1. Nalley, Catlin

Article Content

ORLANDO-Findings presented at the 2019 ASH Annual Meeting suggest that the combination of ibrutinib and venetoclax is an effective chemotherapy-free oral regimen for high-risk, previously untreated chronic lymphocytic leukemia (CLL) patients (Abstract 34).

CLL. CLL... - Click to enlarge in new windowCLL. CLL

"Historically, treatment for CLL has been chemotherapy. In recent years, we have seen the development of new targeted therapies such as ibrutinib and venetoclax," noted Nitin Jain, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "Preclinical evidence suggests that, when combined, ibrutinib and venetoclax work synergistically. There is also clinical rationale that supports the combinations of these two oral drugs."


Jain and colleagues designed this study in an effort to better understand the impact of this non-chemotherapy approach for CLL patients who have a high risk of progression under chemotherapy regimens. The researchers published initial results of this trial early this year in the New England Journal of Medicine (2019;380(22):2095-2103) with a median follow-up of 14.8 months. They now report longer follow-up of the trial data with a median follow-up of 27 months.


Methodology, Results

Eighty patients with previously untreated CLL were enrolled in the study with a median age of 65 years (26-83). Thirty percent of the patients were 70 years or older.


Researchers reported that 92 percent of patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median follow-up was 27 months. Ibrutinib monotherapy (420 mg daily) was administered for 3 cycles followed by the addition of venetoclax (weekly dose-escalation to 400 mg daily target dose). Investigators administered the combined therapy for 24 cycles.


"After 2 years, patients with MRD-negative disease will stop both the drugs and will be monitored without any active treatment," Jain explained. "If the patient were to be MRD-positive at the end of 2 years of the combined treatment, they can continue with the ibrutinib monotherapy."


Fourteen (17%) patients came off the trial, five during the ibrutinib monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1] and nine during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=2; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1; sudden cardiac death/pneumonia, n=1]. Ibrutinib dose reductions occurred in 52 percent of patients. Twenty-nine percent reduced the dose of venetoclax.


Following 3 cycles of ibrutinib monotherapy, none of the 75 patients who went on to initiate venetoclax achieved bone marrow (BM) undetectable MRD (U-MRD). After 3 cycles of the combination, 12/74 (16%) patients achieved BM U-MRD remission. Following 6 cycles, 30/72 (42%) reached BM U-MRD remission. With 12 cycles, 45/69 (65%) showed BM U-MRD remission. And after 24 cycles of ibrutinib plus venetoclax, 34/46 (74%) achieved BM U-MRD remission.


"These numbers are quite encouraging," Jain noted. "We are seeing high remission rates in the bone marrow with the combination of these two non-chemotherapy drugs.


"This study as well as others are leading the field away from chemotherapy in this patient population," he continued. "We are entering an era of combination therapies with the goal that it will allow patients a treatment-fee interval where their disease could be monitored without any active regimens. And then, if the disease were to come back in the future, they could be treated with the same regimen or a different strategy as needed."


Continued Study

An important next step of this ongoing study, according to Jain, is to take a closer look at the outcomes of patients who stop treatment after 2 years.


"This is extremely important because we are making a proactive decision to stop therapy for these patients," he said. "When will the disease return? And for how many patients? These are very important questions for which we don't yet know the answer."


Another aspect of the study that goes hand in hand with this is a better understanding of the patient characteristics that are linked with higher response. "As we continue to follow these patients, we will be able to look at the data and prioritize the right strategy for patients based on the specific genetics of their disease, as well as their risk of recurrence," Jain told Oncology Times. "We are assessing this and, hopefully, in the next few years we will be able to answer these questions with longer follow-up."


This combination approach is being explored in a number of randomized studies, Jain noted. "And as findings are reported, we will know whether this research will pave the way for the approval of this strategy as a standard of care for these patients."


Catlin Nalley is a contributing writer.