Literature Scan
with wild-type patients ( HR = 2.2 ; 95 % CI 1.5-3.2 ; p < 0.001 ).
“ Surprisingly , monoallelic TP53 patients did not differ from TP53 wild-type patients with regard to response to therapy , OS , and AML progression ,” the researchers observed . “ The shift in survival for monoallelic patients with the number of co-mutations indicates diversity of disease pathogenesis and highlights the need for future prognostic models that consider a large spectrum of gene mutations .”
The authors concluded “ that biallelic TP53 should be distinguished from monoallelic TP53 mutations in future [ editions ] of Revised International Prognostic Scoring System and in correlative studies of treatment response .” And , since TP53 tends to be “ the most frequently mutated gene in cancer , the representation and effect of TP53 allelic state warrant investigation across cancer indications ,” they added .
Study authors report relationships with Celgene and the MDS Foundation .
Reference Bernard E , Nannya Y , Hasserjian RP , et al . Implications of TP53 allelic state for genome stability , clinical presentation and outcomes in myelodysplastic syndromes . Nat Med . 2020 ; 26:1549-1556 .
TECARTUS™ ( brexucabtagene autoleucel ) suspension for intravenous infusion
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION . See full Prescribing Information . Rx only .
WARNING : CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
• Cytokine Release Syndrome ( CRS ), including life-threatening reactions , occurred in patients receiving TECARTUS . Do not administer TECARTUS to patients with active infection or inflammatory disorders . Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids .
• Neurologic toxicities , including life-threatening reactions , occurred in patients receiving TECARTUS , including concurrently with CRS or after CRS resolution . Monitor for neurologic toxicities after treatment with TECARTUS . Provide supportive care and / or corticosteroids as needed .
• TECARTUS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the YESCARTA and TECARTUS REMS Program .
INDICATIONS AND USAGE TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma ( MCL ).
This indication is approved under accelerated approval based on overall response rate and durability of response . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial .
DOSAGE AND ADMINISTRATION
Administration : TECARTUS is for autologous use only . The patient ’ s identity must match the patient identifiers on the TECARTUS cassette and infusion bag . Do not infuse TECARTUS if the information on the patient-specific label does not match the intended patient .
Preparing Patient for TECARTUS Infusion : Confirm availability of TECARTUS prior to starting the lymphodepleting chemotherapy regimen . Pre-treatment : Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg / m 2 intravenously and fludarabine 30 mg / m 2 intravenously on each of the fifth , fourth , and third days before infusion of TECARTUS . Premedication : Premedicate with acetaminophen and diphenhydramine or another H1- antihistamine approximately 30 to 60 minutes prior to TECARTUS infusion . Avoid prophylactic use of systemic corticosteroids as it may interfere with the activity of TECARTUS .
Preparation of TECARTUS for Infusion : Coordinate the timing of TECARTUS thaw and infusion . Confirm the infusion time in advance , and adjust the start time of TECARTUS thaw such that TECARTUS will be available for infusion when the patient is ready . Confirm patient identity : Prior to TECARTUS preparation , match the patient ’ s identity with the patient identifiers on the TECARTUS cassette . Do not remove the TECARTUS infusion bag from the cassette if the patient information on the cassette label does not match the intended patient . Once patient identity is confirmed , remove the TECARTUS infusion bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label . Inspect the infusion bag for any breaches of container integrity such as breaks or cracks before thawing . If the bag is compromised , follow the local guidelines ( or call Kite at 1-844-454-KITE ). Place the infusion bag inside a second sterile bag per local guidelines . Thaw the infusion bag at approximately 37 ° C using either a water bath or dry-thaw method until there is no visible ice in the infusion bag . Gently mix the contents of the bag to disperse clumps of cellular material . If visible cell clumps remain , continue to gently mix the contents of the bag . Small clumps of cellular material should disperse with gentle manual mixing . Do not wash , spin down , and / or re-suspend TECARTUS in new media prior to infusion . Once thawed , TECARTUS should be administered within 30 minutes but may be stored at room temperature ( 20 ° C to 25 ° C ) for up to three hours .
Administration : For autologous use only . Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period . Do NOT use a leukodepleting filter . Central venous access is recommended for the administration of TECARTUS . Confirm that the patient ’ s identity matches the patient identifiers on the TECARTUS infusion bag . Prime the tubing with normal saline prior to infusion . Infuse the entire contents of the TECARTUS bag within 30 minutes by either gravity or a peristaltic pump . TECARTUS is stable at room temperature for up to three hours after thaw . Gently agitate the TECARTUS bag during infusion to prevent cell clumping . After the entire contents of the TECARTUS bag are infused , rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered . TECARTUS contains human blood cells that are genetically modified with replication-incompetent retroviral vector . Follow universal precautions and local biosafety guidelines for handling and disposal of TECARTUS to avoid potential transmission of infectious diseases .
Monitoring : Administer TECARTUS at a certified healthcare facility . Monitor patients at the certified healthcare facility daily for at least seven days following infusion for signs and symptoms of Cytokine Release Syndrome ( CRS ) and neurologic events . Instruct patients to remain within proximity of the certified healthcare facility for at least four weeks following infusion .
Management of Severe Adverse Reactions
Cytokine Release Syndrome : Identify CRS based on clinical presentation . Evaluate for and treat other causes of fever , hypoxia , and hypotension . If CRS is suspected , manage according to the recommendations below . Patients who experience Grade 2 or higher CRS ( e . g ., hypotension , not responsive to fluids , or hypoxia requiring supplemental oxygenation ) should be monitored with continuous cardiac telemetry and pulse oximetry . For patients experiencing severe CRS , consider performing an echocardiogram to assess cardiac function . For severe or life-threatening CRS , consider intensive care supportive therapy .
CRS Grading and Management Guidance
• CRS Grade 1 a : Symptoms require symptomatic treatment only ( e . g ., fever , nausea , fatigue , headache , myalgia , malaise ).
— If not improving after 24 hours , administer tocilizumab c 8 mg / kg intravenously over 1 hour ( not to exceed 800 mg ).
— Corticosteroids : Not applicable
• CRS Grade 2 : Symptoms require and respond to moderate intervention . Oxygen requirement less than 40 % FiO 2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity . b
— Administer tocilizumab 8 mg / kg intravenously over 1 hour ( not to exceed 800 mg ). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen . Limit to a maximum of 3 doses in a 24-hour period ; maximum total of 4 doses if no clinical improvement in the signs and symptoms of CRS . If improving , discontinue tocilizumab .
— Manage with corticosteroids per Grade 3 if no improvement within 24 hours after starting tocilizumab . If improving , taper corticosteroids .
• CRS Grade 3 : Symptoms require and respond to aggressive intervention . Oxygen requirement greater than or equal to 40 % FiO 2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis .
— Administer tocilizumab per Grade 2 . If improving , discontinue tocilizumab . — Administer methylprednisolone 1 mg / kg intravenously twice daily or equivalent dexamethasone
( e . g ., 10 mg intravenously every 6 hours ) until Grade 1 , then taper corticosteroids . If improving , manage as Grade 2 . If not improving , manage as Grade 4 .
• CRS Grade 4 : Life-threatening symptoms . Requirements for ventilator support or continuous veno-venous hemodialysis ( CVVHD ), or Grade 4 organ toxicity ( excluding transaminitis ).
— Administer tocilizumab per Grade 2 . If improving , discontinue tocilizumab .
— Administer methylprednisolone 1000 mg intravenously per day for 3 days . If improving , taper corticosteroids , and manage as Grade 3 . If not improving , consider alternate immunosuppressants .
( a ) Lee et al 2014 , ( b ) Refer to management of neurologic toxicity , ( c ) Refer to tocilizumab Prescribing Information for details .
Neurologic Toxicity : Monitor patients for signs and symptoms of neurologic toxicities ( grading guidance below ). Rule out other causes of neurologic symptoms . Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry . Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities . Consider non-sedating anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities .
Neurologic Toxicity ( NT ) Grading and Management Guidance
• NE Grade 1 : Examples include : somnolence – mild drowsiness or sleepiness ; confusion – mild disorientation ; encephalopathy – mild limiting of ADLs ; dysphasia – not impairing ability to communicate .
— If concurrent CRS , administer tocilizumab per management guidance for Grade 1 CRS . — If there is no concurrent CRS , use supportive care .
• NE Grade 2 : Examples include : somnolence – moderate limiting instrumental ADLs ; confusion – moderate disorientation ; encephalopathy – limiting instrumental ADLs ; dysphasia – moderate impairing ability to communicate spontaneously ; seizure ( s ).
— If concurrent CRS : Administer tocilizumab per management guidance for Grade 2 CRS . If not improving within 24 hours after starting tocilizumab , administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less , then taper corticosteroids . If improving , discontinue tocilizumab . If still not improving , manage as Grade 3 .
— If no concurrent CRS : Administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less . If improving , taper corticosteroids .
• NE Grade 3 : Examples include : somnolence – obtundation or stupor ; confusion – severe disorientation ; encephalopathy – limiting self-care ADLs ; dysphasia – severe receptive or expressive characteristics , impairing ability to read , write , or communicate intelligibly .
— If concurrent CRS : Administer tocilizumab per management guidance for Grade 2 CRS . In addition , administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours . Continue dexamethasone use until the event is Grade 1 or less , then taper corticosteroids . If improving , discontinue tocilizumab and manage as Grade 2 . If still not improving , manage as Grade 4 .
— If no concurrent CRS : Administer dexamethasone 10 mg intravenously every 6 hours . Continue dexamethasone use until the event is Grade 1 or less , then taper corticosteroids . If not improving , manage as Grade 4 .
• NE Grade 4 : Life-threatening consequences ; urgent intervention indicated ; requirement for mechanical ventilation ; consider cerebral edema .
— If concurrent CRS : Administer tocilizumab per management guidance for Grade 2 CRS . Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days . If improving , then manage as Grade 3 . If not improving , consider alternate immunosuppressants .
— If no concurrent CRS : Administer methylprednisolone 1000 mg intravenously per day for 3 days . If improving , then manage as Grade 3 . If not improving , consider alternate immunosuppressants .
• NE Grade 2-4 : Consider non-sedating , anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
Abbreviation : ADLs , activities of daily living . ( a ) Severity based on Common Terminology Criteria for Adverse Events .
CONTRAINDICATIONS : None . WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome : CRS , including life-threatening reactions , occurred following treatment with TECARTUS . In ZUMA-2 , CRS occurred in 91 % ( 75 / 82 ) of patients receiving TECARTUS , including ≥ Grade 3 ( Lee grading system 1 ) CRS in 18 % of patients . Among the patients who died after receiving TECARTUS , one had a fatal CRS event . The median time to onset of CRS was three days ( range : 1 to 13 days ) and the median duration of CRS was ten days ( range : 1 to 50 days ). Among patients with CRS , key manifestations (> 10 %) included fever ( 99 %), hypotension ( 60 %), hypoxia ( 37 %), chills ( 33 %), tachycardia ( 37 %), headache ( 24 %), fatigue ( 19 %), nausea ( 13 %), alanine aminotransferase increased ( 13 %), aspartate aminotransferase increased ( 12 %), and diarrhea ( 11 %). Serious events associated with CRS included hypotension , fever , hypoxia , acute kidney injury , and tachycardia . Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of TECARTUS . Monitor patients daily for at least seven days at the certified healthcare facility following infusion for signs and symptoms of CRS . Monitor patients for signs or symptoms of CRS for four weeks after infusion . Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time . At the first sign of CRS , institute treatment with supportive care , tocilizumab , or tocilizumab and corticosteroids as indicated .
Neurologic Toxicities : Neurologic events , including those that were life-threatening , occurred following treatment with TECARTUS . In ZUMA-2 , neurologic events occurred in 81 % of patients , 37 % of whom experienced Grade 3 or higher ( severe or life-threatening ) adverse reactions . The median time to onset for neurologic events was six days ( range : 1 to 32 days ). Neurologic events resolved for 52 out of 66 ( 79 %) patients with a median duration of 21 days ( range : 2 to 454 days ). Three patients had ongoing neurologic events at the time of death , including one patient with serious encephalopathy . The remaining unresolved neurologic events were either Grade 1 or Grade 2 . Fifty-four ( 66 %) patients experienced CRS before the onset of neurological events . Five ( 6 %) patients did not experience CRS with neurologic events and eight patients ( 10 %) developed neurological events after the resolution of CRS . Eighty-five percent of all treated patients experienced the first CRS or neurological event within the first seven days after TECARTUS infusion . The most common neurologic events (> 10 %) included encephalopathy ( 51 %), headache ( 35 %), tremor ( 38 %), aphasia ( 23 %), and delirium ( 16 %). Serious events including encephalopathy , aphasia , and seizures occurred after treatment with TECARTUS . Monitor patients daily for at least seven days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities . Monitor patients for signs or symptoms of neurologic toxicities for four weeks after infusion and treat promptly .