Sorting Through the Alphabet Soup of Evolving Treatments in CLL

OncologyLiveVol. 19/No. 8
Volume 19
Issue 8

Experts offer their perspectives on developments in the field of chronic lymphocytic leukemia, such as novel combinations and emerging agents.

William G. Wierda, MD, PhD

The rapid introduction of new therapies for chronic lymphocytic leukemia (CLL) during the past several years has remade the treatment paradigm, presenting clinicians with a challenging array of options at a time when further advancements are in the works.

That was the picture that emerged from a recent OncLive Peer Exchange® program in which experts in CLL offered their perspectives on developments in the field. “The availability of novel therapies for CLL has drastically improved outcomes but has also increased the complexity of treating symptomatic patients,” said William G. Wierda, MD, PhD, who moderated the discussion. “Moreover, there remains a substantial unmet need for many patients who relapse.”

The panelists provided insights on novel combination therapies, discussed several promising agents, including phosphoinositide 3-kinase (PI3K) inhibitors, and reviewed areas of research that might open new treatment avenues in the frontline and relapsed/refractory settings.

The CLL Landscape

“It’s a very exciting time because of all the novel therapies, and I think now our goal is to develop new generations of therapy, trying to minimize the toxicity with the oral agents, and to improve upon what we have available by doing the novel—novel combination or novel– conventional combinations to achieve a really deep response,” said Shuo Ma, MD, PhD. She noted that minimal residual disease (MRD) negativity is now achievable and will hopefully translate to a very long progression- free survival (PFS) for patients.CLL is the most prevalent adult leukemia in Western countries, predominantly affecting middle-aged and elderly adults (>90% diagnosed at ≥55 years).1 In the United States in 2018, more than 20,000 new CLL cases are expected to be diagnosed, with approximately 4500 people dying from the disease.2

Novel Combinations in CLL

Until 2014, many patients with CLL had few treatment options, particularly because advanced age often limited tolerance to the severe adverse effects (AEs) commonly experienced with standard chemotherapeutic regimens. By 2015, 4 new effective and better tolerated drugs were approved for CLL: the small-molecule inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) and the anti-CD20 monoclonal antibodies obinutuzumab (Gazyva) and ofatumumab (Arzerra). These advancements led the American Society of Clinical Oncology to name “transformation of CLL treatment” its cancer Advance of the Year in its Clinical Cancer Advances 2015 report.3 In 2016, the FDA approved another small-molecule inhibitor, venetoclax (Venclexta), for patients with CLL and 17p deletion (del[17p]).Currently, in the frontline and relapsed/refractory setting, most combinations recommended by the National Comprehensive Cancer Network include rituximab (Rituxan). Ibrutinib plus bendamustine and rituximab, idelalisib plus rituximab, and venetoclax plus rituximab are the preferred regimens in the relapsed/refractory setting, including for high-risk patients.1 Numerous clinical trials are currently underway that are examining a variety of novel—novel combinations.

Table 1. Selected Combinations in Clinical Trials in CLL4-7

“It’s a bit of an alphabet soup,” said Matthew S. Davids, MD, MMSc, noting that some key agents being combined include ibrutinib, venetoclax, and obinutuzumab (Table 14-7). “We’re really seeing some dramatic rates of MRD negativity,” he noted. However, these studies are still early, mainly in phase II, and, although the data are promising, these combinations are not yet ready for clinical practice. “It’s challenging because right now in the United States, we don’t have access to combinations of these agents, so we can’t really do this off-label. I don’t think most insurers would pay for both novel agents at the same time. So, I think these data are going to need to mature more before we see them in practice,” he said.A major goal with new combinations will be to enable time-limited therapy versus patients having to continue therapy, such as ibrutinib monotherapy, though there is a place for both approaches, noted Davids. “If I have an 82-year-old who wants to have good disease control, I think ibrutinib monotherapy may be a great option. But if I have a 62-year-old who wants to live another 30 years, that might be a patient I want to focus on a timelimited combination approach—get them into an MRD-negative state, and then hopefully give them a long treatment-free interval before they may need treatment again,” he said.

On the other hand, because some novel combinations are showing equivalent tolerance in cohorts of older patients, MRD negativity could be a feasible goal even among some older patients, said Wierda. “With our ibrutinib/venetoclax experience, it appears that that combination is equally well tolerated in patients who are over 70 years, for example, compared with those younger than 70 years, and it’s active. So, I think, from my own perspective, we’re moving into this era where we can talk about MRD-negative remissions in 75-year-olds,” he said.

While such novel combinations of first-generation agents are still being worked out, a plethora of next-generation agents are also showing promise, adding to the treatment conundrum (Table 28-13). “Whether [these agents] will make a difference in these types of combination regimens is going to keep us in business in clinical trials for a long time,” said Davids.

Table 2. Emerging Agents in CLL8-13

Other Promising Agents and Research Avenues in CLL

Although not discussed as part of the Peer Exchange, the literature has provided a cautionary tale on novel combinations. A phase II study (NCT01796470) that combined the PI3K inhibitor idelalisib with the spleen tyrosine kinase inhibitor entospletinib as a treatment for relapsed/refractory CLL and non-Hodgkin lymphoma had to be closed early because 12 patients (18%) developed treatment-emergent pneumonitis, with 2 dying as a result.14 The study design used a short dose-limiting toxicity window and had an insufficient monitoring period for such toxicities. Subsequently, the study authors concluded, “Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/ biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/ chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.”14Some of the most substantial drug development in CLL has occurred with the anti-CD20 monoclonal antibodies. Three are approved: rituximab, ofatumumab, and obinutuzumab. Others, like ublituximab, which has a similar mechanism to obinutuzumab, are showing promise. The availability of multiple options, with more on the horizon, is adding to the challenge of treatment selection, particularly since few head-to-head randomized data are available to provide guidance.

“How many monoclonal CD20 antibodies do we need?” asked Nicole Lamanna, MD. “I don’t mean to be negative. I guess the point is that we have cost issues to deal with. If one is clearly dramatically better, I think that we should push to use that antibody versus what we’re doing, which is a smattering in the United States,” she said, noting that it remains to be seen how all of these agents will ultimately be incorporated into clinical practice.

A variety of new targets are also being actively explored, including the BCL2-regulated apoptotic pathway. In patients with CLL, aberrant expression of BCL2 is common and has been associated with a poor response to chemotherapy and decreased overall survival, making it a prime target for novel agents. However, there are some challenges with targeting BCL2, noted Davids. “As we selectively target BCL2, we do worry that we may see upregulation of other antiapoptotic proteins, so there are now MCL1 inhibitors that have entered the clinic, and it’s possible we’ll see BCL-XL inhibitors in the future. Eventually, we may have a whole toolkit of agents to target the apoptotic pathway, which is exciting,” he said.

An area of great unmet need in CLL is treating patients who develop Richter transformation, which is associated with significantly shorted survivals (~4 months).15,16 In these patients, CLL transforms into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Richter transformation affects an estimated 2% to 10% of patients with CLL during their disease course, with an estimated annual transformation rate of 0.5% to 1% per year.16

A small Mayo Clinic study that enrolled 9 patients with Richter transformation and 16 with relapsed CLL showed pembrolizumab (Keytruda) to have some benefit.17 “Although the CLL patients did not respond to the PD-1— blocking antibody, those with a diffuse large B-cell lymphoma component at the Richter transformation responded, with a 40% [objective] response rate among those patients,” said Ma. “I think this raises the question of whether we can cover the PD-1 blockade, too, as combination therapy with something else, to treat Richter transformation.”

An area of ongoing research is determining the etiology of resistance to new treatments, such as venetoclax, so that strategies can be developed to resensitize patients to treatment. “I think with ibrutinib, it was pretty clear early on that BTK mutations developed, which was a very clear pathway for resistance. Unfortunately, we haven’t seen a similar story evolving yet with venetoclax,” said Davids. “We did see some abstracts presented at [the 2017 American Society of Hematology Annual Meeting] that looked at mutational profiles in a more limited number of patient samples, and there was no clear answer as to what the cause of resistance was.”

One study of 8 patients found diverse patterns of clonal evolution, although homozygous deletions in CDKN2A/B and BTG1 mutations were observed in several patients, indicating these might play a role in acquired venetoclax resistance.18 Larger confirmatory studies will be needed before potential treatment targets for venetoclax resistance can be established.

No matter which treatments are used in clinical practice or assessed in clinical trials, a key consideration needs to be quality-of-life issues, emphasized Steven Coutre, MD. “There’s a really interesting article recently published in Blood Advances that was a survey tool that asked patients what’s important to them.19 Is it oral versus IV, a [adverse] effect profile, or efficacy? It’s pretty revealing. I think it shows that patients want to see that their cancer is controlled for the longest time possible, and they’re willing to tolerate some side effects in exchange, but not too many. So, it’s important for us to keep that in mind as we develop these new therapies and combinations,” he said.


  1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 5.2018. Published March 26, 2018. Accessed April 4, 2018.
  2. American Cancer Society. Cancer facts and figures 2018. Published 2018. Accessed March 25, 2018.
  3. Bauer A. Cancer advance of the year: transformation of CLL treatment. Published January 20, 2015. Accessed March 25, 2018.
  4. Michallet AS, Dilhuydy MS, Subtil F, et al. Phase II, multicenter trial, exploring “chemo-sparing” strategy associating obinutuzumab + ibrutinib followed by a MRD driven strategy, in previously untreated symptomatic medically fit chronic lymphocytic leukemia patients (CLL): preliminary results of the induction phase of the Icll-07 filo study. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 497.
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  6. Flinn IW, Gribben JG, Dyer MJS, et al. Safety, efficacy and MRD negativity of a combination of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia — results from a phase 1b study (GP28331). Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 430.
  7. Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 428.
  8. Barr PM, Saylors GB, Spurgeon SE, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127(20):2411-2415. doi: 10.1182/blood-2015-12-683516.
  9. Byrd JC, Wierda WC, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 498.
  10. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT149.
  11. Verastem submits new drug application to U.S. FDA for duvelisib for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma [press release]. Boston, MA: Verastem, Inc; February 7, 2018. Accessed March 26, 2018.
  12. Sharman JP, Kolibaba KS, Azar J, et al. Evaluating the efficacy, safety, and dose dependent activities of entospletinib in patients with chronic lymphocytic leukemia. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 832.
  13. TG Therapeutics announces positive data from phase 3 GENUINE trial of TG-1101 in combination with ibrutinib in patients with high risk chronic lymphocytic leukemia at the 53rd Annual Meeting of the American Society of Clinical Oncology [press release]. New York, NY: TG Therapeutics; June 3, 2017. Accessed March 28, 2017.
  14. Harris J. Umbralisib shows early promise in CLL and lymphoma. Onclive website. February 21, 2018. Accessed March 28, 2018.
  15. Burris HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study [published online February 20, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30082-2.
  16. Schimmer AD, Munk-Pedersen I, Minden MD, Reed JC. Bcl-2 and apoptosis in chronic lymphocytic leukemia. Curr Treat Options in Oncol. 2003;4(3):211-218.
  17. Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123(11):1647-1657. doi: 10.1182/blood-2013-11-516229.
  18. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129(26):3419-3427. doi: 10.1182/blood-2017-02-765685.
  19. Frenzel LP, Herling CD, Abedpour N, et al. Mechanisms of venetoclax resistance in chronic lymphocytic leukemia. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 263.
  20. Mansfield C, Masaquel A, Sutphin J, et al. Patients’ priorities in selecting chronic lymphocytic leukemia treatments. Blood Adv. 2017;1(24):2176-2185. doi: 10.1182/bloodadvances.2017007294.
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