According to data published in Blood, Ibrutinib plus venetoclax demonstrated a favorable benefit-risk profile in patients with R/R CLL (Relapsed/Refractory Chronic Lymphocytic Leukemia ).
The trial named VISION/HOVON 141 is ongoing and aims to determine the feasibility of minimal residual disease-guided treatment cessation and reinitiation in patients with the R/R chronic lymphocytic leukemia (CLL).
Apart from the long-term efficacy of the BTK inhibitor ibrutinib, uMRD (Undetectable Minimal Residual Disease is rarely observed. The Minimal Residual Disease is a crucial predictor of survival and long-term outcomes for relapsed/refractory Chronic Lymphocytic Leukemia (CLL) patients treated with chemo-immunotherapy.
Certain additional novel therapies as well as treatment options are required for this patient group in order to reduce the minimal residual disease.
Venetoclax specifically attaches to a protein named Bcl-2 that in combination with a CD-20 targeting antibody has been noted to increase the rate of undetectable Minimal Residual Disease. Early findings also suggest that there is a correlation between minimal residual disease status and progression-free survival.
Carried out study enrolled total of 230 eligible patients. The primary outcome of the study is the rate of progression-free survival at 27 months following the initiation of treatment. Secondary outcomes include the number of patients with minimal residual disease negativity at 27 months following initiating the treatment, the progression-free survival rate at 7 years, the number of patients reinitiating treatment at 7 years, the number of patients with treatment failure after reinitiating the treatment up to 7 years, the number of patients initiating new chronic lymphocytic leukemia treatment, the number of minimal residual disease negative patients at 12 and 15 months, the number of patients alive up to 7 years, the number of patients with complete remission, partial remission, and stable disease, the number of adverse events, and the number of patients with improved QoL.
Patients in the carried out study were given ibrutinib plus venetoclax until the disease is progressive and for 15 cycles in the initial experimental arm. In this arm, the dose of ibrutinib was 420mg and the dose of venetoclax was minimum of 20mg and maximum of 400mg. Those who've achieved at least a partial response then were randomized 1:2 to receive either ibrutinib maintenance of observations.
Regarding patients with minimal residual disease +ve tumors, they were randomized into the remaining a couple of arms. During arm A, patients were administered ibrutinib as a maintenance treatment until the disease progression or unacceptable toxicity.
For patients randomized into arm B, therapy was restarted following progression or a minimal residual disease over or equal to 10-3 PB at least 1 month later of and minimal residual disease over or equal to 10-2 PB. Treatment would continue for the 12 cycles.
For participating, patients must have been aged 18 years or older, have adequate bone marrow function, creatinine clearance of over or equal to 30ml/min, adequate liver function, negative serological testing for hepatitis B, and WHO/ECOG performance status of 0-3, and a negative pregnancy test at study entry for the candidates with childbearing age.
Patients with any prior therapy with ibrutinib or venetoclax, transformation of chronic lymphocytic leukemia, a history of confirmed progressive multifocal leukoencephalopathy, malignancies other than chronic lymphocytic leukemia requiring systemic therapies, not being treated with the curative intention, or showing signs of progression following the curative treatment, known bleeding disorders, or uncontrolled active infection are not eligible to participate.
Of the 230 patients, the first 24 with undetectable Minimal Residual Disease have been randomized into arm A or B. The interim analysis published in Blood includes data on the first 51 eligible patients reaching the time point for the initial 15 cycles of treatment.
The median age of the evaluable patients was noted to be 67 years. 71% were male, 65% had a WHO performance status of 0, 84% were Binet stage B/C, 71% had received the prior standard CIT, 18% had TP53 aberrations, and 57% had IGHV unmutated status.
Included 51 patients in the report, 49 patients completed the first couple of cycles, and 43 completed all the 15 cycles of treatment. Of the enrolled patients who didn't continue, a couple of patients refused to continue, a couple of patients discontinued due to the toxicity of intolerance, a couple of patients discontinued for a second malignancy, and a couple of patients discontinued due to death. Single patient died of tick-borne encephalitis and a single patient died of Richter’s transformation.
The grade-2 adverse events were the highest grade of adverse events in the 16% of patients. Grade-3 and grade-4 adverse events were experienced by 50 percent and 26 percent of patients respectively.
20% of patients reported grade-2 or higher atrial fibrillation, 14% reported bleeding. CR was reached for the 29 patients and 13 patients reached PR. Over half, 55 percent, of patients reached the undetectable minimal residual disease in peripheral blood at cycle 15 and 33 percent also obtained bone marrow aspirate undetectable Minimal Residual Disease.
The concordance undetectable Minimal Residual Disease status b/w peripheral blood and bone marrow was 71 percent. The remaining 29% of patients had low Minimal Residual Disease in the bone marrow while undetectable Minimal Residual Disease in the peripheral blood.
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