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Ibrutinib Plus Venetoclax Shows Promise in Treatment-Naïve CLL
First-line combination therapy with ibrutinib and venetoclax was associated with higher rates of undetectable measurable residual disease ( MRD ), remission , and three-year progression-free survival ( PFS ) in patients with chronic lymphocytic leukemia ( CLL ). This is according to results of a new study published in JAMA Oncology , which suggest that Bruton tyrosine kinase [ BTK ] inhibitor ibrutinib plus BCL2 inhibitor venetoclax may be an effective oral nonchemotherapy regimen for patients with CLL . 1
Previous data suggests patients with CLL given BTK inhibitor monotherapy with ibrutinib or acalabrutinib rarely enter complete remission ( CR ) or have undetectable MRD remission .
In contrast , venetoclax is often combined with obinutuzumab , a CD20 monoclonal antibody , for one year in treatment-naïve patients . For this combination regimen , the documented undetectable MRD rate is approximately 76 % in peripheral blood and 57 % in bone marrow . 2
Researchers led by Nitin Jain , MD , of the University of Texas MD Anderson Cancer Center evaluated the synergistic and complementary therapeutic activities of the ibrutinib and venetoclax combination in 80 patients with treatmentnaïve CLL . Dr . Jain and colleagues focused their analysis on MRD and remission durability .
To be eligible for enrollment in the study , patients with CLL were required to meet at least one of the following criteria :
• del ( 17p )
• TP53-mutated CLL
• del ( 11q )
• unmutated immunoglobulin heavy-chain variable gene
• age 65 or older
The treatment regimen started with ibrutinib 420 mg / day monotherapy . After three cycles of ibrutinib monotherapy , participants received venetoclax in addition to ibrutinib . Venetoclax followed a standard weekly dose ramp-up from 20 mg / day to a target of 400 mg / day . The combination regimen was administered for 24 planned 28-day cycles .
Researchers assessed MRD in bone marrow while patients were receiving combination therapy . Following completion of treatment , the investigators monitored MRD in blood samples every six months .
Best response , defined as CR and CR with incomplete count recovery , was the primary endpoint , assessed at any time during treatment for up to two months after the study . Other time-to-event outcomes , such as PFS and overall survival ( OS ), were also assessed .
At baseline , the median age of patients was 65 years ( range = 26-83 ). Approximately 18 % of patients had del ( 17p ) and 14 % had TP53-mutated CLL . The majority of patients were men ( 71 %).
A total of five patients discontinued the study while on the initial ibrutinib monotherapy for reasons unrelated to disease progression . The median follow-up for all patients , including those who discontinued treatment , was 38.5 months , and ranged from 5.6 to 51.1 months .
In an intent-to-treat analysis of the overall cohort , 56 % of patients ( n = 45 ) demonstrated bone marrow undetectable MRD remission at the end of 12 cycles . Approximately 66 % ( n = 53 ) of patients demonstrated bone marrow undetectable MRD remission at 24 cycles . The majority of patients ( 75 %) achieved bone marrow undetectable MRD remission as best response .
Patients with < 1 % bone marrow MRD at initial response assessment following the start of combination therapy had a significantly greater likelihood of achieving bone marrow undetectable
MRD remission by the end of cycle 12 ( 77 % vs . 20 %; p < 0.001 ). Additionally , those who showed a > 2-log reduction in bone marrow MRD at the end of cycle three were significantly more likely to show bone marrow undetectable MRD remission at the end of cycle 12 ( 83 % vs . 20 %; p < 0.001 ).
Three-year PFS and OS rates were 93 % and 96 %, respectively . In patients with del ( 17p )/ TP53-mutated CLL , the estimated three-year PFS was 86 %. None of the patients in the study had disease progression , but two patients developed diffuse large B-cell lymphoma Richter transformation .
Limitations of this study included its lack of placebo control , single-center design , small sample size , and short follow-up period .
Study authors report relationships with AbbVie , which sponsored this trial .
References
1 . Jain N , Keating M , Thompson P , et al . Ibrutinib plus venetoclax for firstline treatment of chronic lymphocytic leukemia : A nonrandomized phase 2 trial [ published online ahead of print , 2021 Jun 10 .] JAMA Oncol . doi : 10.1001 / jamaoncol . 2021.1649 .
2 . Fischer K , Al-Sawaf O , Bahlo J , et al . Venetoclax and obinutuzumab in patients with CLL and coexisting conditions . N Engl J Med . 2019 ; 380:2225-2236
Isatuximab Plus Carfilzomib and Dexamethasone Improves PFS in Relapsed / Refractory MM
Recent results suggest that in patients with relapsed multiple myeloma ( MM ), combination therapy consisting of carfilzomib and dexamethasone ( Kd ) plus isatuximab is associated with improvements in progression-free survival ( PFS ) and depth of response .
According to the study authors , led by Philippe Moreau , MD , of University Hospital Hôtel-Dieu in Nantes , France , the benefit of adding immunoglobin ( Ig ) G1 monoclonal antibody isatuximab to Kd showed the potential to be “ a new standard of care ” for patients with relapsed MM . Previous findings from the phase III ICARIA-MM study resulted in approval of isatuximab combined with dexamethasone and pomalidomide for the treatment of relapsed and refractory MM in patients who received two or more prior therapies .
In this phase III multicenter , international study by Dr . Moreau and colleagues , researchers compared the isatuximab plus Kd regimen to Kd alone in patients with relapsed / refractory MM who had previously received one to three lines of therapy .
A total of 179 patients were randomized to receive isatuximab plus Kd , while 123 patients were assigned to treatment with Kd alone . Participants in the triplet combination group received intravenous isatuximab 10 mg / kg each week for the first four weeks , and then every two weeks thereafter .
Treatment was continued until either disease progression or unacceptable toxicity occurred . The investigators evaluated rates of PFS over a median study follow-up period of 20.7 months .
The median age of the study population was 64 years . Overall , patients had received a median of two prior lines of therapy . Approximately 44 % had received one previous line of therapy , 33 % had received two previous lines of therapy , and 23 % had received three or more previous lines of therapy .
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