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Ibrutinib and Venetoclax Combo Confers High Response in Mantle-Cell Lymphoma
In results from a phase II study published in The New England Journal of Medicine , the combination of the Bruton tyrosine kinase ( BTK ) inhibitor ibrutinib and the BCL2 inhibitor venetoclax was associated with high response rates in patients with relapsed / refractory and treatment-naive mantle cell lymphoma ( MCL ).
Both agents have demonstrated clinical activity alone , explained the authors , led by Constantine S . Tam , MD . “ These findings confirm the high activity of ibrutinib and venetoclax in combination in patients with MCL ,” Dr . Tam , of St . Vincent ’ s Hospital and the Peter MacCallum Cancer Center in Melbourne , Australia , told ASH Clinical News . “ In particular , the achievement of deep , minimal residual disease ( MRD )– negative remission may translate to longer-duration remissions , and the possibility of therapy interruption , which we are exploring in trials .”
“ We have identified genomic markers of resistance of ibrutinib-venetoclax therapy , which we would like to use to identify patients ... likely to have a poor response .”
— CONSTANTINE S . TAM , MD
The open-label , single-arm ABT-199 and Ibrutinib in Mantle Cell Lymphoma ( AIM ) study included 23 patients with relapsed or refractory MCL and one patient with previously untreated MCL ( median age = 68 years ; range = 47-81 years ). Eligible participants were not suitable candidates for cytotoxic chemotherapy and were required to have a neutrophil count of ≥750 / mm 3 , platelet count of ≥50,000 / mm 3 , and Eastern Cooperative Oncology Group performance status score ≤2 . Twelve patients ( 50 %) had aberrations of TP53 , and 75 percent had a high-risk prognostic score .
Treatment consisted of a starting dose of single-agent ibrutinib 560 mg / day for four weeks to reduce the risk of tumor lysis syndrome . Following this phase , venetoclax was introduced at 50 mg / day and increased each week to a maximum dose of 400 mg / day . However , after another trial reported that the recommended phase II dose in MCL was 800 mg / day , the study protocol was amended to allow escalation to venetoclax 800 mg / day after week 16 if a complete response ( CR ) had not occurred . Treatment continued until disease progression or unacceptable toxicity .
Investigators assessed disease response via CT and PET imaging , as well as MRD ( measured via flow cytometry or polymerase chain reaction ) in the bone marrow and peripheral blood , at four , 16 , 28 , 40 , and 56 weeks of treatment .
At 16 weeks , the CR rate assessed by CT imaging ( primary endpoint ) was 42 percent ( n = 10 ), “ which was higher than the historical result of 9 percent at this time point with ibrutinib monotherapy ( p < 0.001 ),” the authors reported . When the investigators included PET assessments , the CR rate at week 16 was 62 percent ( n = 15 ), and two patients achieved partial response ( 8 %). The latter two patients subsequently achieved a CR , one of which occurred after escalation to venetoclax 800 mg / day , the researchers noted .
Of the 19 patients assessed with CT and 16 assessed with PET who were evaluable for MRD in bone marrow samples via flow cytometry , 16 ( 84 %) and 9 ( 56 %), respectively , were MRD-negative . Most patients with a CR were also MRD-negative ( 93 % in bone marrow ; 82 % in peripheral blood ).
After a median follow-up of 15.9 months ( range = 1.4-26.2 months ), the median duration of response and median progression-free survival ( PFS ) had not been reached , with an estimated 12-month PFS rate of 75 percent and an estimated 18-month PFS rate of 57 percent in the entire population . Among the 17 patients who responded to ibrutinib-venetoclax treatment , 78 percent remained progression-free at 15 months .
Rates of 12- and 18-month overall survival were 79 percent and 74 percent , respectively .
The most common adverse events ( AEs ) reported in this population “ were predominantly of grade 1 or 2 in severity ” and included :
• diarrhea ( n = 20 ; 83 %)
• fatigue ( n = 18 ; 75 %)
• nausea or vomiting ( n = 17 ; 71 %)
• bleeding , bruising , or postoperative hemorrhage ( n = 13 ; 54 %)
• musculoskeletal or connective-tissue pain ( n = 12 ; 50 %)
Two patients experienced tumor lysis syndrome during the study . Other serious AEs included :
• diarrhea ( n = 3 ; 12 %)
• atrial fibrillation ( n = 2 ; 8 %)
• pyrexia ( n = 2 ; 8 %)
• pleural effusion ( n = 2 ; 8 %)
• cardiac failure ( n = 1 ; 4 %)
• soft-tissue infection ( n = 1 ; 4 %)
Based on the findings of this phase II trial , the investigators initiated a phase III study comparing single-agent ibrutinib with the ibrutinib-venetoclax combination . “ The global phase III study will provide an objective evaluation of [ this combination ’ s ] efficacy ,” Dr . Tam explained . “ Locally , we have identified genomic markers of resistance of ibrutinib-venetoclax therapy , which we would like to use to identify a priori patients who are likely to have a poor response for risk-stratified therapy in a planned follow-up study .”
Limitations of the phase II study include its small number of participants , the lack of a comparator arm , and the relatively short follow-up period .
The authors report financial relationships with Janssen , AbbVie , the Victorian Cancer Agency , the Leukemia & Lymphoma Society , and the Peter MacCallum Cancer Foundation .
REFERENCE
Tam CS , Anderson MA , Pott C , et al . Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma . N Engl J Med . 2018 ; 378:1211-23 .
28 ASH Clinical News August 2018