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Frontline ibrutinib + rituximab superior to gold standard for young patients with CLL

Pearl Toh
12 Dec 2018
Dr Tait Shanafelt

First-line therapy with the BTK* inhibitor ibrutinib plus the anti-CD20 immunotherapy rituximab confers significant survival advantage over the current gold-standard regimen of fludarabine, cyclophosphamide, and rituximab (FCR) for young, fit patients with treatment-naïve chronic lymphocytic leukaemia (CLL), according to the E1912 trial, a large cooperative group study supported by the US National Cancer Institute.

“Ibrutinib and rituximab provides superior PFS and OS** compared with FCR ... [and] was well tolerated in patients aged 70 years,” said study principal investigator Dr Tait Shanafelt from Stanford University in Stanford, California, US.

After a median follow-up of 33.6 months at the first interim analysis, the primary endpoint of PFS was significantly prolonged with ibrutinib + rituximab compared with FCR in both the intent-to-treat (ITT; hazard ratio [HR], 0.35; p<0.00001) and the per-protocol analyses (HR, 0,32; p<0.00001). [ASH 2018, abstract LBA-4]

According to Shanafelt, the between-group difference crossed the boundary for superiority. He also noted that the rates of PFS and OS for FCR group at 3 years were 73 percent and 92 percent, respectively in the current study, which are identical to those observed in the previous GCLLSG CLL10 study which enrolled a similar patient population (70 percent for PFS and 90 percent for OS). “This suggests that FCR performed as expected in the current study,” he said.

Moreover, PFS benefit was seen across subgroups regardless of age, gender, performance status, disease stage, and the presence of splenomegaly.

Importantly, as Shanafelt pointed out, PFS benefit was also seen with ibrutinib + rituximab in the subgroup with unmutated IgVH*** status (HR, 0.26; p<0.00001), which has been associate with a poorer prognosis compared with mutated IgVH. Although the risk of disease progression or death was also lower with ibrutinib + rituximab vs FCR in the IgVH-mutated subgroup, the difference between groups was smaller and not statistically significant (HR, 0.44; p=0.07).

In addition, OS was significantly longer with ibrutinib + rituximab than FCR in the ITT population (HR, 0.17; p<0.0003) as well as the per-protocol population (HR, 0.13; p<0.0001).

In terms of safety, the combination therapy of ibrutinib + rituximab was associated with fewer grade 3 AEs (58.5 percent vs 72.1 percent; p=0.004). In particular, there were significantly lower rates of grade 3 neutropenia, anaemia, thrombocytopenia, and any infection (p<0.001 for all) in the ibrutinib + rituximab group vs the FCR group. “Ibrutinib and rituximab was well tolerated in patients ≤70 years,” said Shanafelt.

The phase III study randomized 529 patients aged ≤70 years (median age 58 years, 32.7 percent female) with untreated CLL (63.3 percent ECOG performance status=0, 71.1 percent IgVH unmutated) in a 2:1 ratio to receive either a combination regimen of ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2 followed by 500 mg/m2 on day 1 of cycles 3–7) or six cycles of intravenous FCR# every 28 days. Patients with IgVH 17p deletion were excluded due to known poor disease response to FCR.

“CLL is one of the most common lymphoid malignancies, accounting for 11 percent of lymphoid neoplasms,” said Shanafelt. “The need for indefinite therapy should be evaluated in future clinical trials testing novel agent combination therapy.”

 


 

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Most Read Articles
Dr. Wong Soon Tee, 28 May 2020
Acne is a common skin problem seen in primary care. Dr Wong Soon Tee of Assurance Skin Clinic at Mt Elizabeth Novena Hospital, Singapore shares his insights with Pearl Toh on how to manage acne in the primary care setting.
11 Aug 2020
During the Allergic Rhinitis (AR) Boot Camp held in conjunction with the Bayer Pharmacist Congress 2020, Professor Dr Baharudin Abdullah discussed the management of AR in the primary care setting and the importance of using patient profiles to guide the choice of antihistamines.
Rachel Soon, 28 Aug 2020
MOH Director-General Tan Sri Dato' Seri Dr Noor Hisham Abdullah speaks about NHMS 2019 and pharmacists' roles in combating NCDs among Malaysians.
Audrey Abella, 07 Sep 2020
Mavacamten, a first-in-class myosin inhibitor, may be the first targeted therapy to address the underlying cause of obstructive hypertrophic cardiomyopathy (OHCM), the EXPLORER-HCM trial has shown.