT SAFETY INFORMATION BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed. Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities. Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA. ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA. Grade 3 or higher CRS (Lee grading system) occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 - 23 days) and the median duration of CRS was 7 days (range: 1 - 63 days) in all patients including the patient who died. The most common manifestations of CRS included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome and HLH/MAS. Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Fifty four percent (68/127) of patients received tocilizumab; 35% (45/127) received a single dose while 18% (23/127) received more than 1 dose of tocilizumab. Overall, across the dose levels, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Overall rate of CRS was 79% and rate of Grade 2 CRS was 23% in patients treated in the 300 x 106 CAR+ T cell dose cohort. For patients treated in the 450 x 106 CAR+ T cell dose cohort, the overall rate of CRS was 96% and rate of Grade 2 CRS was 40%. Rate of Grade 3 or higher CRS was similar across the dose range. The median duration of CRS for the 450 x 106 CAR+ T cell dose cohort was 7 days (range: 1-63 days) and for the 300 x 106 CAR+ T cell dose cohort was 6 days (range: 2-28 days). In the 450 x 106 CAR+ T cell dose cohort, 68% (36/53) of patients received tocilizumab and 23% (12/53) received at least 1 dose of corticosteroids for treatment of CRS. In the 300 x 106 CAR+ T cell dose cohort, 44% (31/70) of patients received tocilizumab and 10% (7/70) received corticosteroids. All patients that received corticosteroids for CRS also received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. CAR T cell-associated neurotoxicity occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 - 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median duration of neurotoxicity was 5 days (range: 1 - 61 days). The median duration of neurotoxicity was 6 days (range: 1 - 578) in all patients including those with ongoing neurotoxicity at the time of death or data cut off. Thirty-four patients with neurotoxicity had CRS. Neurotoxicity had onset in 3 patients before, 29 patients during, and 2 patients after CRS. The rate of Grade 3 neurotoxicity was 8% in the 450 x 106 CAR+ T cell dose cohort and 1.4% in the 300 x 106 CAR+ T cell dose cohort. The most frequently reported (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%). Grade 4 neurotoxicity and cerebral edema in 1 patient has been reported with ABECMA in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have been reported after treatment with ABECMA in another study in multiple myeloma. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time. Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient treated in the 300 x 106 CAR+ T cell dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. The rate of HLH/MAS was 8% in the 450 x 106 CAR+ T cell dose cohort and 1% in the 300 x 106 CAR+ T cell dose cohort. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4-9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards. ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at or 18884235436. Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA. Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, preemptive, and/or therapeutic antimicrobials according to standard institutional guidelines. Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. Viral Reactivation: Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing. Prolonged Cytopenias: Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In the KarMMa study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. Rate of prolonged neutropenia was 49% in the 450 x 106 CAR+ T cell dose cohort and 34% in the 300 x 106 CAR+ T cell dose cohort. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Median time to cytopenia recovery was similar across the 300 and 450 x 106 dose cohort. Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to institutional guidelines. Hypogammaglobulinemia: Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA. Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA. Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin. Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite. Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide. REBLOZYL U.S. INDICATION Reblozyl, a first-in-class therapeutic option, promotes late-stage red blood cell maturation in animal models. Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. Reblozyl is currently approved in the U.S. for the treatment of: anemia in adult patients with beta thalassemia who require regular red blood cell transfusions, and anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). Reblozyl is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia. U.S. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thrombosis/Thromboembolism In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly. Hypertension Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents. Extramedullary Hematopoietic Masses In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study). In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double- blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia. Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses. Embryo-Fetal Toxicity REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post- implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose. ADVERSE REACTIONS Beta Thalassemia Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML). Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%). Myelodysplastic Syndromes Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients. The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. LACTATION It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose. Please see full Prescribing Information for REBLOZYL. INREBIC U.S. INDICATION INREBIC® (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). U.S. IMPORTANT SAFETY INFORMATION WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. WARNINGS AND PRECAUTIONS Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. Anemia: New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent. Thrombocytopenia: New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated. Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed. Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC. Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. ADVERSE REACTIONS:The most common adverse reactions for INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%). DRUG INTERACTIONS: Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC. PREGNANCY/LACTATION: Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose. RENAL IMPAIRMENT: Reduce INREBIC dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions. HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with severe hepatic impairment. Please see full Prescribing Information, including Boxed WARNING, and Summary of Product Characteristics for INREBIC. ONUREG U.S. INDICATION ONUREG® (azacitidine tablets) is approved in the U.S. for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. U.S. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components. WARNINGS AND PRECAUTIONS Risks of Substitution with Other Azacitidine Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment with ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG for intravenous or subcutaneous azacitidine. Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs. Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS): In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG or placebo. 107 received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG for MDS have not been established. Treatment of MDS with ONUREG is not recommended outside of controlled trials. Embryo-Fetal Toxicity: ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose. ADVERSE REACTIONS Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG. Most common (≥10%) adverse reactions with ONUREG vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%). LACTATION There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose Please see full Prescribing Information for ONUREG. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results will be consistent with the results to date, that the product candidates described in this release may not receive regulatory approval for the indications described in this release and, if approved, whether such product candidates for such indications will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2021, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. 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2022 年，城市仍然在沉重地呼吸着，一眼望去皆是看不到头的蓝色口罩，但在这张看不见的网背后，无数科研工作者、药物研发企业却在突破阻隔前行。自 20 世纪 80 年代以来，基因组学、蛋白组学、表观遗传学以及肿瘤免疫学等基础科学研究不断深入，下一代基因组测序技术迅猛发展，近十年来，靶向药迅速成为肿瘤治疗界的「新宠」。1997 年 FDA 批准利妥昔单抗上市，用于治疗非霍奇金淋巴瘤，正式拉开了肿瘤靶向治疗的序幕；2001 年第一个小分子靶向药物甲磺酸伊马替尼上市，用于治疗慢性粒细胞性白血病，开创了以酪氨酸激酶为靶点药物的先河；2019 年，Fedratinib 作为 FDA 批准的继芦可替尼（ruxolitinib）后第 2 款治疗骨髓纤维化治疗药物，在肿瘤靶向药物史上，画上了浓墨重彩的一笔，但其上市旅程不可谓不曲折。它就是今日文章的主角。因骨髓纤维化诞生，曾受巨头看好，却命途多舛故事起源于 2006 年。TargeGen 公司在 John Hood 博士作为主要研发负责人的带领下开始研究用于治疗骨髓增殖性肿瘤（MPNs）的药物，发现了多款小分子激酶抑制剂，其中就包括 JAK2 抑制剂 fedratinib。作为一种缩短生命的克隆性疾病，MF（Myelofibrosis，骨髓纤维化）呈现出一系列特征：骨髓纤维化、血细胞计数异常、髓外造血、脾脏肿大、血栓出血性并发症和宪法症状。在 MF 患者中，JAK2、CALR 和 MPL 的突变分别约占 60%、20% 和 10%。我们可以看到 JAK2 突变比例居于首位。Fedratinib 作为一款小分子 JAK2 抑制剂自诞生以来，在接续的临床试验中释放出优秀的治疗能力，改善了许多患者的生存水平。基于 TG101348（fedratinib）在多种临床适应症中的潜力，2010 年 6 月，赛诺菲（Sanofi）收购了 TargeGen 公司。赛诺菲随后赞助了更多的临床研究，包括在中危-2/高危 MF 患者中进行的 289 名患者的关键性 III 期试验（JAKARTA）。此前 Fedratinib 已经完成了一项针对骨髓纤维化患者的多中心临床 1/2 阶段试验。除了骨髓纤维化，Fedratinib 对其他各种血液学恶性肿瘤也可能有效，例如多血症（PV）。Fedratinib 适应症开发来自：Insight 数据库（http://db.dxy.cn/v5/home/）随后，2013 年 5 月 17 日，赛诺菲宣布，在骨髓纤维化患者中开展的有关选择性 JAK2 抑制剂 SAR302503（fedratinib）的关键性 III 期 JAKARTA 临床研究，各剂量组均达到了研究的主要终点。该项研究的主要终点是评价脾脏体积减小≥35% 的患者比例。JAKARTA 试验结果来自：Insight 数据库基于强有力的后期临床研究数据，赛诺菲与美国和欧洲当局举行了监管会议，预计将提交新药申请和上市许可申请。在 TargeGen 或赛诺菲赞助的 18 项临床试验中，总计有 877 名受试者接受了 fedratinib 治疗，一些参加 1 期试验的患者此时已服药超过 5 年。但正路并不一定就是一条平坦的直路，难免有些曲折和崎岖险阻，更绕一些弯。2013 年 11 月，赛诺菲向 FDA 通报了所有研究中的 8 名受试者，他们在接受 fedratinib 治疗后出现了提示韦尼克脑病（WE）的神经系统症状，一种由硫胺素营养不良引起的神经系统疾病。这是一种风险极高的罕见神经疾病，往往与维生素 B1 缺乏相关，患者大脑内的多个部分会出现病变，带来共济失调、精神异常等神经系统功能障碍。作为回应，FDA 暂停了该临床试验的进行。经过一项彻底的风险-效益（risk-benefit）分析，包括与 FDA、研究人员、独立的神经学专家和神经放射科医师的讨论，赛诺菲确定，fedratinib 带给患者的安全性风险，超过了该药可能带来的临床益处。2013 年 11 月 18 日，赛诺菲宣布将停止有关实验性 JAK2 抑制剂 fedratinib（SAR302503）的所有临床试验，同时取消提交相关监管申请的计划。图片来源：站酷海洛同一赛道上，其他 MF 治疗药物却传出一阵阵紧锣密鼓的喧响。首先是 2011 年由 Incyte 与 Novartis 公司联合研发的 Jakafi®（ruxolitinib）在美国批准上市，Jakafi® 是抗骨纤维化的 JAK1 与 JAK2 激酶抑制剂，适用于治疗中度或高危骨髓纤维化，包括原发性骨髓纤维化、后真性红细胞增多症骨髓纤维化和原发性血小板增多症骨髓纤维化等。紧接着，2014 年 8 月，百特国际（Baxter International）和合作伙伴 CTI 生物制药公司联合宣布，FDA 已授予 pacritinib 快车道地位，用于治疗中危及高危骨髓纤维化，包括但不限于伴有血小板减少症的患者、正经历其他 JAK2 疗法出现血小板减少症的患者、以及对其他 JAK2 疗法不耐受或其症状经其他 JAK2 疗法管理不佳的患者。在困局中寻突破，于艰难处觅新机由于赛诺菲终止临床试验，停用了 fedratinib 的一些患者病情恶化甚至死亡，一方面，其他患者不得不重新寻找新的治疗方法；另一方面，无数医生与患者请求继续提供 fedratinib。患者的需求是每一位新药研发工作者的重要动力。2016 年 3 月，Fedratinib 最初的主要研究者 Hood 博士成立了 Impact Biomedicines 公司，从赛诺菲取回了 fedratinib 的开发权利。Fedratinib 相关医药交易来自：Insight 数据库Impact 通过研究患者出现韦尼克脑病的数据发现，后续临床中可以通过补充维生素 B1 避免类似副作用的发生。在临床审查发现大部分相关受试者出现恶病质或其他系统性营养挑战后，FDA 同意解除对 fedratinib 的临床搁置。至此，fedratinib 开始重新踏上征程。对被解除临床搁置的 fedratinib 而言，引发相关领域头部企业的高度兴趣并不令人惊讶。2017 年 10 月 13 日，Impact 获得了 2200 万美元的投资。仅在 2 周后，Impact 宣布，当轮融资一共获得了 9000 万美元。2018 年 1 月，新基医药收购 Impact Biomedicines，获得 fedratinib 的所有权利，并于 2018 年底在美国进行了上市申报。后续随着新基被 BMS 收购，Fedratinib 从最初赛诺菲转到了另一巨头 BMS 手中。很快，2019 年 3 月，FDA 对 fedratinib 用于治疗骨髓纤维化患者的上市申请给予了优先审查，将目标行动日期定为 9 月 3 日。该优先审查的批准是基于 III 期临床试验 JAKARTA 在原发性或继发性骨髓纤维化患者中的数据支持。结果显示，与安慰剂相比，fedratinib 将 47％ 患者的脾脏大小在 24 周时减少 35％，同时 36％ 患者的症状评分改善至少 50％，达到了临床试验的主要和次要终点。同年 8 月 16 日，FDA 批准菲卓替尼（fedratinib）（商品名：Inrebic®）用于治疗中度-2 或高危原发性或继发性（真性红细胞增多症后或原发性血小板增多症后）骨髓纤维化（MF）成人患者。不过同时 fedratinib 的药品标签上也仍然带有黑框警告，提示严重和致命性脑病（包括韦尼克脑病）的风险：在 INREBIC 治疗的患者中发生了严重和致命的脑病，包括 Wernicke 脑病。在临床试验中，有 1.3%（8/608）接受 INREBIC 治疗的患者报告了严重病例，0.16%（1/608）的病例是致命的。2021 年 2 月 8 日，欧盟委员会（EC）授予 Inrebic®（fedratinib）完全上市许可，用于原发性骨髓纤维化、真性红细胞增多症后骨髓纤维化、原发性血小板增多症骨髓纤维化成人患者，治疗疾病相关脾肿大（脾脏增大）或症状，包括没有接受过 JAK 抑制剂的患者（JAK 抑制剂初治患者）和曾接受过诺华/Incyte 公司口服 JAK1/JAK2 抑制剂 Jakavi®/Jakafi®（Ruxolitinib）芦可替尼/鲁索替尼治疗的患者（JAK 抑制剂经治患者）。Fedratinib 研发关键节点来自：Insight 数据库自此，Fedratinib 成为近 10 年来欧洲第一款治疗骨髓纤维化的新疗法，同时也将是第一款在 ruxolitinib 治疗失败、对 ruxolitinib 不耐受的或 JAK 抑制剂初治的骨髓纤维化患者中显著减少脾脏体积和症状负担的每日一次口服疗法。百尺竿头须进步，十方世界是全身虽然 fedratinib 已在美国和欧盟获批上市，但正所谓「不进则退」，随着医药行业的激烈变化，各治疗领域竞争呈现白热化态势，创新药物研发重地的癌症治疗领域持续保持热度，MF 治疗药物领域更不会例外。一是芦可替尼的市场拓展仍在加速。作为首款抗骨纤维化药物，芦可替尼的前进脚步从未停止。以中国境内来说，2017 年 3 月，芦可替尼通过优先审评程序获国家药监局批准上市，扎根中国市场。不仅如此，2022 年 5 月 27 日其新适应症上市申请获 CDE 受理。芦可替尼国内适应症获批情况来自：Insight 数据库国内仿制药企业也在瞄准时机，2022 年 7 月 14 日，CDE 官网显示，南京正大天晴递交的 4 类化药磷酸芦可替尼片上市申请获受理。这是首家报产该品种的本土药企，大概率有望取得该品种首仿。对于 ruxolitinib，乃至 fedratinib 都是强有力的竞争对手。二是 pacritinib 正在迎头赶上。伴有重度血小板减少的骨髓纤维化患者，治疗选择有限。如果减少芦可替尼的剂量，会导致患者的临床获益降低；而停药反而导致患者的生存期进一步降低，平均总生存期（OS）为 7~14 个月，因此产生了一个重要的医疗需求未得到满足的治疗领域。应运而生的就是 pacritinib，它能够特异性抑制 JAK2、IRAK1 和 CSF1R，但并不抑制 JAK1 的活性，避免了抑制 JAK1 带来的潜在副作用。2022 年 2 月 28 日（西雅图）CTI BioPharma Corp. 宣布 FDA 已批准 VONJO®（pacritinib）用于治疗患有中度或高危原发性的成人或继发性（真性红细胞增多症或原发性血小板增多症后）骨髓纤维化，其血小板计数低于 50×109/L。VONJO®成为第 1 个专门针对细胞减少性骨髓纤维化患者需求的获批疗法。公司财报显示，2022 第二季度 VONJO®的产品净收入为 1230 万美元。总的来说，JAK 抑制剂的应用，极大改善了 MF 患者的生活质量，但是对 MF 新型治疗策略的探索从未停止。目前，同种异体造血干细胞移植（AHSCT）治疗是 MF 患者唯一的治愈性选择。然而，由于发病率和死亡率高，AHSCT 受到严格限制，ruxolitinib 是对有脾脏肿大和宪法症状的中危-2 或高风险 MF 患者的一线治疗，但大多数 MF 患者对 ruxolitinib 产生耐药性或不耐受，MF 治疗仍是医学界的一个挑战。现阶段，MF 治疗主要集中于 3 个研究方向：JAK 抑制剂的单药治疗、非 JAK 靶向药物的单药治疗、ruxolitinib 和其他药物的联合治疗。研究旨在解决未满足的医疗需求，例如贫血和血小板减少、MF 进展为急性髓性白血病（AML）、ruxolitinib 治疗反应不佳或耐药以及与以上情况相关而表现出总生存期较短的问题。在 MF 领域，包括艾伯维（AbbVie）的口服 BCL-XL/BCL-2 抑制剂 navitoclax、MorphoSys 公司的靶向表观遗传学「reader」蛋白 BET 的潜在「first-in-class」靶向疗法 pelabresib、强生公司的端粒酶抑制剂 Imetelstat 等药物的临床研究正在如火如荼进行，这些研究有望改变当前 MF 的治疗格局，带来新生与变革。而对于 fedratinib 而言，上市不是终点，而是起点。对于 MF 疾病治疗策略的探索，可能费工费时，可能曲折坎坷，也可能会有失误，甚至失败，但也唯有探索才能前进，才能破茧重生。参考资料1. Christian Schindler , Inga Strehlow . Cytokines and STAT Signaling . Advances in Pharmacology . 1999 ; 47 : 113-174.2. Therapeutic potential of JAK2 inhibitors . Hematology Am Soc Hematol Educ Program (2009) 2009 (1): 636-642.3. Yiming Luo MD , Madison Alexander BA , Massimo Gadina PhD , et al . JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition . Journal of Allergy and Clinical Immunology . 2021 ; 4(148) : 911-925 . 4. Ann Mullally , John Hood , Claire Harrison , Ruben Mesa . Fedratinib in myelofibrosis . Blood Advances . 2020 ; 8(4) : 1792-1800 . 5. FDA grants priority review to filing for Celgene's JAK2 inhibitor fedratinib in myelofibrosis , March 06, 2019. 6. GSK completes acquisition of Sierra Oncology , 1 July 2022, London UK . 7. Health Canada Approves INREBIC® (fedratinib) , First New Treatment in Nearly a Decade for Patients Living with Myelofibrosis , Oncology , 21/09/20 . 8. Fuping Wang , Tian Qiu , Haitao Wang , Qiong Yang . State-of-the-Art Review on Myelofibrosis Therapies . Clinical Lymphoma Myeloma and Leukemia . 2022 ; 5(22) : 350-362. 9. US FDA accepts new drug application for GSK’s momelotinib for the treatment of myelofibrosis , 17 August 2022 . 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：加一PR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn点击卡片进入 Insight 小程序全球新药管线随时随地查！↓↓ 点击解锁更多新功能