Venetoclax/Rituximab Combo Achieves Durable, High MRD-Negative Status in CLL

Arnon P. Kater, MD, PhD

The combination of venetoclax (Venclexta) and rituximab (Rituxan) for relapsed/refractor chronic lymphoblastic leukemia (CLL) produced high rates of undetectable minimal residual disease (uMRD), which was associated with prolonged progression-free survival (PFS), a new analysis of a randomized trial showed.¹

Almost 5 times as many patients attained uMRD status with venetoclax and rituximab as compared with bendamustine and rituximab, and the proportion of patients who maintained that status at 24 months was more than 20 times higher in the venetoclax/rituximab arm. As compared with MRD-positive status, uMRD was associated with a 62% reduction in the hazard for disease progression or death.

MRD status in peripheral blood had 90% concordance with MRD status in bone marrow, as reported at the 2018 ASH Annual Meeting.

“Undetectable MRD status in peripheral blood at the end of combination therapy was highly predictive of prolonged progression-free survival in both treatment arms,” said Arnon P. Kater, MD, of the University of Amsterdam. “MRD status was more valuable in predicting treatment outcome than response data. Undetectable MRD at the end of combination therapy correlated with progression-free survival both in patients with partial response and complete response.”

“These are the first data to demonstrate the value of undetectable MRD as a predictive marker of improved clinical outcome for a fixed-duration chemotherapy-free regimen,” he added.

The data also showed that peripheral blood MRD status can serve as a surrogate for bone marrow MRD status in patients treated with venetoclax and rituximab, said Kater.

MRD status has proven to be predictive of PFS for patients with CLL treated with chemoimmunotherapy, but the predictive value of MRD with novel agents remains uncertain. Data from the randomized MURANO trial afforded an opportunity to examine the predictive value of MRD with a chemotherapy-free regimen for CLL.

MURANO was a phase III randomized trial that evaluated rituximab in combination with venetoclax or bendamustine in 389 patients with relapsed/refractory CLL. Patients received venetoclax for 2 years and rituximab for the first 6 months, or 6 cycles of bendamustine plus rituximab for 6 months.

The primary analysis showed that fixed-duration treatment with venetoclax and rituximab was associated with an 84% reduction in the hazard for disease progression or death at 3 years, as compared with rituximab and bendamustine.²

Kater reported findings from an examination of peripheral blood MRD kinetics (including concordance with bone marrow MRD status) and the association with PFS. Median follow-up at the time of the analysis was 36.0 months.

In the MURANO trial, uMRD was defined as <1 leukemic cell per 10,000 leukocytes (<10-4), low (L) MRD+ as ≥10-4 to <10-2, and high (H) MRD+ as ≥10-2.

An analysis of 1859 paired peripheral blood specimens showed 86% concordance with allele-specific oligonucleotide PCR and/or multicolor flow cytometry. Comparison of 50 paired peripheral blood and bone marrow samples of patients treated with venetoclax/rituximab revealed 90% concordance for MRD.

At the end of combination therapy, the venetoclax arm had a uMRD rate of 63% versus 15% for the bendamustine arm. The uMRD status was maintained in 48% of venetoclax-treated patients at 24 months versus 2% of the bendamustine group.

Focusing only on the venetoclax arm, Kater said uMRD at the end of combination therapy (N = 120) was associated with a 62% reduction in the hazard for disease progression for death as compared with patients who had MRD-positive status (N = 42).

In both treatment arms, uMRD was associated with significantly better PFS compared with L-MRD+ (HR, 0.18; HR, 0.44; respectively) and compared with H-MRD+ (HR, 0.15; HR 0.08; respectively). Additionally, patients with L-MRD+ had better PFS than did patients with H-MRD+ status after combination therapy (HR 0.24; HR 0.22; respectively).

At the end of treatment, 48% of patients in the venetoclax arm versus 2% in the bendamustine arm had uMRD status.

“The combination of venetoclax and rituximab achieved deep and durable molecular responses,” said Kater. “The high undetectable MRD levels at the end of combination therapy were maintained during venetoclax monotherapy and after the end of therapy. After completion of fixed-duration venetoclax/rituximab, rates of progressive disease and re-emergence of MRD positivity were low.”

In April 2016, the FDA granted an accelerated approval to venetoclax for patients with CLL or small lymphocytic lymphoma (SLL) harboring a 17p deletion (del[17p]), following at least 1 prior therapy. Based on the MURANO trial, the FDA converted this to a standard approval in June 2018 for the treatment of patients with CLL/SLL, with or without del(17p), following at least 1 prior therapy. The FDA simultaneously approved the BCL-2 inhibitor for use in combination with rituximab in the same patient population. In September 2018, the FDA added MRD data from the MURANO trial to the label for venetoclax for its approved use in combination with rituximab for previously-treated patients with CLL.

References

1. Kater AP, Hillmen P, Eichhorst B, et al. First Prospective Data on Impact of Minimal Residual Disease on Long-Term Clinical Outcomes after Venetoclax Plus Rituximab Versus Bendamustine Plus Rituximab: Phase III MURANO Study. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 695.
2. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa171397.

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