1. Fuerst, Mark L.

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SAN DIEGO-Ibrutinib-based therapy is a more effective and safer first-line therapy for younger patients with previously untreated chronic lymphocytic leukemia (CLL) than the current standard of care, according to a new study presented at a press conference at the 2018 ASH Annual Meeting (Abstract LBA-4).

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The results of a head-to-head phase III trial show ibrutinib plus rituximab therapy induced a two-thirds reduction in the risk of disease progression and significantly improved overall survival (OS) relative to the standard treatment of IV fludarabine, cyclophosphamide, and rituximab (FCR).


A 6-month course of FCR has historically been the most effective treatment for CLL, especially in patients 70 years of age and younger. "We have seen tremendous improvement in the efficacy of CLL treatment with the development of chemo-immunotherapy. FCR is the most active chemo-immunotherapy regimen developed to date," said lead author Tait D. Shanafelt, MD, of the Stanford University School of Medicine.


"We found ibrutinib-based therapy is both more effective and less toxic than our previous best therapy for CLL patients. These findings have immediate practice-changing implications. They establish the combination of ibrutinib plus rituximab as the most effective first-line treatment for CLL patients age 70 and younger."


The elucidation of CLL B-cell biology has identified novel therapeutic targets. Targeted therapy with ibrutinib was designed, in part, to interrupt or target Bruton's tyrosine kinase, a protein that is critical to the survival of CLL leukemia cells. "Ibrutinib targets the Achilles' heel of CLL cells, whereas previous chemotherapy was much less targeted," noted Shanafelt.


Initial trials of ibrutinib demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Subsequent phase III trials showed improved progression-free survival (PFS) and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients.


"Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients under age 70 relative to the most efficacious chemo-immunotherapy regimens, such as FCR, is unknown," said Shanafelt, who noted that CLL is one of the most common lymphoid malignancies, accounting for 11 percent of lymphoid neoplasms.


Study Details

The trial enrolled 529 patients, median age 57 years, with previously untreated, symptomatic CLL between Jan. 31, 2014, and June 9, 2016. Two-thirds of patients received ibrutinib plus rituximab (354 patients) and one-third received a 6-month course of FCR (175 patients).


Patients were randomly assigned to receive ibrutinib 420 mg per day until disease progression and rituximab 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2,500 mg/m2 on day 1 of cycles 3-7, or six courses of IV fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 1-3 with rituximab 50 mg/m2 on day 1 of cycle 1,325 mg/m2 on day 2 of cycle 1,500 mg/m2 on day 1 of cycles 2-6 every 28 days. Those with deletion 17p were excluded from participating given the poor response of these patients to FCR therapy.


After a median 33.4 months at the time of the analysis, PFS was significantly better in patients who received ibrutinib plus rituximab compared with FCR. The researchers observed 37 events in the ibrutinib-based group and 40 events in the FCR group, leading to a hazard ratio (HR) of 0.35 in favor of ibrutinib-rituximab. In addition, the HR for OS also favored the ibrutinib-rituximab arm (0.17).


In subgroup analyses for PFS, ibrutinib-based therapy was superior to FCR independent of age, sex, daily living abilities (performance status), and disease stage, and was also superior for IGHV unmutated patients, but not IGHV mutated patients.


The ibrutinib-treated patients also experienced fewer side effects. Grade 3 and 4 treatment-related adverse events were observed in 58 percent of the ibrutinib group and 72 percent of the FCR-treated patients. FCR was more frequently associated with grade 3 and 4 neutropenia (44%) as compared to the ibrutinib-based therapy (23%) and infectious complications as well (17.7% vs. 7%, respectively).


Researchers will continue to monitor patients to determine the durability of these results and how they evolve over time. "We know FCR does some collateral damage to the immune system that can be long-lasting and leave patients vulnerable to infections, whereas ibrutinib can enhance immune function," said Shanafelt. "Understanding the long-term effects of these two therapies on the immune system and the risk of infection will be very informative."


In conclusion, Shanafelt stated: "Ibrutinib and rituximab provides superior PFS and OS compared to FCR for patients with previously untreated CLL. Ibrutinib and rituximab were well-tolerated in patients under age 70. These results establish ibrutinib and rituximab as the most efficacious first-line therapy for patients with CLL under age 70. Future studies evaluating combination strategies are needed to determine if the need for indefinite therapy can be eliminated should be pursued."


Mark L. Fuerst is a contributing writer.