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Literature Scan

Evaluating the TP53 State and Its Implications for Myelodysplastic Syndromes Outcomes

In a new study published in Nature Medicine , researchers evaluated the effect of the TP53 allelic state on the clinical presentation and outcomes of patients with myelodysplastic syndromes ( MDS ) and determined that the multi-hit mutation state – more than the presence of the TP53 mutation itself – predicted genome instability , treatment resistance , and disease progression . Multi-hit status also identified patients with very – high-risk disease , while outcomes did not appear to differ among those with monoallelic mutations or with wild-type TP53 , according to study authors , led by Elsa Bernard , PhD , of Memorial Sloan Kettering Cancer Center in New York .
Based on these results , Dr . Bernard and researchers suggested that clinicians should assess the TP53 allelic state in patients with MDS for diagnostic and prognostic precision in managing the disease .
The investigators assessed genome-wide allelic imbalances and TP53 mutations in a sample of 3,324 patients with MDS . Overall , 11 % of patients ( n = 360 ) had ≥1 copy neutral loss of heterozygosity region , whereas 47 % ( n = 1571 ) had ≥1 chromosomal aberration .
There were 486 putative oncogenic mutations in TP53 at variant allele frequency ( VAF ) of ≥2 % in 378 patients . Of these , 274 patients had a single TP53 mutation ( 72.5 %), 100 had two TP53 mutations ( 26.5 %), and 4 had three TP53 mutations ( 1 %).
Two-thirds of TP53-mutated patients had multiple hits ( more than one gene mutation , mutation and deletion , or mutation and copy neutral loss of heterozygosity ), resulting in biallelic loss , the authors reported :
• monoallelic TP53 state with 1 residual wild-type TP53 copy ( n = 125 )
• multi-hit TP53 state with ≥2 TP53 hits in each patient and probably no residual TP53 function in clonal cells ( n = 253 )
In the overall cohort , the median age at the time of MDS diagnosis was 71 years . The most common diagnosis was de novo MDS ( n = 2,855 ), followed by therapy-related MDS ( n = 229 ), secondary MDS
( n = 51 ), and MDS with undetermined cause (“ missing data ” [ n = 189 ]).
A significantly greater proportion of patients with
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INDICATION
TECARTUS is a CD19-directed genetically modifi ed 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 verifi cation and description of clinical benefi t in a confi rmatory trial .
IMPORTANT SAFETY INFORMATION
BOXED 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 .
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 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

IN RELAPSED / REFRACTORY MCL

TP53 mutations had ≥1 chromosomal deletion compared with wild-type cases ( 67 % vs . 5 %, respectively ; odds ratio [ OR ] = 35 ; 95 % CI 27-46 ), and approximately 85 %
Not an actual patient .
ZUMA-2 was a phase 2 , single-arm , open-label , multicenter trial evaluating the effi cacy and safety of a single infusion of TECARTUS TM in adult patients with relapsed or refractory mantle cell lymphoma who had previously received anthracycline- or bendamustine-containing chemotherapy , an anti-CD20 antibody , and
to infusion of TECARTUS . Following infusion , monitor patients for signs and symptoms of CRS daily for at least seven days at the certifi ed healthcare facility , and for four weeks thereafter . Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time . At the fi rst sign of CRS , institute treatment with supportive care , tocilizumab , or tocilizumab and corticosteroids as indicated .
Neurologic Toxicities , 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 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 by 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 . 85 % of all treated patients experienced the fi rst CRS or neurological event within the fi rst 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 .
Monitor patients daily for at least seven days at the certifi ed healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly .
REMS Program : Because of the risk of CRS and neurologic toxicities , TECARTUS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the YESCARTA and TECARTUS REMS Program which requires that :
• Healthcare facilities that dispense and administer TECARTUS must be enrolled and comply with the REMS requirements . Certifi ed healthcare facilities must have on-site , immediate access to tocilizumab , and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after TECARTUS infusion , if needed for treatment of CRS .
• Certifi ed healthcare facilities must ensure that healthcare providers who prescribe , dispense , or administer TECARTUS are trained in the management of CRS and neurologic toxicities . Further information is available at www . YescartaTecartusREMS . com or 1-844-454-KITE ( 5483 ).
54 ASH Clinical News