On November 4, 2021 Bristol Myers Squibb (NYSE: BMY) reported the presentation of research across a wide range of hematologic diseases at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, which will take place in Atlanta, Georgia, and virtually, from December 11 to 14, 2021 (Press release, Bristol-Myers Squibb, NOV 4, 2021, View Source [SID1234594403]). Data from more than 80 company-sponsored studies will be featured, including 23 oral presentations, highlighting key research and development programs in lymphomas, leukemias, multiple myeloma and myeloid diseases, and showcasing our commitment to delivering transformative medicines across major hematologic diseases.
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Key data being presented by Bristol Myers Squibb and its partners at the 2021 ASH (Free ASH Whitepaper) Annual Meeting and Exposition include:
First presentation of results from pivotal Phase 3 TRANSFORM study evaluating CD19-directed chimeric antigen receptor (CAR) T cell therapy Breyanzi (lisocabtagene maraleucel) head-to-head against the current standard of care treatment approach for second-line relapsed or refractory (R/R) large B-cell lymphoma (LBCL)
Two-year follow-up data from the pivotal TRANSCEND NHL 001 study of Breyanziin third-line and later R/R LBCL
First clinical results for anti-SIRPα antibody CC-95251 plus rituximab, as well as first clinical results for CELMoD CC-99282, both in patients with R/R non-Hodgkin’s lymphoma
First disclosure of safety and efficacy results from dose expansion of the MM-001 study evaluating CELMoD iberdomide in combination with dexamethasone in patients with R/R multiple myeloma
First disclosure of preliminary results from the Phase 1/2 MM-002 study of CELMoD CC-92480 in combination with dexamethasone and bortezomib in patients with R/R multiple myeloma
Further analyses from the pivotal KarMMa trial in R/R multiple myeloma evaluated baseline predictors of complete responses and outcomes for patients treated with subsequent anti-myeloma therapies, including alternative B-cell maturation antigen (BCMA)-directed therapies, after treatment with Abecma (idecabtagene vicleucel),the first-in-class BCMA-directed CAR T cell therapy
Abstracts highlighting multiple Bristol Myers Squibb’s therapies in hard-to-treat myeloid diseases, including longer-term data and analyses of different acute myeloid leukemia subtypes and baseline characteristics with Onureg (azacitidine tablets) from the Phase 3 QUAZAR AML-001 study and safety with Inrebic(fedratinib) from the Phase 3b FREEDOM trial in myelofibrosis
Updated analyses of Reblozyl (luspatercept-aamt) from the Phase 2 BEYOND study in beta thalassemia and from the Phase 3 MEDALIST study in lower-risk myelodysplastic syndromes
"Our presence at ASH (Free ASH Whitepaper) continues our longstanding commitment to hematology and underscores the potential of our innovative research platforms to deliver meaningful, new treatment options for people with unmet needs living with hematologic diseases," said Samit Hirawat, M.D., executive vice president, chief medical officer, global drug development, Bristol Myers Squibb. "These data reinforce our progress in advancing transformative research across a wide range of hematologic malignancies including multiple myeloma, lymphoma, and myeloid diseases."
Selected Bristol Myers Squibb studies at the 63rd ASH (Free ASH Whitepaper) Annual Meeting and Exposition include:
Abstract Title
Author
Presentation Type/#
Session Title
Session Date/Time
Acute Myeloid Leukemia
Prognostic Impact of NPM1 and FLT3 Mutations at Diagnosis and Presence of Measurable Residual Disease (MRD) after Intensive Chemotherapy (IC) for Patients with Acute Myeloid Leukemia (AML) in Remission: Outcomes from the QUAZAR AML-001 Trial of Oral Azacitidine (Oral-AZA) Maintenance
Hartmut Döhner
Oral
Abstract #804
617. Acute Myeloid Leukemia: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: New options of risk assessment and prediction of therapy response in AML
Monday, December 13,
5:45 PM
Long-term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial
Andrew Wei
Oral
Abstract #871
615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Updates in treatment for high-risk AML
Monday, December 13,
6:15 PM
Beta Thalassemia
Luspatercept Redistributes Body Iron to the Liver in Transfusion-Dependent-Thalassemia (TDT) During Erythropoietic Response
Maciej Garbowski
Oral Abstract
#761
102. Iron Homeostasis and Biology: Disorders of Iron and Heme and Novel Treatments
Monday, December 13,
5:30 PM
Luspatercept Improves Health-Related Quality of Life (HRQoL) Symptoms and RBC Transfusion Burden in Patients with Non-Transfusion-Dependent β-thalassemia (NTDT) in the BEYOND Trial
Antonis Kattamis
Poster Abstract #3081
112. Thalassemia and Globin Gene Regulation: Poster III
Monday, December 13,
6:00 – 8:00 PM
Graft vs. Host Disease
Overall Survival of Patients Treated with Abatacept in Combination with a Calcineurin Inhibitor and Methotrexate After Allogeneic Hematopoietic Stem Cell Transplantation – Analysis of the Center for International Blood and Marrow Transplant Research Database
Leslie Kean
Poster Abstract #3912
722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III
Monday, December 13, 6:00 – 8:00 PM
Lymphoma
Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed by Autologous Stem Cell Transplantation (ASCT) as Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 TRANSFORM Study
Manali Kamdar
Oral Abstract
#91
704. Cellular Immunotherapies: Cellular Therapies for Lymphomas
Saturday, December 11,
9:30 AM
Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy
Veronika
Bachanova
Oral Abstract
#230
624. Hodgkin Lymphomas and T/NK cell Lymphomas: Hodgkin Lymphoma Clinical Trials
Hematology Disease Topics & Pathways:
Clinical Trials
Saturday, December 11, 2:15 PM
Nivolumab First-Line Therapy for Elderly Hodgkin Lymphoma Patients: a LYSA Phase II Study
Julien Lazarovici
Oral Abstract
#232
624. Hodgkin Lymphomas and T/NK cell Lymphomas: Hodgkin Lymphoma Clinical Trials
Saturday, December 11, 2:45 PM
OUTREACH: Results from a Phase 2 Study of Lisocabtagene Maraleucel (liso-cel) Administered as Inpatient (Inpt) or Outpatient (Outpt) Treatment in the Nonuniversity Setting in Patients (Pts) with R/R Large B-Cell Lymphoma (LBCL)
John Godwin
Poster Abstract
#1762
704. Cellular Immunotherapies: Clinical: Poster I
Saturday, December 11,
5:30 – 7:30 PM
Six-Year Results from the Phase 3 Randomized Study Relevance Show Similar Outcomes for Previously Untreated Follicular Lymphoma Patients Receiving Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed By Rituximab Maintenance
Franck Morschhauser
Poster Abstract
#2417
623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Sunday, December 12,
6:00 – 8:00 PM
Differential Effects of Iberdomide Versus Revlimid on Leukocyte Trafficking, Immune Activation and DLBCL Tumor Cell Killing
Yumi Nakayama
Oral Abstract
#718
622. Lymphomas: Translational-Non-Genetic: Lymphoma biology
Monday, December 13,
3:30 PM
Completed Induction Phase Analysis of MAGNIFY: Phase 3b Study of Lenalidomide + Rituximab (R2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Frederick
Lansigan
Oral Abstract
#812
623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Follicular Lymphoma: Advances in Treatment Approaches
Monday, December 13,
4:45 PM
Discovery and Preclinical Characterization of CC-95251, an Anti-SIRPa Antibody that Enhances Macrophage-Mediated Phagocytosis of Non-Hodgkin Lymphoma (NHL) Cells when Combined with Rituximab
Henry Chan
Poster Abstract
#2271
605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Monday, December 13,
6:00 – 8:00 PM
Characteristics of Post-Infusion Chimeric Antigen Receptor (CAR) T Cells and Endogenous T Cells Associated with Early and Long-term Response in Lisocabtagene Maraleucel (liso-cel)–Treated Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)
Jerill Thorpe
Poster Abstract
#2417
704. Cellular Immunotherapies: Clinical: Poster III
Monday, December 13,
6:00 – 8:00 PM
Two-Year Follow-up of TRANSCEND NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed or Refractory (R/R) Large B-Cell Lymphomas (LBCL)
Jeremy Abramson
Poster Abstract
#2840
704. Cellular Immunotherapies: Clinical: Poster III
Monday, December 13,
6:00 – 8:00 PM
Cost-effectiveness of Liso-cel versus Axi-cel for Treatment of Relapsed or Refractory Large B-Cell Lymphoma
Christopher Parker
Poster Abstract
#3003
902. Health Services Research—Lymphoid Malignancies: Poster II
Monday, December 13,
6:00 – 8:00 PM
Clinical Activity of CC-99282, a Novel, Oral Small Molecule Cereblon E3 Ligase Modulator (CELMoD) Agent, in Patients (Pts) with Relapsed or Refractory Non-Hodgkin Lymphoma (R/R NHL) – First Results from a Phase 1, Open-Label Study
Jean-Marie Michot
Poster Abstract
#3574
626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster III
Monday, December 13,
6:00 – 8:00 PM
Multiple Myeloma
Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Dose-Expansion Phase of the CC-220-MM-001 Trial
Sagar Lonial
Oral Abstract #162
653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Novel Targets and Amyloid
Saturday, December 11, 1:15 PM
Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the CONNECT Multiple Myeloma (MM) Disease Registry
Sundar Jagannath
Oral Abstract
#117
905. Outcomes Research- Lymphoid Malignancies: Multiple Myeloma and Other Plasma Cell Disorders
Saturday, December 11,
10:00 AM
Baseline Correlates of Complete Response to Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy in Patients with Relapsed and Refractory Multiple Myeloma: Subanalysis of the KarMMa Trial
Nina Shah
Poster Abstract
#1739
704. Cellular Immunotherapies: Clinical: Poster I
Saturday, December 11 5:30 – 7:30 PM
Matching-Adjusted Indirect Comparisons of Efficacy Outcomes in Patients with Relapsed and Refractory Multiple Myeloma for Idecabtagene Vicleucel (KarMMa) vs. Selinexor Plus Dexamethasone (STORM Part 2) and Belantamab Mafodontin (DREAMM-2): Updated Analysis with Longer Follow-up
Paula Rodriguez-Otero
Poster Abstract
#1978
905. Outcomes Research—Lymphoid Malignancies: Poster I
Saturday, December 11,
5:30 – 7:30 PM
Updated Clinical and Correlative Results From the Phase I CRB-402 Study of the BCMA-Targeted CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma
Noopur Raje
Oral Abstract #548
Cellular Immunotherapies: Cellular Therapies for Myeloma
Sunday, December 12
4:45 PM
CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002
Paul Richardson
Poster Abstract
#2731
653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Sunday, December 12
6:00 – 8:00 PM
Subsequent Anti-myeloma Therapy after Idecabtagene Vicleucel (Ide-cel, bb2121) Treatment in Patients with Relapsed/Refractory Multiple Myeloma from the KarMMa Study
Paula Rodriguez-Otero
Poster Abstract
#2743
653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Sunday, December 12 6:00 – 8:00 PM
Updated Health-Related Quality of Life Results from the KarMMa Clinical Study in Patients with Relapsed and Refractory Multiple Myeloma Treated with the B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Idecabtagene Vicleucel (ide-cel, bb2121)
Michel Delforge
Poster Abstract
#2835
704. Cellular Immunotherapies: Clinical: Poster II
Sunday, December 12, 6:00 – 8:00 PM
Idecabtagene Vicleucel (ide-cel, bb2121), a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy: Qualitative Analyses of Post-Treatment Interviews (Months 6–24) for Patients with Relapsed and Refractory Multiple Myeloma in the KarMMa Clinical Trial
Nina Shah
Poster Abstract
#3041
Session Name: 905. Outcomes Research—Lymphoid Malignancies: Poster II
Sunday, December 12 6:00 – 8:00 PM
Large-Scale Mass Cytometry Reveals Significant Activation of Innate and Adaptive Immunity in Bone Marrow Tumor Microenvironment of Iberdomide-Treated Myeloma Patients
Oliver Van Oekelen
Oral Abstract
#730
651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: The Myeloma Immune Microenvironment
Monday, December 13, 3:30 PM
Myelodysplastic Syndrome
Treatment Duration and Exposure Adjusted Safety Analysis in the MEDALIST Study (luspatercept)
Uwe Platzbecker
Poster Abstract
#1524
637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster I
Saturday, December 11 5:30 – 7:30 PM
Myelofibrosis
Safety and Tolerability of Fedratinib, an Oral Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate- or High-risk Myelofibrosis (MF) Previously Treated with Ruxolitinib: Results from the Phase 3b FREEDOM Trial
Vikas Gupta
Oral Abstract
#389
634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Sunday, December 12, 10:30 AM
Spleen and Symptom Responses with Fedratinib (FEDR) Patients with Myelofibrosis (MF) and Substantial Splenomegaly
Jean‐Jacques Kiladjian
Poster Abstract
#2576
634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II
Sunday, 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
Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T cell therapy with a defined composition and 4-1BB costimulatory domain. Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose. The 4-1BB signaling domain enhances the expansion and persistence of the CAR T cells.
Indications
Breyanzi is approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma 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 also approved in Japan for the treatment of patients with R/R LBCL and follicular lymphoma.
U.S. 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 (CRS)
CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) 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 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.
Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). 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. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.
Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients.
Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.
The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.
CRS and Neurologic Toxicities Monitoring
Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
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 www.BreyanziREMS.com, 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. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI 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.
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. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
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 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) 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 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, during this initial period.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.
The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.
ABECMA Indications
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 availableat www.AbecmaREMS.com 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.
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
REBLOZYL Indication
REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions
REBLOZYL is indicated for the treatment of 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 syndromes 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 RBC transfusions in patients who require immediate correction of anemia
Important Safety Information
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) 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.
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.