Refining the Management of Patients With CLL: Update on Prognostic/Predictive Factors and New Therapies

Course Director

William G. Wierda, MD, PhD

William G. Wierda, MD, PhD
Professor, Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas

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Part 1 of a 2-part series

Dr. Wierda provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, and accurate staging and prognostication are necessary to assist with monitoring, treatment planning and prediction of potential clinical outcomes. Evolving research into molecular underpinnings of CLL, including the key genetic and chromosomal aberrations, may yield new prognostic and predictive tools that can further refine the clinical decision-making for patients with CLL. Despite the availability of effective treatment regimens, CLL is still largely an incurable disease, but new and emerging therapies with high efficacy and low toxicity are showing promise for transforming the treatment of CLL. Given the heterogeneity of the clinical manifestations and prognosis of CLL, an individualized treatment approach is warranted.


This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
William G. Wierda, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc.; Genentech, Inc./Hoffmann-La Roche Inc.; Gilead; GlaxoSmithKline; Merck & Co., Inc.; and Pharmacyclics, Inc.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What progress is being made in research to improve upon the current prognostic and predictive factors/models used to help guide clinical decisions for patients with CLL?

Dr. Wierda: There are a number of traditional prognostic factors like age, clinical stage, lymphocyte doubling time, and bone marrow pattern of involvement. We still assess those, and it is useful information. We've tended to focus more recently on the newer prognostic factors: Immunoglobulin heavy-chain variable gene sequence analysis, or mutation status is one of those; ZAP70 [Zeta-chain-associated protein kinase 70] expression in the leukemia cells is another; cytogenetics by either karyotype or by FISH is [yet] another.1-11 And then we've also had data published more recently about response assessment and minimal-residual disease evaluation at the end of treatment.12-13

I think most importantly for the practicing clinician is to think about these prognostic factors in terms of how they may be used to manage their patients. Immunoglobulin heavy-chain mutation status, ZAP70—they can help us to anticipate how frequently we need to see patients; however, they're not really used at this point in terms of making management decisions.

Narrator: Dr. Wierda notes that some of the factors, including immunoglobulin heavy-chain variable gene sequence and mutational status, don’t change throughout the course of the disease, but many of them do.

Dr. Wierda: So, if you have a patient who's newly diagnosed and you evaluate chromosome abnormalities by FISH, for example, the results that you see may be different for that same patient after the patient's been treated with their initial therapy and has developed relapsed disease. So for the factors that can change—particularly FISH and cytogenetic abnormalities—the important time to evaluate that factor would be whenever you're considering either starting treatment or changing treatment for a patient.

FISH is really the prognostic factor that's most useful in evaluating and managing patients' treatment decisions, and treatment changes are made based on FISH and identification of the high-risk features. The first one is 17p deletion. When that abnormality is identified, that particular group of patients is typically refractory to alkylating-agent–based therapy and purine-analog–based therapy. They have very poor outcomes when they start to need treatment and have active disease.7,14-15

There is a subgroup of those patients who don't need treatment. It's a small portion of them, 20[%] to 30%,16 so you shouldn't act on the presence of 17p because you may be doing the patient a disservice by initiating therapy if they don't need therapy.

However, if you have a patient who has developed indications for treatment—they have active disease, symptomatic [disease], or have developed anemia or thrombocytopenia—and they have a 17p deletion, we really don't have any standard treatments for those patients. So that's a particular group that we've been focusing on for developing and identifying novel agents that can be used to treat them and to improve their outcomes—both progression-free and overall survival.

The other cytogenetic abnormality that we identify with FISH that can potentially impact on how patients are managed is the presence of an 11q deletion.7,17-20 We have found in randomized trials that those patients are sensitive particularly to alkylating agent/purine analog combinations, or alkylating-agent–based therapies, particularly the FCR [fludarabine/cyclophosphamide/rituximab] regimen. And they are also responsive to bendamustine/rituximab. So if you have a patient who needs either front-line therapy or salvage therapy, and they have an 11q deletion, then you should be considering a chemoimmunotherapy-based regimen that has an alkylating agent in it.

You can typically get them into a remission, but the problem is their consistently relapsing disease—even though they are sensitive to chemotherapy—and for that reason, this patient population with 11q deletion remains in what I could consider a higher-risk category.

The other feature that's a prognostic factor is refractory disease—and particularly purine-analog refractoriness. If a patient becomes purine-analog–refractory, then management clearly will need to change for that patient. Those are patients for whom we try to get to a stem cell transplant. It's not necessarily a factor that can be measured, but more of a clinical feature.

The biggest area in terms of new prognostic factors is gene sequencing analysis and identifying genes that are mutated in patients with CLL. There are data out there with regard to p53 and identifying patients who have mutations in p53 as a high-risk group.21-23 So if it's possible to do gene sequencing, I would recommend doing sequencing for TP53. And we would put that type of patient with TP53 mutations into the high-risk category, such as those with a 17p deletion.

Other genes that have been reported in the literature that aren't routinely sequenced but that we're generating data for and trying to identify what are the important prognostic ones are SF3B1. NOTCH1 is another one [that], when mutated, can put patients in a high-risk group.23-25 BIRC3 is another, again, [that] when mutated, would put patients into a high-risk category.23 We've made efforts to include and are generating and collecting data with regard to ATM mutations, and how that's prognostic and how that might also impact on patient management issues.

Again, this is all research-based, so most of these tests and sequencing analyses are not readily available to the practicing clinician. It's a complicated field. Again, most of the prognostic factors that we evaluate can change in an individual patient over time. And most likely a lot of the treatments that we use may drive or alter those changes. So, clearly, we need to have a concerted effort to first collect information on the prognostic factors for patients and also to have serial sampling for patients and to be able to connect that information with the patient's clinical course, particularly what treatments they've received, and when and how they develop refractory disease.

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What is the status of development of new therapies targeting the B-cell receptor signaling pathway in CLL?

Dr. Wierda: So in terms of the new therapies, there are a number that I'm particularly excited about. Most of these new agents don't have the typical side effects that we struggle with, that being myelosuppression. And most of them are oral agents and are dosed on a daily or twice-daily basis and very well tolerated, particularly in the elderly population.

The first group of drugs are small-molecule inhibitors of the B-cell receptor signaling pathway. The hypothesis is that CLL cells receive signals from their environment through the B-cell receptor that confers a survival advantage from those signals. And if you block those signals, then the cells will undergo apoptosis and die.26-28

The first target molecule would be Bruton's tyrosine kinase, or BTK. There is a BTK inhibitor called ibrutinib, which is probably the closest to getting FDA approved. This is an agent that irreversibly inhibits BTK. Again, it's given orally and has a very favorable toxicity profile.

There have been phase 1/phase 2 data that have been reported. There was a New England Journal [of Medicine] paper recently that was published evaluating the activity of ibrutinib in relapsed patients with CLL.29 There are other manuscripts in preparation with ibrutinib being evaluated in untreated patients who are over 65 years of age.

The response rate with ibrutinib is about 80%, and in the relapsed setting at 2 years, about 75% of the patients are progression-free.29 So ibrutinib clearly has activity in terms of generating responses, and these responses are durable. The best response is not seen until the patients have been on treatment for a number of months. They don't discontinue treatment, so the intent is for them to remain on treatment.

And there are a couple of aspects to all of these molecules that are unique: Patients have rapid response in terms of lymph-node shrinkage as well as liver and spleen shrinkage. But these agents will interfere with the interactions between CLL cells and their microenvironment, and they disrupt tissue homing. What we see when patients initially go on drug is a transient increase in their circulating leukemia count.27-28,30-33 And as they remain on the drugs for several months, then the leukemia count will subsequently go down.

The randomized phase 3 trial in the relapsed setting for ibrutinib has accrued.34 That's a randomized trial comparing ibrutinib to ofatumumab. And there's a phase 2 trial with ibrutinib for relapsed patients with 17p deletion, which also has completed enrollment.35 And I think the biggest benefit from this drug that we'll be able to see initially in the short-term is in terms of treatment for patients with 17p deletion.

Really, these agents, because they act by a novel mechanism of action, are applicable to essentially all of the risk categories that we have identified and I've talked about previously in terms of the prognostic factors.

They are potentially relevant in the front-line setting as well as in the salvage setting. The salvage clinical trials will likely have data available and approval in the relapsed setting with ibrutinib versus the front-line setting. But I know [that in] the front-line setting the trials are ongoing.

There are other Bruton's tyrosine kinase inhibitors in development. Another one is AVL-292, or CC-292. There is not yet a registration study that's ongoing for CC-292, but that drug is in development.

And there are three agents that are in development as inhibitors of PI3 kinase as therapy for CLL. Idelalisib, or CAL-101, or GS-1101: This is a drug that has been evaluated in phase 1/2 trials36,37 and is currently in registration trials in combination with immunotherapy or monoclonal antibody therapy or chemoimmunotherapy.38-40

The same kinetics as I mentioned with the BTK inhibitor are relevant for the PI3 kinase inhibitor—that is, rapid lymph-node reduction when patients go on drug, and this concurrent transient increase in absolute lymphocyte count or leukemia count, which will subsequently resolve over time as patients remain on drug.

The other two [PI3K inhibitors] that are in development are IPI-145 and TGR-1202. And there have been data that there certainly is activity with those agents, but again, they're further behind in development.

The other B-cell receptor pathway inhibitor that I should mention targets Syk, which is fostamatinib, as well as GS9973. We don't have much clinical data with regard to those agents, but certainly we'll be hearing more about them.

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What other novel therapies are showing promise in expanding the management options and improving outcomes in CLL?

Dr. Wierda: The other group or category of small-molecule inhibitors targets BCL-2. BCL-2 is a protein that's in the cell cytoplasm. It's overexpressed, or high levels are found, in CLL. It gives a survival advantage and an antiapoptotic advantage to CLL cells. It's thought that these elevated levels are responsible for the prolonged survival of the leukemia cells. And so ABT-199 inhibits or blocks BCL-2, and the cells will undergo apoptosis. ABT-199 was specifically designed just to block BCL-2 and not to block BCL-XL, so we don't see thrombocytopenia as a dose-limiting toxicity with ABT-199.

We see responses in patients, and we've reported responses in patients who are refractory to fludarabine, and we've also reported responses in patients with 17p deletion when they're treated with ABT-199.41 The drug is highly active. The development has been delayed by the fact that tumor lysis has been seen with this agent in dose initiation as well as dose escalation, and so we had to go back and redesign the trials in order to do a more gradual dose escalation. There's a trial that we've opened recently that is a phase 2 trial with ABT-199, specifically for relapsed patients with 17p deletion.42 The registration trials have not yet begun for ABT-199.

And then the third class of drugs is the CD20 monoclonal antibodies. We've had rituximab available for many years, and that clearly is active. It has some activity as a single agent, but it's more effective, in my opinion, in chemoimmunotherapy regimens.

GA101 [or obinutuzumab] is a type 2 CD20 antibody that's recently been reported in terms of a randomized trial in combination with chlorambucil, and this trial demonstrated superiority in progression-free survival for patients who received chlorambucil plus GA101 over chlorambucil alone.43 These are patients who had comorbidities and who were not otherwise candidates for chemoimmunotherapy or treatment with FCR.

There were patients who achieved the minimal-residual disease–free complete remission when treated with chlorambucil plus GA101, and I think this speaks to the activity of the drug, because I wouldn't expect to see that in patients who were treated with chlorambucil plus rituximab. So this is a drug that I'm excited about.

Narrator: On November 1, the US Food and Drug Administration approved obinutuzumab [or GA101] for use in combination with chlorambucil to treat patients with previously untreated CLL.44

Dr. Wierda: So there's a lot of exciting things happening in CLL. There are a number of new agents that are available. They work by novel mechanisms of action. They work in patients who have both low-risk features as well as the high-risk features. They're not curative agents, though; and I think the next wave of significant advances in managing patients with CLL will be efforts to reconstitute the immune system, which should be helpful in reducing their risk for infections and reducing their risk for second cancers.

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Improving Outcomes in Chronic Lymphocytic Leukemia: Expert Perspectives on Current and Emerging Treatment Strategies

  1. Implementing Individualized Approaches to Management of Different Subtypes of Patients With CLL