A fixed-duration regimen of venetoclax plus obinutuzumab demonstrated superior progression-free survival, complete response rates, and minimal residual disease (MRD) negativity compared with chlorambucil plus obinutuzumab as first-line therapy for older patients with chronic lymphocytic leukemia (CLL) and comorbidities, according to the results of the CLL14 trial presented at the 2019 ASCO Annual Meeting1 and published simultaneously in The New England Journal of Medicine.2
The new fixed-duration targeted therapy regimen compares favorably with historical results with continuous ibrutinib therapy as upfront therapy for CLL in elderly patients. Moreover, it has the advantage of being administered for a fixed duration rather than continuously, as is the case with ibrutinib.
“Fixed-duration targeted therapy combining venetoclax and obinutuzumab can be applied safely in elderly patients with CLL and comorbidities. Our study showed it is superior to fixed-duration chlorambucil and obinutuzumab. Venetoclax plus obinutuzumab achieves the highest rates of MRD-negative response so far observed in a randomized prospective trial [of patients with CLL],” stated lead author Kirsten Fischer, MD, of the Center for Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Germany.
With short follow-up, there was no difference in survival between venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab. “We hope this will change with longer follow-up,” Dr. Fischer told the audience.
“Venetoclax plus obinutuzumab achieves the highest rates of MRD-negative response so far observed in a randomized prospective trial [of patients with CLL].”— Kirsten Fischer, MD
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Most patients with CLL are older and have comorbidities. “There is a need for more effective and less toxic regimens in this patient population,” Dr. Fischer said.
Fixed-duration chemoimmunotherapy and continuous indefinite targeted therapy with ibrutinib are used as first-line treatment for CLL. “We decided to develop a new targeted therapy with a fixed duration, and based on preclinical and clinical data, we selected venetoclax plus obinutuzumab,” she continued. “We wanted to see whether we could improve upon a median progression-free survival of 31 months with chlorambucil plus obinutuzumab.”
The open-label, randomized, phase III CLL14 trial was conducted at 196 sites in 21 countries. The study enrolled 432 previously untreated patients with CD20-positive CLL requiring treatment. All patients had to have a score greater than 6 on the Cumulative Illness Rating Scale or a creatinine clearance less than 70 mL/min, both of which would indicate clinically relevant comorbidities. Patients were randomly assigned 1:1 to receive either venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab for 12 cycles lasting 28 days each.
Demographic and disease characteristics were well balanced between the two treatment arms. The median age was 72 years, median Cumulative Illness Rating Scale score was 8, and median creatinine clearance was 66.4 mL/min. In total, 13.8% of patients had a TP53 deletion, mutation, or both, and 59.8% had unmutated IGHV (an unfavorable prognosis factor).
Among patients in the venetoclax/obinutuzumab group, 13.4%, 64.4%, and 22.2% were at low, medium, and high risk of tumor-lysis syndrome, respectively. However, there were no cases of tumor-lysis syndrome that met diagnostic criteria.
The planned treatment of 12 cycles was given to 77.8% of the venetoclax/obinutuzumab group and 74.8% of the chlorambucil group. The median duration of treatment and median dose intensity were similar between the two treatment arms.
After a median follow-up of 28 months, median progression-free survival was not reached in either group. Estimates of 24-month progression-free survival were 88.2% in the venetoclax/obinutuzumab group vs 64.1% for chlorambucil/obinutuzumab, a significant difference that favored the experimental arm (P < .0001).
The superiority of venetoclax/obinutuzumab was seen in patients with unmutated IGHV as well as in those with TP53 alterations, for whom median progression-free survival was not reached. Thus far, with a relatively short follow-up of 28 months, no difference in overall survival has been observed. “It might be too early to see an effect on survival,” Dr. Fischer said.
The CLL14 investigators were impressed by the rates of MRD negativity achieved with the venetoclax-containing regimen. Three months following completion of treatment, in the intent-to-treat population, the rate of MRD negativity in peripheral blood was 75.5% vs 35.2% for chlorambucil/obinutuzumab (P < .001) and in bone marrow, 56.9% vs 17.1%, respectively (P < .001).
The rate of overall response was 84.7% vs 71.3%, respectively (P < .001). Complete response rates were 49.5% vs 23.1%, respectively (P < .001).
The rates of patients with a complete response and MRD negativity in the peripheral blood were significantly higher in the venetoclax/obinutuzumab group—42.1% vs 14.4%, respectively (P < .001). MRD-negativity rates in the bone marrow were also significantly higher in the venetoclax/obinutuzumab group—33.8% vs 10.6%, respectively (P < .001). “MRD negativity was achieved early with venetoclax and stayed that way over time,” Dr. Fischer noted.
Safety was evaluated in 426 patients. At least one adverse event of any grade was reported in 94.5% of the venetoclax/obinutuzumab group and 99.5% of those in the chlorambucil/obinutuzumab arm. Adverse events that led to treatment discontinuation were reported in 16.0% and 15.4% of patients, respectively.
The most common grade 3 or 4 event was neutropenia. Grade 3 or 4 febrile neutropenia occurred in 5.2% and 3.7% of the two groups, respectively, and grade 3 or 4 infections occurred in 17.5% and 15%, respectively. Tumor-lysis syndrome was reported in three and five patients, respectively, but none of these cases met the clinical criteria for tumor-lysis syndrome. The rate of grade 3 and 4 infusion reactions was similar in both arms (9% and 10.3%, respectively).
Fatal events during treatment occurred in 5 patients in the venetoclax/obinutuzumab group compared with 4 in the chlorambucil/obinutuzumab group and after treatment in 11 vs 4 patients, respectively. Second primary cancers were found in 13.7% of the venetoclax/obinutuzumab group and 10% of those on chlorambucil/obinutuzumab.
Future of CLL
“This study is immediately practice-changing in the front-line setting,” said formal discussant Matthew S. Davids, MD, MMSc, of Dana-Farber Cancer Institute, Boston. He singled out the fixed duration of treatment and the very high rates of MRD negativity achieved in the trial without the need for chemoimmunotherapy as distinguishing this regimen from others being studied in CLL.
“This study is immediately practice-changing in the front-line setting.”— Matthew S. Davids, MD, MMSc
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Dr. Davids was enthusiastic about the landscape of new therapies for CLL in general. “The future of CLL is now. The findings of CLL14 suggest we may be able to have our cake and eat it too—that is, more effective and less toxic treatment,” he said.
“The results of CLL14 look promising. The toxicity profile is favorable and distinct from that of ibrutinib, with no clinical tumor-lysis syndrome. After only 1 year of therapy, progression-free survival at 2 years is 88% for venetoclax/obinutuzumab,” he added.
“The findings are impressive. Every prior chemotherapy and chemoimmunotherapy regimen led to shorter progression-free survival in patients with unmutated IGHV than patients with mutated IGHV. As with other novel agents in this space, the progression-free survival on the venetoclax regimen was equivalent, irrespective of IGHV mutation status. The rate of MRD negativity is also remarkably high given the lack of chemotherapy in this regimen: 76% in the blood and 57% in the bone marrow at 3 months after therapy in an intent to treat analysis. So far the durability of these deep responses appears promising, but longer follow-up is needed,” Dr. Davids continued.
Issues that remain to be resolved are the duration of therapy, the additional effect of obinutuzumab on efficacy, and how a practicing oncologist will choose between ibrutinib vs ventoclax plus obinutuzumab. “For most patients, we should be considering venetoclax plus obinutuzumab as one of the options front-line CLL therapy,” he said. ■
DISCLOSURE: Dr. Fischer has received travel expenses from Roche. Dr. Davids disclosed financial relationships with AbbVie, Acerta Pharma, Adaptive Biotechnologies, AstraZeneca, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, Pharmacyclics, Roche, Syros Pharmaceuticals, Verastem, and TG Therapeutics.
1. Fischer K, Al-Sawaf O, Bahlo J, et al: Effect of fixed-duration venetoclax plus obinutuzumab on progression-free survival and rates and duration of minimal residual disease negativity in previously untreated patients with chronic lymphocytic leukemia and comorbidities. 2019 ASCO Annual Meeting. Abstract 7502. Presented June 4, 2019.
2. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.