Updated follow-up analysis of the phase III E1912 study showed that ibrutinib/rituximab induced higher rates of progression-free survival (PFS) when compared against fludarabine, cyclophosphamide, and rituximab in patients ≤70 years with previously untreated chronic lymphocytic leukemia (CLL), according to Tait D. Shanafelt, MD, who presented the findings at the 2019 ASH Annual Meeting.
Tait D. Shanafelt, MD
Updated follow-up analysis of the phase III E1912 study showed that ibrutinib/rituximab (IR) induced higher rates of progression-free survival (PFS) when compared against fludarabine, cyclophosphamide, and rituximab (FCR) in patients ≤70 years with previously untreated chronic lymphocytic leukemia (CLL), according to Tait D. Shanafelt, MD, who presented the findings at the 2019 ASH Annual Meeting.
After a median follow-up of 48 months, the hazard ratio (HR) for PFS remained stable compared with data released at the 2018 ASH Annual Meeting. Results continued to favor IR over FCR (HR, 0.39; 95% CI, 0.26-0.57; P < .0001).1The HR at of the 3 year follow-up was 0.35 (95% CI, 0.22-0.56;P< .001). The 3-year PFS rates were 89.4% in the ibrutinib/rituximab arm versus 72.9% in the FCR arm.2
The HR for overall survival (OS) also favored IR over FCR (HR, 0.34; 95% CI, 0.15-0.79;P= .009). The 3-year OS rates were 99% in the IR arm compared with 93% in the FCR arm.
Some 73% (n = 257) of IR patients remain on treatment at the latest follow-up. Only 7% of patients in this arm progressed while on therapy, noted Shanafelt, an associate dean of the School of Medicine and director of the WellMD Center at Stanford Medicine, California.
In E1912, which enrolled patients with CLL who required therapy, 354 patients were randomized to IR and 175 were randomized to FCR. Patients with deletion 17p13 were excluded from E1912 given their known poor response to FCR therapy. The rate ofTP53mutation was higher in the IR arm compared with the FCR arm (9% vs 3%, respectively).
Throughout the trial, ibrutinib was administered at 420 mg orally on days 1 to 28 until progression. In cycle 1, patients received ibrutinib alone and in cycle 2 patients were administered ibrutinib with rituximab at 50 mg/m2intravenously (IV) on day 1 and at 325 mg/m2on day 2. For cycles 3 to 7, rituximab was given at 500 mg/m2IV on day 1 along with baseline ibrutinib. FCR was given at the standard dose for 6 cycles. The median age of the overall study population was 58 years.
Results through July 18, 2019 were presented. When PFS was evaluated according toIGHVstatus, “ibrutinib appears to be superior to FCR in theIGHVunmutated subset,” Shanafelt said. In this subset, the HR for PFS was 0.28 (95% CI, 0.17-0.48;P<.0001), and the 3-year PFS rates were 89% and 65%, respectively. In those with mutatedIGHV, the HR again favored IR but failed to achieve significance (HR, 0.42; 95% CI, 0.16-1.36;P= .086), and the 3-year PFS rates were 88% and 82%, respectively.
There were 4 deaths due to CLL progression in the FCR arm and only 1 in the IR arm. Two deaths in the FCR arm were due to myelodysplastic syndrome.
Among the 95 patients who discontinued ibrutinib, the median time on treatment prior to discontinuation was 20.3 months. Among all patients who started IR (n = 352), the reasons for ibrutinib discontinuation were progression or death (7%); an adverse event (14%); and another reason (7%), such as other health conditions, patient preference, or lost to follow-up. In the 95 patients who discontinued ibrutinib, 24% did so for progression or death, 51% for an adverse event, and 25% for another reason.
Of those who discontinued ibrutinib for a reason other than progression, the median time to progression after discontinuation was 23.0 months, “indicating that some of these patients have a reasonably long interval before additional therapy is required,” Shanafelt said.
“Among patients who are able to remain on ibrutinib therapy, progression is a rare event,” he said.
The rates of grade ≥3 treatment-related adverse events (TRAEs) throughout the entire study period were 70% in the IR arm and 80% in the FCR arm (OR, 0.56; 95% CI, 0.34-0.90;P= .013).
Grade 3-5 TRAEs that occurred at a significantly greater rate in the IR arm compared with FCR arm were arthralgia (5.1% vs 0.6%), diarrhea (2.6% vs 0.6%), hypertension (8.5% vs 1.9%), atrial fibrillation (2.8% vs 0%), and other cardiac AEs (3.4% vs 0%). Significantly more common grade 3-5 TRAEs in the FCR arm were anemia (15.8% vs 4.3%), hemolysis (2.5% vs 0%), a decrease in the neutrophil count (43% vs 27%), a decrease in the platelet count (15.8% vs 3.1%), febrile neutropenia (15.8% vs 2.3%), and sepsis (3.2% vs 0.6%).
On multivariable analyses evaluating pretreatment factors associated with ibrutinib discontinuation for a reason other than progression or death, only the Cumulative Illness Rating Scale score predicted discontinuation (HR, 1.13 per each unit increase; 95% CI, 1.03-1.23;P= .009).