By Benjamin L. Lampson, MD, PhD, & Jennifer R. Brown, MD, PhD
Over the past 5 years, the field of chronic lymphocytic leukemia (CLL) has seen the emergence of multiple new classes of therapies, including Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and BCL-2 inhibitors. These therapies have revolutionized treatment of the disease, but we still have much to learn about their long-term safety and efficacy, the ways they can be combined, and the ways they can be improved. In this blog post, we provide an overview of some recent research that falls into each of these three areas.
With regards to the long-term efficacy of these novel therapies, we are just beginning to see results of long-term follow-up studies of patients who received ibrutinib or venetoclax early in their development or approval. After 5 years of follow-up in trial patients who received ibrutinib, an impressive median progression-free survival (PFS) of 51 months was demonstrated in relapsed, refractory CLL; complex karyotype and/or del(17p) were predictors of a shorter duration of response (Blood 2018;131:1910-1919).
We are also now beginning to see phase III data comparing ibrutinib to chemotherapy for the treatment of up-front disease and, in general, the drug compares favorably. Ibrutinib plus rituximab has superior PFS and overall survival compared to fludarabine, cyclophosphamide, and rituximab (FCR) for the treatment of patients under 70 without del(17p) (ASH 2018, Abstract LBA-4), and ibrutinib or ibrutinib plus rituximab has superior PFS compared to bendamustine plus rituximab for the treatment of patients over age 65 (ASH 2018, Abstract 6). At present, these findings have short follow-up and the benefits are seen in the subgroup of patients with higher risk IGHV-unmutated disease, without a significant difference in low-risk patients, who can have very long PFS with chemoimmunotherapy—even cure with FCR in the younger subgroup.
Additionally, researchers examined the real-world experience with ibrutinib and found that toxicity—not disease progression—was the primary reason for ibrutinib discontinuation, with 41 percent of patients having discontinued ibrutinib after a median follow-up of 17 months (Haematologica 2018; doi:10.3324/haematol.2017.182907).
With regards to toxicity, we are developing a broader picture of the spectrum of ibrutinib-related toxicities. Multiple reports this year documented an increased risk of invasive fungal infections, particularly aspergillosis, in patients receiving ibrutinib (Clin Infect Dis 2018;67:687, Blood 2018;131:1882-1884). This may be due to BTK inhibition within macrophages (Blood 2018: doi:https://doi.org/10.1182/blood-2017-12-823393).
Effects on the cardiovascular system range from mild to life-threatening. New hypertension develops in approximately 30-40 percent of patients on long-term ibrutinib (ASH 2018, Abstract 4423; ASCO 2017, Abstract 7525) and can usually be controlled with prescription medications. The incidence of atrial fibrillation increases over time on the drug and—in the real-world setting—has been reported in up to 25 percent of patients after a median follow-up of 17 months (Haematologica 2018;103:874-879). Ventricular arrhythmias and sudden deaths have been reported at higher-than-expected frequencies as well (Blood 2017;129:2581-2584, Leuk Lymphoma 2018:1-4).
Data has been presented demonstrating that patients can safely receive venetoclax with rituximab continuously for at least 2 years, and 69 percent of patients have no detectable minimal residual disease (MRD) in the peripheral blood after this combination therapy (ASH 2018, Abstract 184). With more experience with venetoclax and with adherence to a 5-week ramp-up dosing schedule, the risk of tumor lysis syndrome (TLS) is very low; only two cases (1.6%) of laboratory TLS were seen in a recent aggregate analysis. Diarrhea (41%), neutropenia (40%), and nausea (39%) were the most frequent adverse events, but neutropenic fever is uncommon (Clin Cancer Res 2018; doi:10.1158/1078-0432.CCR-17-3761). In general, patients tolerate venetoclax very well after the initial ramp-up.
In most cancers, the use of a monotherapy eventually leads to the emergence of drug resistance. Thus, there has been much interest in combining BTK inhibitors, anti-CD20 monoclonal antibodies, BCL-2 inhibitors, and/or chemotherapy in the hopes of avoiding resistance and achieving deeper, more durable responses. We now know that venetoclax/obinutuzumab (Blood 2017;129:2702-2705), ibrutinib/obinutuzumab, ibrutinib/venetoclax, and ibrutinib/obinutuzumab/venetoclax (ASH 2018, Abstract 693) can be safely combined and achieve high rates of undetectable MRD, although we await longer-term efficacy and safety data. In these trials, we should pay close attention to rates of complete responses and achievement of minimal residual disease negativity, as these can likely serve as rapid proxies for a durable response.
Finally, we look forward to improvements on current therapies, which include both next-generation versions of drugs that fall within pre-existing drug classes and drugs that operate via entirely novel mechanisms. Within the first category, the next-generation BTK inhibitors acalabrutinib and zanubrutinib are currently in phase III trials, are more specific for BTK, and may have better toxicity profiles than ibrutinib.
PI3-kinase inhibitors continue to be a promising drug class, with duvelisib recently approved as monotherapy based on an overall response rate of 74 percent in relapsed/refractory CLL (Blood 2018;132(23):2446-2455).
Early phase I results with umbralisib, a PI3k-delta/CK-1 epsilon inhibitor, demonstrated lower rates of colitis than other PI3K-delta inhibitors (Lancet Oncol 2018;19(4):486-496), and—in keeping with the theme of combination therapy introduced above—the drug is now in phase III trials in combination with the novel anti-CD20 antibody ublituximab.
Novel drug classes include MCL-1 inhibitors, CDK9 inhibitors, and CAR T cells. While CLL cells are typically dependent on the anti-apoptotic protein BCL-2 rather than MCL-1, patients who relapse on venetoclax may develop MCL-1 dependent disease and thus sensitivity to MCL-1 inhibitors (Blood 2018; doi:https://doi.org/10.1182/blood-2018-02-791350). CDK9 promotes the expression of MCL-1, and thus CDK9 inhibition with the small molecule voruciclib has therapeutic potential (Sci Rep 2017;7(1):18007); this drug is now in phase I trials in CLL.
CAR T cells clearly provide durable complete remissions in about 25-30 percent of treated patients (Sci Transl Med 2015;7(303):303ra139). Future CAR-T studies in CLL will focus on refining our ability to identify patients who will benefit, as well as modifying the treatment approach to enhance efficacy. Indeed, results from this year’s ASH meeting suggest that higher response rates and reduction in severe cytokine release may be associated with ibrutinib around the time of CAR-T infusions, albeit with other ibrutinib-related toxicities (ASH 2018, Abstract 298; ASH 2018, Abstract 299). A recent interesting report demonstrated that disruption of the TET2 gene by a lentivirally inserted CAR transgene serendipitously enhanced the potency of an infused CAR T cell and led to a complete remission of the recipient’s CLL, identifying potential ways to improve future immunotherapeutic approaches (Nature 2018;558:307-312).
The field of CLL therapy is rapidly evolving, and it is inspiring to think that even more exciting findings lie ahead.
Benjamin L. Lampson, MD, PhD, is a Clinical Fellow at Dana-Farber Cancer Institute, Boston. Jennifer R. Brown, MD, PhD, is Director of the CLL Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School.