The treatment of patients with chronic lymphocytic leukemia (CLL) has been drastically altered by the introduction of two new first-in-class orally dosed drugs: the BCL-2 inhibitor venetoclax and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib.
For venetoclax, its first FDA approval was granted in April 2016 for the treatment of CLL patients who had disease with a 17p deletion and one prior therapy. In June 2018, venetoclax was approved in the U.S. in combination with the CD20-targeting monoclonal antibody rituximab for previously treated CLL patients with or without the 17p deletion. Most recently, in May 2019, the combination of venetoclax and obinutuzumab (a CD20-targeting monoclonal antibody) was approved by the FDA for treatment-naïve CLL patients. At that time, the FDA also granted that combination the breakthrough therapy designation.
The first-in-class BTK inhibitor ibrutinib received FDA approval for previously treated CLL patients in February 2014, which was an expansion from its prior November 2013 approval for mantle cell lymphoma. In July 2014, the use of ibrutinib was expanded by the FDA to those CLL patients carrying a 17p deletion. Then, in March 2016, the FDA expanded the use of ibrutinib as a first-line therapy for CLL. Most recently, in January 2019, approval by the FDA was granted to the combination of obinutuzumab and ibrutinib for treatment-naïve CLL patients. This approval was noteworthy, as it was the first non-chemotherapy-based combination approval for treatment-naïve CLL patients.
Recently, the long-term results from the phase III RESONATE clinical trial (NCT01578707) were published (Blood 2019;133:2031-2042). One of the many clinicians that participated in this study was Jennifer A. Woyach, MD, Associate Professor at Ohio State University.
“The long-term follow-up from this trial continues to show efficacy and safety of ibrutinib. It is clearly superior to ofatumumab in the relapsed setting for CLL,” she noted.
Vastly improved health outcomes have been noted for CLL patients on the BTK inhibitor ibrutinib. In the phase III RESONATE study, the use of ibrutinib monotherapy was compared to the CD20-targeting monoclonal antibody ofatumumab in relapsed, high-risk CLL patients.
In this long-term follow-up analysis, ibrutinib maintained a clear advantage in progression-free survival (PFS), with a hazard ratio (HR) of 0.133 (95% CI: 0.099-0.178). Additionally, there was a continued overall survival (OS) benefit, with an HR of 0.591 (95% CI 0.378-0.926). However, this advantage was somewhat less than what was observed before crossover to ibrutinib was implemented for patients in the ofatumumab arm, where the HR was 0.426 (95% CI: 0.220-0.823). One notable observation was that the overall response to ibrutinib increased with time, with a total of 91 percent of patients exhibiting a response.
It was of interest to note that there was no dependence of PFS benefit that was associated with baseline risk factors. However, shorter PFS values were noted in those patients having two or more prior therapies relative to those having less than two. Also, patients having disease with TP53 and SF3B1 mutations tended to have a shorter PFS than those lacking these genetic aberrations.
Ibrutinib was fairly well-tolerated, with serious adverse events (AEs) (i.e., grade 3 or higher) generally decreasing over time, resulting in a small number of therapy discontinuations. Progressive disease resulted in discontinuation for 27 percent of the patients taking ibrutinib.
In RESONATE, the most frequently observed AEs (all grades) were consistent with previous studies utilizing ibrutinib. The most common serious (i.e., grade 3 or greater) hematologic AEs included neutropenia—23 percent, anemia—9 percent, and thrombocytopenia—8 percent. Correspondingly, the most frequently encountered serious non-hematologic AEs included pneumonia—17 percent, hypertension—8 percent, urinary tract infection—6 percent, atrial fibrillation—6 percent, and diarrhea—6 percent. During long-term observation of ibrutinib-arm participants, 12 developed major hemorrhage, while 42 developed second primary malignancies (non-melanoma skin cancers—29; non-skin cancers—12; melanoma—1).
With ibrutinib therapy, one particular AE of interest is atrial fibrillation (AF). Throughout follow-up, there was a total of 22 patients in the trial (i.e., the intention-to-treat population) who had AF (any grade). Over the course of follow-up, the following levels of grade 3 or higher AF were observed: year 0-1—4 percent; year 1-2—0 percent; year 2-3—2 percent; and year 3-4—1 percent.
AEs resulting in discontinuation tended to decrease over time, going from 11 percent in year 0-1 down to 3 percent in years 3-4. Over time, the frequency of AEs resulting in dose reduction remained fairly constant from year to year: Year 0-1 — 6 percent; year 1-2 — 9 percent; year 2-3 — 4 percent; and year 3-4 — 7 percent. A total of 26 patients had dose reductions due to AEs, and of these, six were able to re-escalate ibrutinib dosing. For these patients, ibrutinib therapy was continued for a median of 931 days post-dose reduction, while four patients subsequently discontinued treatment. Ibrutinib therapy was continued for a median 686 days in the 20 patients who did not undergo re-escalation; 11 of these patients eventually discontinued therapy.
“Most patients tolerate ibrutinib well, however, there are definitely side effects like joint pain which are low-grade but problematic when you consider years of therapy,” Woyach observed. “There are also side effects like arrhythmias and bleeding that can be devastating for some patients. Overall, I believe it is better tolerated than chemoimmunotherapy, but I think that with more research we could find better-tolerated ways to give the drug, and potentially better-tolerated agents.”
When asked how serious AEs were handled for those CLL patients taking ibrutinib, she replied, “It depends on the side effect. For patients with serious bleeding events or pneumonitis, most physicians will discontinue ibrutinib. Ventricular arrhythmias would also prompt discontinuation. Atrial fibrillation can be medically managed with continuation of therapy; however, as more agents are becoming available that do not have this side effect, I am now favoring discontinuation for most patients with new atrial fibrillation on ibrutinib.”
Next-Generation BTK Inhibitors
There are a number of next-generation BTK inhibitors currently being studied in the clinical setting, including acalabrutinib, zanubrutinib (formerly BGB-3111), and tirabrutinib (formerly ONO-4059).
“I think these agents will be very helpful for those patients who either have side effects on ibrutinib or contraindications to ibrutinib. Head-to-head studies will determine whether any of these drugs should replace ibrutinib,” Woyach stated.
One of these compounds being evaluated in a number of clinical trials is acalabrutinib. In the phase III ASCEND study (NCT02970318), acalabrutinib monotherapy was compared with the anti-CD20 monoclonal antibody rituximab plus the investigator's choice of idelalisib or bendamustine in relapsed or refractory CLL. In this study, acalabrutinib met its primary endpoint, PFS, at the interim analysis.
In the phase III ELEVATE-RR study (NCT02477696), acalabrutinib is being directly compared to ibrutinib in previously treated CLL patients. Three regimens are being evaluated in the phase III ELEVATE-TN clinical trial (NCT02475681) in treatment-naïve CLL patients. Those regimens include obinutuzumab plus chlorambucil, acalabrutinib plus chlorambucil, and acalabrutinib monotherapy.
Another potentially useful combination therapy that is being evaluated in two different studies for CLL patients is the triplet combination of acalabrutinib-venetoclax and obinutuzumab. In a phase II study (NCT03580928), the triplet combination is being evaluated in an open-label, single-arm study. In a phase III study, venetoclax plus acalabrutinib with or without obinutuzumab is being compared to investigator's choice of chemoimunotherapy (i.e., fludarabine with cyclophosphamide plus rituximab or bendamustine plus rituximab).
Another next-generation BTK inhibitor is zanubrutinib. In one particularly important phase III study (NCT03734016), zanubrutinib monotherapy is being directly compared to ibrutinib monotherapy in relapsed/refractory CLL patients. In another open-label phase III study (NCT03336333), zanubrutinib monotherapy is being evaluated against the combination of bendamustine plus rituximab in treatment-naïve CLL patients.
Yet another next-generation BTK inhibitor is tirabrutinib, which is at an earlier stage in the clinical process. This compound is being evaluated in a phase I dose-escalation study (NCT01659255) in patients with relapsed/refractory CLL or non-Hodgkin lymphoma. In a phase II study (NCT02983617), the combination of zanubrutinib plus the spleen tyrosine kinase inhibitor entospletinib with or without obinutuzumab is being tested in patients with relapsed/refractory CLL.
Noting the potential of these compounds, Woyach stated, “I think they may improve the safety profile, and the more selective inhibitors may be better combination partners for antibodies.”
Working Towards the ‘Home Run’
In a comment piece that accompanied the Blood article, Clemens-Martin Wendtner, MD, of Ludwig-Maximilian University in Munich, addressed on the long-term RESONATE results.
“For the time being, we have to accept that novel drugs such as ibrutinib and venetoclax represent a quantum leap in the armamentarium against CLL, but are not the home run for all patients suffering from this still-incurable disease, making further research necessary in the field.”
Commenting on that statement, Woyach said, “I think that is absolutely true. While ibrutinib and venetoclax have been transformative for CLL therapy, there are patients who relapse and patients who do not tolerate the drugs. Further clinical trials are needed to understand the optimal way to give these agents, as well as develop new drugs for patients who relapse after these novel therapies.”
When asked what she thought a “home run” treatment might look like for patients with CLL, she replied, “For me, [this] should be a therapy that would either cure the disease, or suppress it with indefinite therapy with a reasonable expectation that the patient will not relapse within their lifetime. I think we need to continue trials to define the optimal sequencing and combinations of agents we already have.
“Laboratory research should also be continued in the search for new therapeutic targets, either for monotherapy or as combination partners for BTK inhibitors or BCL2 inhibitors,” Woyach noted. “As well, we should continue to investigate CAR-T and other immune therapies in this disease.”
Richard Simoneaux is a contributing writer.
Preclinical Studies Show Ibrutinib Inhibits Genetic Instability in CLL Cells
Recently, Oncology Times interviewed Joseph Slupsky, BSc, PhD, at the Institute of Translational Medicine, University of Liverpool, U.K., regarding his recent commentary on the safety of ibrutinib (Blood 2019;133:2006-2007).
Your comment is titled “Ibrutinib is safer than we think.” Could you elaborate on that?
“The title refers to the treatment of CLL and the potential emergence of ibrutinib-resistant clones of malignant cells in this disease. Ibrutinib is relatively safe for physicians to treat patients with CLL from a toxicity point of view. However, another safety issue is whether use of a drug leads to development of disease that is more aggressive.”
What were the findings in the preclinical study by Compagno, et al, that gave clinicians concern about ibrutinib?
“This study found that PI3Kδ blockade resulted in increased activation-induced cytidine deaminase (AID) expression in normal B cells isolated from mice that had been stimulated with a combination of CD40 ligand (CD40L) and interleukin-4 (IL-4), as well as in MEC-1 cells. This had the effect of enhancing genetic instability in these cells. Concern about ibrutinib was raised because they found it also induces AID expression in MEC-1 cells.”
How was their use of MEC-1 cells perhaps not the best choice for a preclinical model to test what occurs in vivo in humans treated with ibrutinib?
“MEC-1 cells are a cell line derived from a CLL patient whose malignant cells have transformed into another B-cell malignancy. Thus, the malignant cells are no longer CLL, but have taken on a phenotype that is similar to diffuse large B-cell lymphoma cells.”
How do the findings from Morande, et al, differ from those of Compagno, et al?
“By using primary human CLL cells in their study, Morande, et al, provide focus to our understanding of ibrutinib therapy for this disease. A particular strength of their work is the examination of CLL cells within in vivo and in vitro settings. Thus, these investigators find that ibrutinib treatment reduces levels of AID in cells from patients enrolled in a clinical trial, showing that this corresponds to a reduction in the number of cells that are class switched (i.e., CLL cells that have switched their B-cell receptor from an IgM to an IgG configuration; this is a measure of AID activity) and that are actively proliferating.
“They then provide in vitro models of this phenomenon where they use CD40L and IL-4 as microenvironmental factors to stimulate primary CLL cells, both in the presence and in the absence of ibrutinib. Here, they make similar findings to their in vivo studies; ibrutinib treatment blocks induction of AID expression and CLL cell proliferation. What is truly different is the proposal of a potential mechanism through which ibrutinib might inhibit AID expression.”
How do the findings of Morande, et al, refine our knowledge about CLL treatment with ibrutinib?
“The findings provide compelling evidence that CLL treatment with ibrutinib, or ibrutinib-like compounds, may be beneficial in that it prevents a mechanism of genetic instability in the malignant cells (i.e., upregulation of AID expression) and the means of expanding selected clones because CLL cell proliferation is blocked in ibrutinib-treated patients. In terms of disease control, ibrutinib might have more utility as a frontline therapy because of this.”