Five-Year Follow-Up Shows Response to Ibrutinib Deepens Over Time for CLL Patients

Treatment with continuous, single-agent ibrutinib led to durable responses in patients with chronic lymphocytic leukemia (CLL), even among previously untreated patients, patients older than 65 years, and those with TP53 mutations.

“In most cancers, with the notable exception of chronic myeloid leukemia, single-agent therapy is limited by the rapid emergence of drug resistance,” wrote Inhye E. Ahn, MD, of the National Heart, Lung, and Blood Institute and co-authors in a recent study published in Blood. “Our data with extended follow-up of patients on ibrutinib suggests that a large proportion of [patients with] CLL achieve durable disease control on single-agent ibrutinib, with excellent tolerability.”

“With continuing the treatment for almost five years, not only were the remissions lasting, but, in many cases, they improved from partial to complete remissions (CR), including some patients who achieved minimal residual disease (MRD) negativity,” Kanti Rai, MD, professor at Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, told ASH Clinical News when asked for comments on the study’s findings. (Read more from Dr. Rai in “Perspectives” at the end of this article.)

The open-label, single-center study enrolled 86 patients (median age = 66 years; range = 33-85 years) between December 2011 and January 2014. Participants had CLL or small lymphocytic lymphoma that required therapy, an Eastern Cooperative Oncology Group performance status score of ≤2, neutrophil count ≥500/µL, and platelet count ≥30,000/µL.

Most patients were treatment-naïve (n=53; 61.6%), had advanced disease (Rai stage III/IV; n=58; 67.4%), and had unmutated immunoglobulin heavy-chain variable region gene (IGHV; n=57; 66.3%). The 33 patients (38.4%) with relapsed/refractory disease had been treated with up to seven prior regimens.

Patients received ibrutinib 420 mg once-daily until disease progression or unacceptable toxicity.

As of December 31, 2017 (data cutoff), 49 patients (57%) remained on study after a median of 4.8 years (range = 4-6 years). Four patients (4.7%) died because of infection (n=3) and cardiac events (n=1). Twenty-five patients discontinued ibrutinib because of progressive disease (23.3%) or adverse events (AEs; 5.8%). Six patients (7.0%) withdrew for various other reasons, and two patients did not meet the eligibility criteria and were excluded.

AEs that led to treatment discontinuation included asymptomatic interstitial pulmonary infiltrates, progressive multifocal leukoencephalopathy, and persistent grade 3 diarrhea with biopsy-confirmed microscopic colitis (n=1 for each). Two patients (2.3%) discontinued because of second malignancies requiring systemic therapy. Nine patients (10.5%) required ibrutinib dose reductions.

“The safety profile of continuous therapy with ibrutinib for [more than] five years was similar to what has been reported with shorter treatment duration,” the researchers reported. “No new safety signals emerged, and most AEs were grade 1 or 2 and transient.” The most common treatment-related grade 3 or 4 hematologic AEs were neutropenia (n=33; 38.4%), thrombocytopenia (n=13; 15.1%), and anemia (n=6; 7.0%), which occurred “primarily during the first few months of ibrutinib.” Grade 3/4 non-hematologic AEs reported by two or more patients included infection (9.3%), atrial fibrillation (5.8%), diarrhea (3.5%), rash (2.3%), and arthritis (2.3%).

Response after six cycles of therapy (primary endpoint) was evaluable in 81 patients, with an overall response rate (ORR) of 95.1 percent (95% CI 87.8-98.6).

To determine if responses to ibrutinib varied based on high-risk disease or patient age, the researchers evaluated two subgroups: 51 patients with TP53 mutation (median age = 62 years; range = 33-82 years) and 35 older patients (median age = 69 years; range = 63-85 years).

The ORRs in the TP53 and older cohorts were similar to the overall group (95.8 percent and 93.9 percent, respectively), and ORR was not significantly different between subgroups based on treatment history, age, bulky lymphadenopathy, splenomegaly, IGHV subgroups, and baseline β2-microglobulin (all p>0.05). “Onset of response was quick, providing symptomatic relief within days, but long-term therapy was required for complete responses (CRs),” the researchers noted, adding that the most common reason for not achieving CR was residual lymphadenopathy or splenomegaly on computed tomography scans.

See TABLE for all treatment responses.

Continuous treatment with ibrutinib also led to progressively greater clearance of MRD, the authors observed. Median MRD in blood was 5.3×10-2 cells/leukocyte at three years and 4.3×10-2 at four years; median MRD in BM was 7.3×10-2 cells/leukocyte at three years and 6.2×10-2 cells/leukocyte at four years (ranges not provided).

Seven patients who achieved CR were MRD-negative in either blood or BM.

After a median follow-up of 57 months (range not reported), the estimated five-year progression-free survival (PFS) was lower in the TP53 cohort than the older cohort (58.2% vs. 81.2%, respectively; p=0.026). Median five-year overall survival (OS) was 75.7 percent and 83.8 percent, respectively (p=0.10).

In both cohorts, patients with treatment-naïve disease had better survival outcomes, compared with patients with relapsed/refractory disease:

  • TP53 cohort: 74.4% vs. 19.4% for PFS (p=0.0002) and 85.3% vs. 53.7% for OS (p=0.023)
  • older cohort: no disease progression or deaths were reported in the treatment-naïve cohort, while the five-year PFS and OS were 64.8% and 71.6%, respectively

Overall, 20 patients experienced disease progression after a median of 37.6 months (range = 0.4-54.7 months); four patients (4.8%) had Richter’s transformation and two (2.4%) had prolymphocytic transformation. Seven of these patients (35%) were alive at data cutoff.

“Most previously untreated patients, even those with a TP53 aberration, achieved durable responses, making intensification of therapy less urgent and avoidance of unnecessary toxicity more important,” the authors concluded. “Future research should aim to identify patients at risk of early treatment failure who would benefit most from combination therapy.”

The study is limited by its small patient population and lack of a comparator arm. Also, “due to the preferential inclusion of patients with TP53 aberration, the genetic risk profile is skewed toward high-risk disease,” the authors noted.

Pharmacyclics provided support for the study.

The corresponding authors report financial support from Pharmacyclics and Merck. One of the corresponding authors, who developed the study design, is now employed by Merck, but was employed by the National Institutes of Health at the time of the study.


Reference

Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase II study. Blood. 2018 February 26. [Epub ahead of print]

“Ibrutinib has filled a long-standing unmet medical need in several populations of patients with CLL, including the four studied in this trial. The most widely used and proven effective therapy for CLL is the regimen of FCR (fludarabine, cyclophosphamide, rituximab), but FCR is not considered appropriate for older patients with CLL or effective for disease with TP53 or del17p mutations. The combination of obinutuzumab and chlorambucil is effective for older patients with CLL, but not for patients with TP53 or del17p disease, and there are no long-term follow-up data to compare with ibrutinib. The only drug with proven efficacy in patients with del17p CLL is the BCL2 inhibitor venetoclax. However, this is a relatively new agent with limited patient numbers and follow-up data.

Although this study reveals that, with prolonged therapy, 27 percent (older cohort) and 29 percent (TP53 cohort) of patients can achieve CRs, our hope is to take yet another step forward to further increase CR rates and achieve CRs at an earlier phase of therapy. Efforts to achieve this goal are ongoing in several clinical trials in which venetoclax and obinutuzumab are being combined with ibrutinib.

The development of ibrutinib for CLL has been a major step forward in our goal to find a cure for this disease. This study was well-conducted, and the conclusions reached were all appropriate and justified.”

Kanti Rai, MD, professor at Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health

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