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Single-agent ibrutinib significantly prolongs survival in older patients with CLL
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ORLANDO, Fla. — Ibrutinib monotherapy yielded superior PFS, OS and overall response rates compared with chlorambucil in older patients with chronic lymphocytic leukemia or small lymphocytic leukemia, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.
“The majority of CLL patients with small lymphocytic leukemia [SLL] are elderly, with frequent comorbidities,” Alessandra Tedeschi, MD, a hematologist at Niguarda Hospital in Milan, said during a press conference. “As a consequence, the clinical activity in these patients may not be reached, which may prevent them from achieving their potential lifespan.”
Alessandra Tedeschi
Although alkylating therapies like chlorambucil are commonly used in these patients, novel therapies are needed, according to Tedeschi.
Thus, Tedeschi and colleagues sought to evaluate the safety and efficacy of ibrutinib (Imbruvica; Pharmacyclics, Janssen) — an FDA-approved oral Bruton’s tyrosine kinase inhibitor — in this patient population. Ibrutinib previously demonstrated high activity in older patients (≥ 65 years) with treatment-naive CLL, according to study background.
The researchers compared single-agent ibrutinib with chlorambucil among 269 treatment-naive older patients (median age, 73 years; 70% ≥ 70 years) with CLL or SLL. Forty-five percent of patients had an advanced Rai stage, 20% had deletion 11q and 69% had baseline comorbidities.
The researchers randomly assigned patients aged 65 years or older to ibrutinib (420 mg daily until progression) or chlorambucil (0.5-0.8 mg/kg on days 1 and 15 of a 28-day cycle, for up to 12 cycles).
PFS served as the primary endpoint. Secondary endpoints included OS, ORR — which included complete response (CR) and complete response with incomplete blood count recovery (CRi) — rate of hematologic improvement and safety.
The researchers allowed patients with independent review committee (IRC)-confirmed progression to transfer to an extension study where next-line therapy, including ibrutinib, could be initiated.
Forty percent of patients assigned chlorambucil completed 12 cycles of therapy (median dose, 0.6 mg/kg).
After a median follow-up of 18.4 months, patients assigned ibrutinib achieved significantly longer PFS as assessed by the IRC (median not reached vs. 18.9 months; HR = 0.16; 95% CI, 0.09-0.28) and by investigators (18-month PFS, 93.9% vs. 44.8%; HR = 0.09; 95% CI, 0.04-0.17).
Further, ibrutinib significantly prolonged OS (median not reached for either arm; HR = 0.16; 95% CI, 0.05-0.56), and more patients assigned ibrutinib achieved 2-year OS (98% vs. 85.3%).
Three deaths occurred in the ibrutinib arm, compared with 17 deaths in the chlorambucil arm.
The IRC-assessed ORR for ibrutinib was 86% (4.4% CR/CRi) vs. 35.3% (1.5% CR/CRi) for chlorambucil. ORR was higher for ibrutinib at all evaluated time points.
Investigator-assessed ORR for ibrutinib was 90.4% (9.6% CR/CRi) vs. 35.3% (4.5% CR/CRi) for chlorambucil.
The researchers observed significant reductions in lymph node burden (91.2% vs. 36.8%; P < .0001) and spleen enlargement (75.7% vs. 39.1%; P < .0001) among patients assigned ibrutinib.
Sustained hematologic improvements occurred at significantly higher rates among patients assigned ibrutinib, including patients with baseline anemia (84% vs. 45%; P < .0001) or thrombocytopenia (77% vs. 43%; P = .0054).
The median duration of treatment was 17.4 months for patients assigned ibrutinib and 7.1 months for chlorambucil.
The most frequent adverse events included diarrhea, fatigue, cough and nausea for ibrutinib, and nausea, fatigue, neutropenia, anemia and vomiting for chlorambucil. Fewer patients assigned ibrutinib discontinued treatment due to adverse events (9% vs. 23%).
Atrial fibrillation occurred in 6% of patients assigned ibrutinib and 1% of patients assigned chlorambucil. Hypertension occurred more frequently in the ibrutinib arm; however, it was managed without dose modification or discontinuation.
Major hemorrhage occurred in 4% of patients assigned ibrutinib and 2% of patients assigned chlorambucil over a median follow-up of 1.5 years.
At the time of study closure, 87% of patients assigned ibrutinib remained on treatment.
“Most interestingly, ibrutinib significantly improved bone marrow function,” Tedeschi said. “This is very important for elderly patients, for whom bone marrow failure is a common cause of death. In this older population with high comorbidities, the majority of patients continue on treatment with ibrutinib. Thus, ibrutinib should be considered as a first-line treatment.” – by Cameron Kelsall
Reference:
Tedeschi A, et al. Abstract 495. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Tedeschi reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Ajay K. Gopal, MD
Investigators in Europe randomly assigned patients aged older than 65 years with chronic lymphocytic leukemia to receive ibrutinib (Imbruvica; Pharmacyclics, Janssen) or chlorambucil. This is important because this subset of patients may not tolerate highly intensive chemotherapy-based therapies. This trial’s findings showed that there was a more than doubling of PFS rate, from about 44% at 18 months with chlorambucil to over 90% at 18 months with ibrutinib. This is clearly statistically significant and clinically meaningful. Importantly, there was also an OS benefit.Should this change practice? This remains to be seen, because single-agent chlorambucil is rarely used as a standard therapy, at least in the U.S. for patients with advanced CLL. Typically, any modern therapy is combined with an anti-CD20 monoclonal antibody. The major caveat of this study was that the comparator arm was not the standard of care, certainly not in the U.S. Unfortunately, trials such as these are often designed to gain approval rather than address the most clinically meaningful questions.
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