Venetoclax Plus Obinutuzumab Leads to Long-Lasting MRD Negativity in Patients with CLL

In a multinational, open-label phase 3 CLL14 trial, researchers have determined that fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) induced deep, high, and long-lasting minimal residual disease negativity (MRD), or less than 1 myeloma cell per million bone marrow cells, in previously untreated patients with chronic lymphocytic leukemia (CLL). The findings were presented at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois and simultaneously published in the New England Journal of Medicine (NEJM).

“The vast majority of geriatric patients with CLL have clinically relevant comorbidities. Such unfit patients require a less toxic regimen,” lead study author Kirsten Fischer, MD, said in the presentation. “However, if we look at the standard of care for these patients, it is either fixed duration chemotherapy or continuous, indefinite targeted therapy. That was the reason that we decided to develop a new therapy: a fix-duration targeted therapy.”

The study included 432 patients with CLL who were randomized to receive either chlorambucil-obinutuzumab (ClbG), as the standard-of-care therapy, or venetoclax 400 mg daily plus obinutuzumab for 6 cycles. Investigators examined the MRD in peripheral blood and bone marrow approximately 3 months after treatment.

“We were aware that the chlorambucil-obinutuzumab treatment has a 31-month progression free survival, but that same information was unknown for venetoclax with obinutuzumab,” explained Dr Fischer.

Dr Fischer and her team found that venetoclax plus obinutuzumab slowed progression-free survival and achieved MRD much greater (76%) than ClbG, 3 months after treatment ended. Higher MRD rates were achieved early and were more sustainable with venetoclax plus obinutuzumab, with 81% of patients who were MRD-negative compared with 27% of patients with ClbG 12 months after they finished treatment, the researchers found.

At 2 years, 1 year after stopping treatment, nearly 9 out of 10 patients (88.2%) in the venetoclax plus obinutuzumab arm remained progression-free, compared to 64.1% in the ClbG arm. Safety for venetoclax plus obinutuzumab appeared consistent with the known safety profiles of the individual medicines. Common grade 3-4 adverse events with venetoclax plus obinutuzumab, compared to ClbG, were low white blood cell count (52.8% versus 48.1%) and infections (17.5% versus 15.0%).

According to the National Cancer Institute, CLL is a type of cancer in which the bone marrow produces large amounts of lymphocytes, or white blood cells. It is one of the most common types of leukemia in adults and occurs during or after middle age.

“The amount of adverse event was higher in venetoclax plus obinutuzumab, but these events occurred after therapy and were not statistically significant,” explained Dr Fischer. “It is important to note that we [the authors] would not consider these adverse events as indicative of the drug’s safety.”

The FDA approved the combination on May 15, 2019, under the FDA’s Real-Time Oncology Review and Assessment Aid pilot programs, for the treatment of people with previously untreated CLL or small lymphocytic lymphoma.

According to Javier Pinilla-Ibarz, MD, PhD, oncologist at the Moffitt Cancer Center, the CLL 14 trial is bringing back the possibility of having time limited therapy with excellent results in terms of MRD negative status. "It will be part of a new conversation with CLL patients requiring therapy as it will offer the possibility of limited therapy for one year," said Dr. Pinilla-Ibarz in an interview with Specialty Pharmacy Times. "However, different comorbid conditions and the different reasons for which patients require therapy as well as prognostic factors may also play an important role on how we will counsel patients about this new therapies."

“This combination can be applied safely to elderly CLL patients with relevant comorbidity, and provides a superior outcome compared to chlorambucil and obinutuzumab regarding progression-free survival, overall response rate, complete response rate, and MRD-negative responses,” Dr Fischer concluded. “This regimen also achieves the highest the MRD-negative responses that have been so far observed in a randomized prospective study.”

For Dr. Pinilla-Ibarz, the treatment landscape for CLL is shifting constantly. "We have seen the treatment paradigm shift from chemoimmunotherapy to BTK inhibition with long term therapy until progression," he said. "Now the limited paradigm of the old chemoimmunotherapy is back without chemo and it great to see the many alternatives patients will have."

References

Chronic Lymphocytic Leukemia Treatment [website]. National Cancer Institute website. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. Accessed May 29, 2019.

Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of a fixed duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD-) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol 37, 2019 (suppl; abstr 7502). Presented at: 2019 American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2019. Chicago, Illinois.