Paradigm Shift: Ibrutinib plus Rituximab Front-Line Therapy for Patients with CLL Under Age 70

Phoebe Starr

January 2019, Vol 9, No 1 - Leukemia


The combination of the targeted therapy ibrutinib (Imbruvica), a protein kinase inhibitor, and the monoclonal antibody rituximab (Rituxan) extends disease-free survival by 65% and overall survival (OS) by 83% compared with standard-of-care chemotherapy with the fludarabine plus cyclophosphamide and rituximab (FCR) regimen as first-line therapy in patients with chronic lymphocytic leukemia (CLL) under age 70, according to results of the phase 3 ECOG-ACRIN 1912 trial presented at a late-breaking abstract session at the 2018 American Society of Hematology meeting. In addition, patients who received the chemotherapy-free, pill-based ibrutinib plus rituximab regimen had fewer adverse events than the patients who received FCR.

The ECOG-ACRIN 1912 study is the first phase 3 clinical trial to compare ibrutinib plus rituximab with the current standard-of-care FCR regimen in younger patients with CLL.

“We found ibrutinib-based therapy is both more effective and less toxic than our previous best therapy for CLL patients age 70 and under,” said lead investigator Tait D. Shanafelt, MD, Jeanie and Stew Ritchie Professor, Medicine-Hematology, Stanford University School of Medicine, CA.

“These findings have immediate practice-changing implications. They establish the combination of ibrutinib plus rituximab as the most effective first-line treatment to date for CLL patients age 70 and younger.”

“In this group of patients, CLL has a greater impact on life expectancy, because CLL developed at a younger age than is typical. Patients enrolled in the trial were a higher-risk group than in historical studies,” Dr Shanafelt commented.

The ECOG-ACRIN 1912 Trial

Between January 2014, and June 2016, ECOG-ACRIN 1912 randomized 529 patients with CLL in a 2:1 ratio to first-line therapy with ibrutinib plus rituximab versus chemotherapy with the FCR regimen. In the ibrutinib plus rituximab arm, patients received ibrutinib monotherapy for the first month, and rituximab was added for a total of 7 cycles, followed by ibrutinib monotherapy until disease progression. The FCR regimen was given for 6 cycles.

Patients who enrolled in the trial had Rai stage I to IV CLL and were symptomatic, requiring CLL treatment. No patient had 17p deletions, and approximately 71% of the patients did not have IGHV mutation. The median age was 57 years (range, 28-70 years).

The median progression-free survival (PFS) and OS were not reached at a median follow-up of 33.4 months. Ibrutinib plus rituximab reduced the likelihood of disease progression by 65% compared with FCR. In the ibrutinib plus ri­tuximab arm, 37 disease progression events occurred in 354 patients versus 40 events in 175 patients in the FCR arm (P <.00001). A subgroup analysis of PFS showed the superiority of ibrutinib plus rituximab versus FCR, irrespective of age, sex, performance status, and disease stage.

The OS was also improved by 83% in the ibrutinib plus rituximab arm. Overall, 4 deaths occurred in the ibrutinib plus rituximab arm versus 10 deaths in the FCR arm (P = .0003).

Adverse Events

The ibrutinib plus rituximab regimen was much less toxic than the FCR regimen. Grades 3 to 5 treatment-related adverse events were reported in 58.5% of patients in the targeted therapy arm versus 72% of patients in the chemotherapy arm (P = .004). The rates of grades 3 to 5 neutropenia, anemia, thrombocytopenia, infection, and neutropenic fever were significantly lower with ibrutinib plus rituximab versus FCR (P <.001 for all). Patients who received ibrutinib had significantly more grade 3 to 5 hypertension versus patients who received FCR (7.4% vs 1.9%, respectively; P = .01).

At a press conference, Dr Shanafelt and other experts pointed out that these findings represent a paradigm shift from 6 months of treatment with intravenous chemotherapy to unlimited treatment with an oral tablet.

Two questions that remain unanswered are (1) whether long-term ibrutinib therapy can be eliminated by using more aggressive therapy upfront, such as combination therapies that include venetoclax (Venclexta), and (2) whether rituximab treatment can be eliminated in these younger patients. Studies are underway to answer these questions.

“The most important take-home message is that this late-breaking study demonstrates a paradigm shift away from chemotherapy to targeted therapy to improve outcomes for our patients,” said Aaron Gerds, MD, MS, Assistant Professor in Medicine (Hematology and Medical Oncology), Cleveland Clinic Taussig Cancer Institute, OH. “This study should change practice.”