In This Article
- 5-Year Ibrutinib Therapy in Treatment-Naïve Patients with Relapsed or Refractory CLL or SLL
- Updated Safety and Efficacy Data for Ibrutinib as First-Line Treatment in Older Patients with CLL or SLL
- Long-Term Follow-Up of Chlorambucil plus Rituximab Combination as Frontline Therapy for Elderly and/or Unfit Patients with CLL, Including Risk Stratification
- Reviewing the Demographics and First-Line Treatment Patterns in Patients with CLL
- Comparing Healthcare Utilization of 2 Drug Regimens in Patients with CLL
5-Year Ibrutinib Therapy in Treatment-Naïve Patients with Relapsed or Refractory CLL or SLL
In the long-term, phase 1b/2 PCYC-1102 clinical trial, single-agent ibrutinib, the first FDA-approved once-daily Bruton’s tyrosine kinase inhibitor, showed efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL), including patients with deletion (del)17p.
The study included 132 patients (aged ≥65 years) with treatment-naïve (N = 31) or with relapsed or refractory (N = 101) CLL or SLL to ibrutinib 420 mg or 840 mg daily until disease progression or until unacceptable toxicity. The overall response rate (ORR), including partial response with lymphocytosis, was assessed based on risk group, including lack of IGHV mutation, complex karyotype, and based on hierarchical order for del17p then del11q.
At 5 years of follow-up, the longest study period for single-agent ibrutinib in this patient population, the ORR was 89%, including complete response (CR) of 14%, for all patients. The ORR was 87% in the treatment-naïve arm (CR, 29%), and 89% in the relapsed or refractory arm (CR, 10%).
The median progression-free survival (PFS) was not reached in the treatment-naïve arm compared with 52 months in the relapsed or refractory arm; the estimated 60-month PFS rates were 92% and 43%, respectively. In the relapsed or refractory arm, the median PFS was 55 months in patients with del11q; 26 months for patients with del17p; and the PFS was not reached in patients without del17p, del11q, trisomy 12, or del13q. Furthermore, the median PFS was 33 months in patients with complex karyotype; it was not reached in patients without complex karyotype; it was 43 months in patients without IGHV mutation, and 63 months in patients with IGHV mutation.
The 5-year overall survival (OS) was 92% in treatment-naïve patients and 57% in those with relapsed or refractory disease. The median OS was not reached in treatment-naïve patients; it was 63 months in patients who received 1 to 2 previous treatments, 59 months in patients who received 3 previous treatments, and 39 months in those who received ≥4 previous regimens. The median duration of response was not reached in treatment-naïve patients and was 45 months in patients with relapsed or refractory disease.
In all patients, the onset of treatment-emergent grade ≥3 adverse events (AEs) was highest in year 1 of therapy and was lower in subsequent years. At approximately 5 years of follow-up, the most common grade ≥3 AEs were, in order of frequency, hypertension, pneumonia, neutropenia, and atrial fibrillation; most of these events decreased over time.
Overall, ibrutinib demonstrated durable responses in patients with treatment-naïve or with relapsed or refractory CLL or SLL, including those with del17p, del11q, or without IGHV mutation. Long-term ibrutinib therapy was effective and well-tolerated, with a manageable safety profile, with 65% of treatment-naïve older patients and 30% of patients with relapsed or refractory disease continuing treatment at 5 years of follow-up.
Updated Safety and Efficacy Data for Ibrutinib as First-Line Treatment in Older Patients with CLL or SLL
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) occur mainly in older patients, who are likely to have several comorbidities and who often are unable to receive aggressive drug therapies, such as alkylating drugs, which are typically used for patients with CLL or SLL. Ibrutinib is the first FDA-approved once-daily inhibitor of Bruton’s tyrosine kinase indicated for the treatment of patients with CLL/SLL, thereby allowing this patient population to receive treatment without chemotherapy.
The phase 3 RESONATE-2 clinical trial compared the efficacy and safety of ibrutinib and chlorambucil in patients (aged ≥65 years) with treatment-naïve CLL or SLL; at a median of 18.4 months of follow-up, ibrutinib showed significant reduction in the risk for disease progression or death by 84%.
Updated results for the RESONATE-2 study at a follow-up of 29 months were reported by Barr and colleagues for treatment-naïve patients with CLL or SLL. A total of 269 patients (median age, 73 years) with treatment-naïve CLL or SLL were randomized to receive ibrutinib 420 mg daily until disease progression or chlorambucil 0.5 mg/kg (maximum 0.8 mg/kg) on days 1 and 15 of a 28-day cycle, for a total of up to 12 cycles. Patients with deletion (del)17p were excluded from this extension study. Patients who received chlorambucil whose disease progressed were allowed to cross over to the ibrutinib arm. The primary end point was progression-free survival (PFS); the secondary end point was overall survival (OS).
At a median of 29 months of follow-up, the increased duration of PFS was sustained, at 89%, with ibrutinib versus 34% with chlorambucil at 24 months. The PFS improved significantly with ibrutinib versus chlorambucil at all the high-risk subgroups, including those with del11q and those without IGHV mutation. Ibrutinib demonstrated a 99% reduction in the risk for disease progression or death, and a 92% reduction in the subgroup of patients with del11q.
Overall, 41% of patients switched from chlorambucil to ibrutinib; the 2-year OS rates based on the OS analysis in the intent-to-treat population resulted in estimated rates of 95% in the ibrutinib arm and 84% in the chlorambucil arm. Similarly, the investigator-assessed overall response rate was 92% with ibrutinib and 36% with chlorambucil.
Ibrutinib showed higher sustained hematologic improvements from baseline versus chlorambucil in patients with anemia (90% vs 45% improvement in hemoglobin) and thrombocytopenia (80% vs 46% improvement in platelet counts). Grade ≥3 adverse events (AEs) in ≥5% of patients included neutropenia, pneumonia, anemia, and hypertension; AEs of any grade leading to dose reductions were reported in 13% of patients. The incidence of the common grade ≥3 AEs in the ibrutinib-treated patients typically decreased over time. Overall, important AEs decreased in frequency with longer follow-up.
At a median of 29 months, ibrutinib continued to demonstrate significant efficacy, with an 88% reduction in the risk for disease progression or death versus chlorambucil.
Long-Term Follow-Up of Chlorambucil plus Rituximab Combination as Frontline Therapy for Elderly and/or Unfit Patients with CLL, Including Risk Stratification
Elderly patients with chronic lymphocytic leukemia (CLL) and younger patients with comorbidities often receive treatment with chlorambucil despite the relative low response rates. Adding an anti-CD20 monoclonal antibody to chlorambucil therapy has been shown to increase the response rates substantially and does not negatively affect tolerability.
A retrospective analysis using results from 15 Italian centers was undertaken to assess the safety and efficacy of the chlorambucil plus rituximab regimen as a frontline therapy in patients aged ≥65 years and/or patients with unfit CLL (Cumulative Illness Rating Scale >6), and to identify patients for whom this regimen could be especially effective.
A subgroup analysis stratified patients according to fluorescence in situ hybridization (FISH) and IGHV mutation. The high-risk group included patients with deletion (del)17p, the intermediate-risk group included patients with del11q and/or no IGHV mutation, and the low-risk group comprised patients without del11q or del17p and/or no IGHV mutation.
A total of 102 patients who had received treatment between 2009 and 2011 were included in the study. The median number of cycles administered was 8 (range, 2-12) with chlorambucil and 6 (range, 1-9) with rituximab. The main 2 treatment schedules were chlorambucil 1 mg/kg administered at each cycle every 28 days, with a fixed daily dose of 10 mg starting from day 1 and repeated during the 8 cycles, and chlorambucil 8 mg/m2 administered each day for 7 days of the 8 cycles of 28 days each. From the third cycle, rituximab was added to chlorambucil; rituximab was given on day 1 of each cycle; rituximab at 375 mg/m2 was used at the first dose and 500 mg/m2 for the next 5 cycles.
Based on an intent-to-treat analysis, the overall response rate (ORR) with this regimen was 87.1%. Overall, 31.7% of patients had a complete response and 55.4% had a partial response. No significant differences in ORR were reported based on age, fitness status, Eastern Cooperative Oncology Group performance status, bulky disease, cytogenetic risk abnormalities, IGHV mutational status, ZAP-70, or CD38 expression. The median progression-free survival (PFS) was 43.7 months and the time to retreatment was 72.3 months.
The median overall survival was not reached by the time of the analysis; 86.1% and 81.2% of patients were alive at 48 months and 60 months, respectively.
The most common serious adverse event (AE) was grade 3 or 4 neutropenia. Grade 3 or 4 extrahematologic AEs were uncommon. According to a subgroup analysis, patients in the low-risk group had a significantly better PFS than those in the intermediate-risk group (65.8 months vs 35.2 months, respectively); 54.9% of patients had progression-free disease at 60 months of treatment.
These results indicate that in elderly and/or unfit patients with CLL, treatment with chlorambucil and rituximab is associated with low toxicity, high ORR, and durable PFS. Particularly good results were seen in patients with an IGHV mutation and no del17p or del11q, suggesting that in this low-risk subset of unfit patients, chlorambucil plus rituximab could represent the optimal therapeutic option.
Reviewing the Demographics and First-Line Treatment Patterns in Patients with CLL
In 2016, approximately 18,960 Americans were estimated to be diagnosed with chronic lymphocytic leukemia (CLL), and 4660 were estimated to die from the disease. The overall estimated 5-year survival rate of CLL in the United States in 2016 was 82.6%. Despite this, the outcomes in patients with this type of cancer who have specific genetic features, such as deletion (del)17p, are less positive when they receive conventional chemoimmunotherapy, such as the combination of fludarabine and cyclophosphamide or bendamustine plus rituximab.
In the past 3 years, several new treatments have been approved by the FDA for the treatment of treatment-naïve patients with CLL, including obinutuzumab (Gazyva), and ibrutinib (Imbruvica). Using the Flatiron’s provider network database, a real-world database that is focused on oncology, investigators assessed demographics and treatment patterns in the past few years.
The Flatiron database includes 230 oncology clinics and >1 million patients with cancer across the United States. As of June 2016, the cohort included 1033 patients diagnosed with CLL between 2011 and 2015 (median age, 70 years) from this database. The distribution of first-line therapies that were initiated between 2011 and 2013 was relatively constant. After the introduction to the market of obinutuzumab in 2014 and ibrutinib in 2015, the use of first-line obinutuzumab plus chemotherapy with chlorambucil increased from 7.2% in 2013 to 13.6% in 2015; similarly, the use of ibrutinib monotherapy or ibrutinib plus rituximab (Rituxan) increased from 9.8% in 2014 to 12.3% in 2015.
Of note, regimens containing fludarabine declined from 21.5% in 2011 to 8.4% in 2015. In addition, the use of rituximab monotherapy declined from 27.7% to 17.3%; and the use of bendamustine plus rituximab declined from 36.1% to 31.6%, and rituximab plus fludarabine plus cyclophosphamide from 4.6% to 2.2% between 2011 and 2015. The reasons that were associated with chlorambucil treatment, as monotherapy or in combination with another agent, versus chemoimmunotherapy included the patient’s older age and Rai stage. Approximately 20% of patients with del17p received treatment with ibrutinib.
From 2011 to 2015, real-world changes in the use of first-line treatment for CLL showed an increased use of newer agents, although no single standard of care was established. Second-line therapy reflects a similar degree of heterogeneity, and no uniform sequencing of therapies has been observed.
Comparing Healthcare Utilization of 2 Drug Regimens in Patients with CLL
It is estimated that 18,960 new cases of chronic lymphocytic leukemia (CLL) were diagnosed in 2016, and 4660 deaths. This type of cancer is more often in older individuals (median age, 71 years) at diagnosis than in patients age <55 years (11%) in the United States. The median survival in patients with CLL ranges from 2 years to >10 years. The first-line standard of care for patients with CLL without deletion (del)17p is a combination chemotherapy with the regimen of fludarabine, cyclophosphamide, and rituximab (FCR) or with the regimen of bendamustine plus rituximab (BR).
An analysis of administrative claims from the Truven Health MarketScan Research database was used to examine differences in healthcare utilization between 2 cohorts of newly diagnosed patients with CLL who received treatment either with BR or FCR. In addition, the investigators analyzed differences across age-groups.
A total of 1795 patients with newly diagnosed CLL were identified who received treatment with first-line BR (N = 946) or with FCR (N = 849). Patients in the BR cohort were significantly older, included more women, and more often had comorbidities compared with the patients who received treatment with the FCR regimen (P <.05 for all differences).
The patients who received the BR regimen had significantly fewer outpatient visits than the patients in the FCR cohort during the first 6 months of therapy, as well as during months 12 to 18 (14.05 vs 17.03, respectively); across all follow-up periods, the patients in the BR cohort were also less likely to have a visit to the emergency department or to be hospitalized (odds ratio [OR], 0.66; P <.05).
Some differences were especially clear between the 2 cohorts. The patients in the FCR cohort who were older (age ≥70 years), had, on average, more outpatient visits (OR for emergency department visit, 1.14), and a greater likelihood of an emergency department visit or a hospitalization stay (OR for hospitalization, 1.50) than the patients in the BR cohort.
Overall, these results suggest that the healthcare utilization among patients with CLL who continue to use the BR regimen is significantly lower than the healthcare utilization of patients who use the FCR regimen long-term. Furthermore, patients aged ≥70 years who received treatment with the FCR regimen had significantly more hospitalizations, outpatient visits, and visits to the emergency department than those who received treatment with the BR regimen.
These results support the use of BR as an effective and safe chemoimmunotherapy option for elderly patients with CLL in the era of novel agents and immunotherapies.