Imbruvica Plus Novel Agent May Improve Progression-Free Survival in Chronic Lymphocytic Leukemia

Adding TG-1101 (ublituximab) to Imbruvica (ibrutinib) to treat patients with relapsed or refractory high-risk chronic lymphocytic leukemia (CLL) led to a higher overall response rate compared with Imbruvica alone, according to a study published in Lancet Haematology.

TG-1101 is a novel anti-CD20 monoclonal antibody, which targets an antigen commonly found on the surface of B cells and plays a role in CLL. Researchers assessed the addition of TG-1101 to Imbruvica, a drug that binds to a protein — Bruton’s tyrosine kinase (BTK) — within B cells, to see whether outcomes can be improved compared with Imbruvica alone.

“BTK inhibitors have dramatically improved outcomes for patients with CLL, but particularly among those individuals with high-risk disease,” said Dr. Jeff Sharman, medical director of Hematology Research U.S. Oncology at Willamette Valley Cancer Institute in Eugene, Oregon, in an interview with CURE®. “Nonetheless, patients with high-risk genetic risk factors still have inferior outcomes relative to patients without high-risk features. We wanted to determine if adding the novel anti-CD20 antibody (TG-1101) could improve outcomes among patients with relapsed/refractory CLL harboring high-risk features.”

In this phase 3 trial, researchers analyzed data from 126 patients with relapsed or refractory CLL who previously received at least one therapy for their disease. These patients also had high-risk cytogenetics, or chromosomes, defined as the presence of a 17p deletion, 11q deletion or TP53 mutation.

“Patients with (17p deletion)/TP53 mutations have consistently demonstrated inferior outcomes,” said Sharman. “In contrast, although early publications demonstrated less favorable outcomes among individuals with (11q deletion) treated with BTK inhibitors, more recent publications have questioned if this remains an adverse outcome.”

Patients were assigned either Imbruvica with TG-1101 (64 patients) or Imbruvica alone (62 patients), which were both administered in 28-day cycles in outpatient settings. Imbruvica was given as a 420 mg oral dose once per day. TG-1101 was administered intravenously at varying doses throughout the first cycle, which then stabilized at 900 mg per day on the first day of the second through sixth cycles. Both treatments were administered until unacceptable toxicity, disease progression or withdrawal of consent from the trial.

Researchers assessed endpoints including overall response rate, which was defined as the percentage of patients who had a complete response or partial response to the therapy, in addition to those with a complete response with incomplete marrow recovery. Safety was also analyzed in patients throughout the trial.

During a median follow-up of 41.6 months, the overall response rate was 83% in patients assigned Imbruvica with TG-1101 compared with 65% in those assigned Imbruvica alone. Researchers also monitored for progression-free survival based on the presence of certain high-risk cytogenetics.

“We show that adding (TG-1101) to (Imbruvica) provides clinically meaningful and statistically significant benefits to progression-free survival among patients with (17p deletion)/TP53 mutations,” said Sharman. “We did not see similar improvements among patients with (11q deletion).”

Safety analyses included 117 of the patients in the trial who received at least one dose of the assigned treatment. Most side effects were grade 1 or 2, or mild to moderate. The most common grade 3 or 4 (severe to life-threatening) side effects observed in patients assigned Imbruvica with TG-1101 or Imbruvica alone included anemia (lack of red blood cells; 8% vs. 9%, respectively), neutropenia (low counts of a type of white blood cell called neutrophils; 19% vs. 12%, respectively) and diarrhea (10% vs. 5%, respectively). In addition, the most common serious side effects were atrial fibrillation (fast, irregular heartbeat; 7% vs. 2%, respectively), pneumonia (10% vs. 7%), febrile neutropenia (fever during neutropenia; 5% vs. 2%, respectively) and sepsis (illness from the body’s response to infection; 7% vs. 2%, respectively).

Two patients assigned Imbruvica with TG-1101 died from failure to thrive and from cardiac arrest, although neither were associated to the treatment. In contrast, five patients assigned Imbruvica alone died from either stroke, cardiac arrest, a specific type of pneumonia and brain bleed, whereas one death was unexplained. The only death related to the treatment was the one caused by cardiac arrest.

Despite the findings of this trial, questions remain regarding the use of drugs like TG-1101 in this specific patient population.

“The role of anti-CD20 antibodies added to (Bruton’s tyrosine kinase) inhibitors remains unsettled,” said Sharman. “Whether it is the nature of the (Bruton’s tyrosine kinase) inhibitor or the type of anti-CD20 antibody which provides benefits remains uncertain.”

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