HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
April 10, 2019
15 min read

Advances in chronic lymphocytic leukemia suggest progress is ‘visible on the horizon’

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The transition from primarily chemotherapy-based approaches to targeted therapies revolutionized treatment of chronic lymphocytic leukemia, the most common adult lymphoproliferative disorder in the U.S.

Trial results presented in December at ASH Annual Meeting and Exposition show how the use of targeted therapies continues to transform CLL management across younger and older patient populations.

“The ASH 2018 meeting marked the full transition of CLL into the novel therapy era, where targeted inhibitors are likely the preferred initial treatment for most patients with the disease,” Tait Shanafelt, MD, Jeanie and Stewart Ritchie professor of medicine and associate dean at Stanford University School of Medicine, told HemOnc Today. “It is a time of great optimism in CLL. We have made tremendous progress and more progress is visible on the horizon.”

Current treatments are able to control CLL as long as necessary among older patients with CLL, according to Tait Shanafelt, MD.
Current treatments are able to control CLL as long as necessary among older patients with CLL, according to Tait Shanafelt, MD. “For this population of patients, long-term disease control with low toxicity may be the right long-term goal, rather than a cure,” he said.

Source: Steve Fisch/Stanford School of Medicine.

However, because many patients with CLL will eventually develop relapsed or refractory disease, research into new disease targets and combinations remains a need.

HemOnc Today spoke with clinicians and investigators about the latest breakthroughs in CLL, the potential role of chimeric antigen receptor T-cell therapy, combinations under investigation for previously treated and treatment-naive patients, and whether cure is a possibility for this disease.

Ibrutinib dominates

Ibrutinib — a Bruton tyrosine kinase inhibitor first approved for previously treated CLL in 2014 — now is approved for use in all stages of the disease, offering the potential for chemotherapy-free treatment.

Two studies presented at ASH showed the effectiveness of ibrutinib (Imbruvica; Pharmacyclics, Janssen) plus rituximab (Rituxan; Genentech, Biogen) for previously untreated patients.

In the first study, Shanafelt and colleagues found ibrutinib plus rituximab prolonged PFS and OS compared with standard chemoimmunotherapy — consisting of fludarabine, cyclophosphamide and rituximab, or FCR, — among a cohort of younger patients with CLL. Researchers said these findings have immediate practice-changing implications and establish ibrutinib-based therapy as the most effective first-line treatment for patients with CLL.

After median follow-up of 33.4 months, researchers observed improved PFS (HR = 0.35; 95% CI, 0.22-0.55) and OS (HR = 0.17; 95% CI, 0.05-0.54) with ibrutinib-based therapy.

Results of a subgroup analysis for PFS showed that ibrutinib-based treatment was superior to the standard treatment regardless of age, sex, performance status and disease stage, or in the presence or absence of del11q23.


The ibrutinib-rituximab combination was superior for IGHV-unmutated patients, but not for IGHV-mutated patients. Although the HR for PFS also favored ibrutinib-rituximab and was similar to other prognostic subgroups among IGHV-mutated patients, the difference was not significant.

Although ibrutinib increased risk for hypertension and atrial fibrillation, the overall number of grade 3 to grade 4 adverse events was lower overall with ibrutinib-based therapy.

“Ibrutinib-based therapy in the first-line setting is the most effective initial treatment we have had for patients with CLL,” Shanafelt said. “This was the first time that ibrutinib was compared to our most effective traditional treatment, FCR, and it appears to be better tolerated than our historical standard.”

In the second study, Jennifer A. Woyach, MD, associate professor in the department of internal medicine at The Ohio State University Comprehensive Cancer Center, and colleagues showed the ibrutinib-rituximab combination — as well as ibrutinib monotherapy — extended PFS compared with standard chemotherapy among older patients with CLL.

Researchers found that a greater proportion of patients achieved 2-year PFS with ibrutinib plus rituximab (88%; 95% CI, 81-92) compared with ibrutinib alone (87%; 95% CI, 81-92) or bendamustine and rituximab (74%; 95% CI, 66-80).

Although median PFS was 43 months with bendamustine plus rituximab, median PFS was not yet reached for either of the ibrutinib-containing arms.

Ibrutinib alone vs. bendamustine and rituximab significantly reduced the risk for progression (HR = 0.37; 95% CI, 0.25-0.56), with a similar HR observed for the ibrutinib and rituximab arm.

This benefit persisted in all patient subgroups except for those with methylated Zap-70, for whom researchers observed a nonsignificant trend toward improved PFS with ibrutinib (HR = 0.82; 95% CI, 0.45-1.48).

“Moving forward, ibrutinib alone is the better treatment option,” Woyach told HemOnc Today. “The study showed ibrutinib and ibrutinib plus rituximab are absolutely identical in terms of efficacy.”

However, there are patient populations that may benefit from the combination of ibrutinib and rituximab, Woyach added.

“The first would be for the patient with autoimmune complications — such as autoimmune hemolytic anemia and immune thrombocytopenic purpura — as they may benefit from rituximab,” she said. “I also may give the combination to the patient presenting with a significantly elevated white blood count, because the additional lymphocytosis that we expect with ibrutinib may lead to complications. However, these are very rare occurrences.”

CAR combinations

Despite these promising data, the fact remains that some patients fail on ibrutinib therapy.

To address this patient population, Jordan Gauthier, MD, senior immunotherapy fellow at Fred Hutchinson Cancer Research Center, and colleagues hypothesized that use of ibrutinib during leukapheresis, lymphodepletion and CAR T-cell therapy could prevent tumor progression after ibrutinib withdrawal, improve CAR T-cell function and reduce incidence of cytokine release syndrome (CRS).


In a phase 1/phase 2 study — also presented at ASH — Gauthier and colleagues evaluated data from patients who received cyclophosphamide and fludarabine lymphodepletion plus JCAR014 (Celgene, Juno Therapeutics), a CD19-specific CAR T-cell therapy, with concurrent ibrutinib. They compared these patients with a prior cohort of patients who did not receive concurrent ibrutinib.

Results showed the combination of cyclophosphamide, fludarabine, JCAR014 and ibrutinib appeared well-tolerated. Grade 1 or worse CRS occurred in 76% of the ibrutinib group and 89% of the no-ibrutinib group; however, patients who received ibrutinib were less likely to experience grade 3 or worse CRS (0% vs. 25%; P = .03).

Researchers also reported higher rates of complete or partial response in the ibrutinib cohort than the no-ibrutinib cohort, although the difference was not statistically significant (83% vs. 65%).

“These results should be taken with a grain of salt,” Gauthier told HemOnc Today. “First, it was a small study. We had only 19 patients in each cohort, and the study was a retrospective analysis, which requires confirmation in a larger prospective trial.

“With this being said, although we observed robust in vivo CAR T-cell expansion in most patients, not one patient developed a grade 3 or higher CRS. We felt that this was an important finding,” he added. “When we looked at certain cytokines associated with severe CRS in the blood (eg, IL-6, MCP-1), levels were significantly lower in patients in the ibrutinib cohort.”

The phase 1/phase 2 TRANSCEND-CLL-004 trial is currently underway to evaluate the efficacy and safety of lisocabtagene maraleucel (JCAR017; Celgene, Juno Therapeutics), another CD19-directed CAR T-cell product, in adults with relapsed or refractory CLL or small lymphocytic leukemia (SLL).

The phase 1 portion will determine the recommended dose of lisocabtagene maraleucel monotherapy; the phase 2 portion will assess lisocabtagene maraleucel monotherapy vs. standard of care. A separate phase 1 cohort will assess the combination of lisocabtagene maraleucel and concurrent ibrutinib.

Initial data from the phase 1 dose-escalation phase — also presented at ASH — showed an 81% overall response rate and a 43% complete response rate among 16 treated patients, 81% of whom had relapsed/refractory disease on ibrutinib.

However, CAR T-cell therapy does not yet appear to solve all the problems in refractory CLL.

David L. Porter, MD
David L. Porter

“When remissions do occur with CAR T-cell therapy, they are deep, dramatic and sustained,” David L. Porter, MD, Jodi Fisher Horowitz professor in leukemia care excellence in the department of medicine at Perelman School of Medicine at University of Pennsylvania and director of cell therapy and transplantation at Abramson Cancer Center, told HemOnc Today. “So, when the therapy works, it works incredibly well in patients with multiply relapsed or refractory high-risk CLL. But, not enough patients actually benefit — the complete sustained response rates are only between 25% and 35%.”


The explanation for this, according to Woyach, is that “T cells in patients with CLL are dysfunctional.”

“Many patients who are referred for CAR T-cell therapy, but are not on ibrutinib, have failed to expand their T cells in vitro,” she said. “We know from multiple preclinical experiments that ibrutinib helps to restore a more normal T-cell phenotype, and we can see this when ibrutinib is given for a longer period. Ibrutinib most likely helps with both the expansion of the CAR T cells, but also the function of the T cell in patients.”

Experts say second- and third-generation therapies appear to have an improved toxicity profile, and some even suggest CAR T-cell therapy could be administered earlier on in the disease trajectory in the near future.

“We know that the potential of CAR T-cell therapy is tremendous, yet we still have a lot to learn with respect to how to best design this therapy, select the right patients to receive it, apply it in the most effective way and minimize toxicity,” Shanafelt said.

Targeting relapsed, refractory disease

New understanding about the biology of CLL has paved the way to develop drugs for additional targets in relapsed or refractory disease. This remains an essential area for research, as the currently approved therapies are generally viewed as noncurative, experts said.

Duvelisib (Copiktra, Verastem Oncology), a novel oral PI3K inhibitor, received FDA approval in September for relapsed or refractory CLL and SLL.

The approval was based in part on the results of the global, multicenter DUO trial, in which Ian Flinn, MD, PhD, director of the lymphoma research program at Sarah Cannon Research Institute, and colleagues assessed the efficacy of twice-daily oral duvelisib compared with IV ofatumumab (Arzerra, Novartis) among 319 patients (median age, 69 years; 60% men).

Results showed longer median PFS in the duvelisib group than the ofatumumab group by both blinded independent review committee (13.3 months vs. 9.9 months; HR = 0.52; P < .0001) and investigator assessment (17.6 months vs. 9.7 months; HR = 0.4; P < .0001).

The researchers estimated a higher probability of PFS with duvelisib at 6 months (78% vs. 72%) and 1 year (60% vs. 39%).

“Paradigms for CLL are changing. We are moving away from cytotoxic chemotherapy toward novel combination regimens and targeted therapies,” Flinn told HemOnc Today. “We now need agents to fill the gap after progression, and duvelisib is an important agent that will fill the gap for those who relapse after one or two prior therapies.”


Another promising treatment combination for relapsed/refractory disease is venetoclax (Venclexta; AbbVie, Genentech), a BCL2 inhibitor, plus rituximab.

The MURANO trial — additional data from which were presented at ASH by John F. Seymour, MD, director of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues — showed that combination was superior to bendamustine-rituximab for patients with relapsed or refractory CLL. The primary analysis of this trial, presented at ASH in 2017, supported the combination’s approval for CLL last June.

Venetoclax-rituximab conferred a higher rate of PFS at 2 years (84.9% vs. 36.3%; HR = 0.17; 95% CI, 0.11-0.25) and 3 years (71.4% vs. 15.2%). This benefit persisted across patient subgroups, including for those with 17p deletion (2-year PFS, 81.5% vs. 27.8%; HR = 0.13; 95% CI, 0.05-0.29).

The 3-year OS rate was 88% with venetoclax-rituximab vs. 80% with bendamustine-rituximab.

“Overall, these data establish the feasibility and support the clinical utilization of fixed-duration venetoclax-rituximab for the majority of patients with relapsed or refractory CLL,” Seymour said during his presentation.

In addition to developing new treatments for resistant disease, researchers aim to determine why disease becomes resistant in the first place.

“CLL can sometimes break through treatment after around 6 months, and so trying to understand the mechanisms of resistance will be very important to design better versions of these compounds or develop better treatment strategies to overcome this,” Brad S. Kahl, MD, professor in the department of medicine oncology in the division of medical oncology at Siteman Cancer Center at Washington University School of Medicine in St. Louis and a HemOnc Today Editorial Board Member, said during an interview.

Experts were given a first glimpse of mechanisms of venetoclax resistance in CLL at ASH. Characterization of a recurrent mutation in the BCL2 protein offered new insights into the pathobiology of venetoclax resistance among patients with progressive CLL.

Blombery and colleagues found cells with the mutation Gly101Val expressed in two B-lineage cell lines — RS4;11 and KMS-12-PE — were 30-fold less sensitive to venetoclax than cells expressing wild-type BCL2. Moreover, the mutation conferred a selective advantage when continuously exposed to sublethal concentrations of venetoclax in 3-week cultures, and in primary patient mutant cells in both short-term survival assays and when cultured.

The mutation could serve as a biomarker for impending relapse.

“Proteins mutate because of mutations in DNA. Consequently, a drug cannot bind where it is supposed to bind and as a result it cannot inhibit where it is supposed to inhibit,” Kahl said. “This is a big discovery to help us better understand why people may initially respond to venetoclax but then later not respond. This discovery will allow drug developers to create novel strategies to tweak the chemical structure of venetoclax and develop second-generation BCL2 inhibitors to overcome this particular mutation.”


Although these data need to be confirmed in more patients before they can be applied to the clinic, experts say this discovery shows the potential role of testing for BCL2 mutations in patients treated with venetoclax indefinitely.

“The one thing that may limit this is that it seems that most of the current trials of venetoclax are only giving the drug for up to 2 years,” Woyach said. “Venetoclax was given indefinitely in the initial trial, so a strategy testing for a mutation may be useful. But, it was very rare that they found a mutation before the 2 years, so I do not know how helpful it will be to detect for the mutation if we are only giving the drug for 2 years.

“We also need to look for this mutation in other cohorts of patients, because this right now is the only cohort of patients where this mutation has been observed,” she added.

First-line treatment

As insights into targeted treatments pay dividends for patients with relapsed and refractory disease, researchers are exploring the potential benefits of moving these combinations into earlier lines of treatment.

For instance, ibrutinib plus obinutuzumab (Gazyva, Genentech), an anti-CD20 monoclonal antibody, received FDA approval in January for treatment-naive patients with CLL or SLL.

The FDA based the expanded approval on results of the phase 3 iLLUMINATE trial, in which patients were randomly assigned to 420 mg ibrutinib continuously in combination with 1,000 mg IV obinutuzumab over six cycles, or chlorambucil on days 1 and 15 of each cycle plus 1,000 mg IV obinutuzumab over six cycles.

At median follow-up of 31 months, patients who received ibrutinib-obinutuzumab achieved significantly longer median PFS (not evaluable vs. 19 months; HR = 0.023; 95% CI, 0.15-0.37).

The PFS benefit appeared even greater among patients with high-risk disease, such as those with 17p deletion, TP53 mutation, 11q deletion or unmutated immunoglobulin heavy chain gene (HR = 0.15; 95% CI, 0.09-0.27).

An independent review committee calculated overall response rates of 89% in the ibrutinib-obinutuzumab group and 73% in the chlorambucil-obinutuzumab group.

“While we do not yet know if this combination is better than ibrutinib alone, this is one strategy just coming out that is of interest,” Woyach said. “There are a lot of trials that are coming out that are now showing promise for new frontline agents for CLL.”

Researchers also are evaluating the combination of venetoclax plus obinutuzumab.

The randomized phase 3 CLL14 trial is comparing that combination with the standard regimen of obinutuzumab plus chlorambucil in 432 patients with treatment-naive CLL and coexisting medical conditions. Preliminary results reported by the manufacturer showed the trial met its primary endpoint of PFS, and in March the combination received breakthrough therapy designation for previously untreated CLL.


Full results will be presented at a future medical meeting, according to the manufacturer.

“I am very excited to hear the final results of the German study group CLL14 trial,” Flinn said. “This has so far been a positive trial that met its primary endpoint of PFS. Most would have predicted this, but the important part will be the details of the investigational arm and the depth of the remissions achieved.

“We ultimately want to know if we are going to see a plateau in any of the PFS or OS curves,” Flinn added. “Preliminary data, including the results of the phase 1b of this combination that were just published in Blood, showed unprecedented complete remission rates and minimal residual disease negativity. I assume this will hold up in the large phase 3 trial.”

The ultimate hope, according to Shanafelt, is that some of these newer combinations will allow for use of nonchemotherapy-based treatment in a time-limited way to achieve deep remissions.

“By eliminating the need for chronic indefinite treatment, we may not only reduce the costs and side effects associated with some of these treatments, but we may also eliminate some of the selected pressure on the residual clonal leukemia cells,” he said. “This, in turn, may reduce the likelihood for mutations that confer resistance to treatments like ibrutinib, because we have given a shorter course in combination, achieved a deep remission and removed the continuous pressure.”

Concept of cure

Despite headway made in CLL treatment in the last several years, many questions remain.

For instance, although some patients have demonstrated no evidence of CLL recurrence 8 years out from CAR T-cell therapy, experts agree that there is a need for better understanding of what makes a CAR T-cell therapy active and effective to reach more patients.

“We need better understanding of what the functional characteristics of CAR T-cell therapy are, what the phenotypical properties are, and whether or not we can better understand what the ideal T-cell product is,” Porter said. “We need to better understand if we can not only select the patients who may have an ideal T-cell profile, but if we can manipulate a patient’s T cells to ensure that they are functional and active so that the majority of patients will respond to therapy.”

Gauthier said what will get the field closer to the concept of cure is achieving deeper responses in patients with high-risk CLL.

“We should strive for deep responses and we now have tools, such as next-generation sequencing, that can be used to molecularly assess these patients,” Gauthier said. “Our goal is to achieve minimal residual disease-negative response by using this next-generation sequencing.


“Achieving deep response will take us further in curing these patients,” he added. “We have shown that venetoclax is capable of getting patients to achieve minimal residual disease-negative response, and we have shown that CAR T-cell therapy is also very efficacious. This is what we are striving for. This will be the way forward.”

Researchers also aim to define the length of time patients can remain off therapy without relapse.

The CLARITY trial is designed to determine the effectiveness and safety of ibrutinib plus venetoclax in patients with relapsed or refractory CLL. Researchers seek to also show how using the drugs together affects the progression and lifespan of leukemia cells.

“This study and other studies are still maturing in terms of data, but we know this combination is extremely effective,” Woyach said. “What will be exciting is to see how long patients can remain off of therapy.”

Kahl said he is anxious to use the word “cure” for these patients.

“The studies that are helping us better understand resistance to these agents will hopefully lead to the development of compounds that can overcome the resistance the tumor cells acquire,” Kahl said. “Presumably, if we can come up with the right ‘cocktail’ of the very best agents, then this will lead to great outcomes.

“We then have to follow these patients for a very long time to ensure they do not relapse 8, 10 or 12 years down the road,” he added. “This is why we are anxious to use the word ‘cure,’ because we never really know if someone is cured when they have a malignancy that may relapse after 10 to 15 years.”

Whether patients can achieve permanent remission is not yet known, Shanafelt said.

“For the novel therapies, such as ibrutinib and venetoclax, we do not yet know if any of these patients are cured. For the most part, we are still in a paradigm for CLL where we may not need to cure many patients,” he said. “CLL is mostly a disease of the elderly, so if we have therapies that provide durable control of the CLL for many years, a large number of patients will not succumb to CLL.”

For younger patients and those with high-risk molecular characteristics, however, the newer agents provide benefit but do not typically provide durable control of CLL long enough, Shanafelt said.

“In this population, we hope that using these agents in combination and continued improvements in CAR T-cell therapy approaches will provide better answers for younger patients and those with high-risk disease,” he said. “For most older patients with CLL, however, the treatments we have today are able to control CLL as long as necessary with acceptable side effect profiles. For this population of patients, long-term disease control with low toxicity may be the right long-term goal, rather than a cure.” – by Jennifer Southall

Click here to read the POINTCOUNTER, “Is ibrutinib-based therapy the preferred initial treatment for all patients with CLL?”


Flinn IW, et al. Blood. 2018;doi:10.1182/blood-2018-05-850461.

The following were presented at ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego:

Blombery P, et al. Abstract LBA-7.

Gauthier J, et al. Abstract 299.

Seymour JF, et al. Abstract 184.

Shanafelt T, et al. Abstract LBA-4.

Siddiqi T, et al. Abstract 3000.

Woyach JA, et al. Abstract 6.

For more information:

Ian Flinn, MD, PhD, can be reached at Sarah Cannon Research Institute, 250 25th Ave. N, Nashville, TN 37203; email: iflinn@tnonc.com.

Jordan Gauthier, MD, can be reached at Fred Hutchinson Cancer Center, 1100 Fairview Ave. N, Seattle, WA 98109; email: jgauthier@fredhutch.org.

Brad S. Kahl, MD, can be reached at Siteman Cancer Center, 4921 Parkview Place, St. Louis, MO 63110; email: bkahl@wustl.edu.

David L. Porter, MD, can be reached at Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Building 421, Philadelphia, PA 19104; email: david.porter@uphs.upenn.edu.

Tait Shanafelt, MD, can be reached at Stanford University School of Medicine, 291 Campus Drive, Li Ka Shing Building, Stanford, CA 94305; email: tshana@stanford.edu.

Jennifer A. Woyach, MD, can be reached at The Ohio State University Wexner Medical Center, 455A Wiseman Hall, 410 W. 12th Ave., Columbus, OH 43210; email: jennifer.woyach@osumc.edu.

Disclosures: Flinn, Gauthier, Kahl, Porter, Shanafelt and Woyach report no relevant financial disclosures.