Breakthrough Therapies Enrich Evolving CLL Paradigm

Herbert A. Eradat, MD, explains how insight into the pathogenesis of chronic lymphocytic leukemia is leading to novel treatment strategies and shed light on unmet needs in the field.

Herbert A. Eradat, MD

Novel therapies and clinical trial designs are steering chronic lymphocytic leukemia (CLL) treatment away from cytotoxic chemotherapy and toward a paradigm of alleviated clinical and financial burden, explained Herbert A. Eradat, MD.

“Now that we have these therapeutic modalities that are inducing deep responses, we can talk about a realistic assessment of minimal residual disease (MRD) and use that to guide treatment discontinuation or reinitiation strategies, similar to what we’re doing in chronic myeloid leukemia (CML),” said Eradat.

Such modalities include the first- and second-generation BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence), respectively. For example, young, treatment-naïve patients who received ibrutinib alone or in combination with rituximab (Rituxan) experienced a significant improvement in progression-free and overall survival compared with standard fludarabine, cyclophosphamide, and rituximab (FCR) in the phase III ECOG E1912 trial.1

Specifically, after a median follow-up of 33.4 months, there was a 65% reduction in the risk of progression or death with the ibrutinib combination versus FCR (HR, 0.35; 95% CI, 0.22-0.50; P <.00001). Ibrutinib’s benefit—either alone or in combination with rituximab—over standard chemoimmunotherapy has also been demonstrated in older patients with comorbidities.

Additionally, acalabrutinib, a second-generation BTK inhibitor with an improved tolerability profile, has also shown a PFS benefit in the frontline setting when used as monotherapy and in combination with obinutuzumab (Gazyva). Positive findings from the phase III ELEVATE-TN and ASCEND studies, respectively, served as the basis for the FDA’s decision to grant the agent a breakthrough therapy designation in August 2019.2,3

The BCL-2 inhibitor venetoclax (Venclexta) is another potent agent that has also shown activity.

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Eradat, associate professor, University of California, Los Angeles Medical Center, explained how insight into the pathogenesis of CLL is leading to novel treatment strategies and shed light on unmet needs in the field.

OncLive: Could you discuss the shift away from traditional chemotherapy in CLL?

Eradat: The key point is that therapeutic strategies are evolving. We're moving away from traditional cytotoxic chemotherapy because we have much more effective and better tolerated therapies. However, there are still areas of need where patients don't respond to treatment and don't have durable responses.

Could you discuss the development of some of these novel therapies?

We have a good understanding of the pathogenesis of CLL. CLL is a disease where the cells don't die properly; that is one pathway by which the disease develops. Another [pathway results from] the dependence of these cells on signals through the B-cell receptor. Most of the novel therapies exploit those 2 particular pathogenic mechanisms. That's partly why these agents tend to be much more effective and better tolerated; they’re going after how the disease develops and thrives. That’s in contrast to traditional cytotoxic chemotherapy, which is just the administration of a poison. It’s supposed to control the disease, but it comes at a cost of significant toxicity.

Could you discuss the impact of ibrutinib?

Ibrutinib has been a miracle drug in CLL. We have consistently seen that patients respond very well to the therapy. The longest follow-up is more than 7 or 8 years, and patients are continuing to respond. The outcomes of patients who have received frontline ibrutinib are excellent. In the relapsed setting, however, there are patients who have progressed. As such, that’s another space where we need alterative agents.

There are some limitations I should mention. All of the currently designed trials are giving ibrutinib as continuous therapy until toxicity or progression, which is a little bit problematic for patients; that puts them at risk for additional [clinical and financial] toxicity.

Notably, oncologists who used to treat patients with FCR and bendamustine-type strategies see ibrutinib as this miraculous pill. Most patients tolerate the regimen well; they take a pill once a day and move on with their lives. They're not coming in for cytotoxic chemotherapy or dealing with genotoxic therapy and secondary malignancies down the road. However, even ibrutinib has its own toxicity profile that affects quality of life. To us, it looks miraculous but to the patient, it's probably less so, because they’re not familiar with the old style of therapy. We have to be aware of that when we use the word “miracle” in association with any of our novel therapies, not just with ibrutinib.

Acalabrutinib has been granted breakthrough therapy designation by the FDA. What data have been seen with the agent as monotherapy and in combination?

Acalabrutinib is a new BTK inhibitor that is being tested in several ongoing clinical trials. The initial trials demonstrated really great efficacy [with the agent], similar to what we see with the first-generation inhibitor, ibrutinib. We have a body of data regarding patients who don't tolerate ibrutinib because of its toxicity profile. Those patients can switch to acalabrutinib and have a continued response without the adverse events [seen with ibrutinib]. The new data that have come out are specific to the relapsed setting and similarly show comparable efficacy to ibrutinib. It provides another option for our patients.

Could you discuss the FDA approval of rituximab-pvvr (Ruxience), a biosimilar to rituximab for patients with CD20-positive CLL in combination with fludarabine and cyclophosphamide?

We’re going to see a significant financial improvement for patients. [Financial toxicity] is something that we don't necessarily always discuss with patients or at medical meetings. I'm hoping biosimilars—especially in CLL—will come down the pipeline. Having a biosimilar formulation available to us will help reduce the cost and availability of the regimen. It’ll be a great improvement for our patients in terms of access to care.

Are there any additional emerging combination strategies that you would like to highlight?

The data from the phase II CAPTIVATE trial were presented by William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center, at the 2019 ASCO Annual Meeting. The trial tested the combination of ibrutinib and venetoclax. One hundred percent of patients had a response. For the first time, we’re seeing deep responses that are leading to MRD negativity. For the first time, we can start to think about discontinuing therapy.

The trial has a novel design and is likely to revolutionize the field. This is in comparison with CML, where we have very sophisticated tables outlining when to test for MRD and what to do with the results of MRD. Moreover, [this trial may also shed light on] when and how to reinitiate therapy, and when to test for resistance. None of that has been available or investigated thoroughly in CLL.

What are the main areas of unmet need?

Some patients with CLL have disease that is categorized by loss of p53 function, either through del(17p) or p53 mutation. These patients respond to our novel therapies, but their response is not durable in comparison to patients without those abnormalities. The second category is patients who have a complex karyotype or an unstable genome. These patients generally have a response to all of our novel therapies, but, unfortunately, have a poor prognosis because their responses are not durable.

Another category is younger patients who have poor molecular characteristics. An additional issue for younger patients is that they tend to be on therapy for a longer period of time; therefore, they may run out of therapeutic options a little quicker. One last area is patients with Richter's transformation. We have better strategies now, but we are limited by the short duration of responses seen in most patients.


  1. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood. 2018;132(suppl 1):LBA-4. doi: 10.182/blood-2018-120779.
  2. Calquence Phase III ELEVATE-TN trial Met Primary Endpoint at Interim Analysis in Previously-Untreated Chronic Lymphocytic Leukemia [news release]. Wilmington, DE: AstraZeneca. Published June 6, 2019. Accessed June 6, 2019.
  3. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator's choice of rituximab plus idelalisib (idr) or bendamustine (br) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2606.