The Transformation of Treatment in CLL: A Q & A With Dr. William G. Wierda

William G. Wierda, MD, PhD

The approval of the first small-molecule targeted therapy for patients with chronic lymphocytic leukemia (CLL) launches a new era that may transform management of the disease, yet significant challenges in translating research advances into improvements for long-term outcomes remain, according to William G. Wierda, MD, PhD, a leading researcher in the field. Wierda discussed emerging therapies for CLL during an interview at the 18th Annual International Congress on Hematologic Malignancies, mid-February 2014 in New York City.

The conference occurred within days of the FDA’s accelerated approval of ibrutinib (Imbruvica) for patients with CLL who have received at least one prior therapy. Ibrutinib, the first Bruton tyrosine kinase (BTK) inhibitor on the market, was approved in November for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

TABLE. Targeted CLL Therapies in Development^1,2

^aSponsors and collaborators may not be participating in every clinical trial for a given agent.

^bIbrutinib is FDA-approved for patients with CLL who have received at least 1 prior therapy. CLL indicates chronic lymphocytic leukemia; del, deletion on short arm of chromosome.

1. Wierda WG. 17p del CLL patients—first-line vs relapsed/refractory. Presented at: 18th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma. February 14-15, 2014; New York, NY.

2. NIH Clinical Trials Registry. www.ClinicalTrials.gov.

In CLL, ibrutinib demonstrated an overall response rate of 58.3% (95% CI: 43.2%-72.4%) among 48 heavily pretreated patients with a median age of 67 years (range, 37-82 y).¹All responses were partial. The duration of response (DOR) ranged from 5.6 months to greater than 24.2 months, with the median DOR not yet reached. The indicated dose is 420 mg daily orally. It remains to be seen whether or not ibrutinib and other targeted therapies will transform CLL like imatinib (Gleevec), a tyrosine kinase inhibitor (TKI), helped transform treatment of chronic myeloid leukemia. Already, ibrutinib is among a growing list of other targeted inhibitors under development for CLL (Table).

The four major groups of inhibitors target BTK, phosphatidylinositol 3-kinase (PI3K), the spleen tyrosine kinase (Syk), and BCL2 proteins.

“It is the whole class of agents that is transformative,”said Wierda, a professor and center medical director in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas, who also served on the program committee for the conference. “We’re entering a phase of a more targeted treatment approach and hopefully a less chemoimmunotherapy/chemotherapybased era.

“We will see a clear improvement in outcomes for patients with CLL, and when I think in terms of during my career, this is clearly a transformative period with significant incremental advances in therapy, particularly for the elderly who have difficulty tolerating myelosuppressive chemoimmunotherapy, and for patients with 17p CLL, for whom we have no effective treatment,” noted Wierda, who has been conducting research in CLL for more than a decade.

However, Wierda said the introduction of TKIs to the armamentarium for CLL would likely present issues of resistance similar to what was experienced in CML and other tumor types.

“Our work is not done,” he said. “We still have a lot of issues to address, and I think there still is clearly room for advances in treatments for patients with CLL.”

Ibrutinib is the second new therapy that the FDA approved for patients with CLL in less than 4 months. In November, the agency approved the monoclonal antibody obinutuzumab (Gazyva) in combination with chlorambucil for patients with previously untreated CLL.

Targeted Therapies: Please describe the patients who would be candidates for treatment with ibrutinib.

Would you consider using ibrutinib earlier if the patient had a del 17p?

Wierda, who serves on the National Comprehensive Cancer Network (NCCN) committee that develops guidelines for treatment of CLL, said the panel has incorporated data concerning both ibrutinib and obinutuzumab into the latest update, and will further review the new therapies at its meeting in late June. In an interview withTargeted Therapies, Wierda discussed these new treatments, including issues in translating these regimens into clinical practice.Wierda:The approval from the FDA is in second line, so patients who had previously received a first-line standard therapy, and have failed and are progressing, would be the appropriate population now for ibrutinib. Before approving ibrutinib for CLL, the FDA designated the agent as a Breakthrough Therapy for patients with a deletion in the short arm chromosome 17 (del 17p).Unfortunately, we don’t yet have a large experience with the 17p-deleted, untreated patient population with ibrutinib, but I think that, if I were to consider any front-line group to use ibrutinib for, it would be the patients with untreated 17p deletion. So far, the early data that we do have with ibrutinib indicate that, in the relapsed population, clearly it’s an advance and improves on their survival, and I think we’ll eventually have data in the front-line setting for the 17p population.

How do patients typically respond to ibrutinib, particularly concerning a transient increase in lymphocyte counts? Are there features of response that could be misleading?

The highest risk group of patients with CLL consists of those patients who are previously treated and have a 17p deletion. Those patients with 17p who are untreated are at very high risk, and constitute a small minority of patients going on front-line therapy—it’s about 5% to 8% of those patients. If they can tolerate standard treatment with chemoimmunotherapy such as FCR [fludarabine + cyclophosphamide + rituximab], their first remission is very short. It’s on the order of 14 months with FCR, but the majority of these patients do not get complete remissions and their disease is not held in check for very long. In my opinion, there is no standard first-line treatment for a patient with 17p deletion, whether they’re able to tolerate FCR, or alemtuzumab [Campath], or alemtuzumab plus steroids. Certainly, if they were not able to tolerate FCR, a treatment option would be a combination such as obinutuzumab and chlorambucil, or some other combination. They’re not going to do well with standard treatments that we use: chemotherapy or chemoimmunotherapy-based treatment.We have an opportunity right now to educate physicians about how these drugs work, and what we see that’s unique to these drugs and to the disease. When a patient goes on ibrutinib, or one of the PI3 kinase inhibitors, essentially what happens is there’s a disruption between the microenvironment and the CLL cells, so that the cells lose their connection with the microenvironment and their ability to stay in areas where they like to grow and to survive, such as lymph nodes and in the bone marrow. When you disrupt this interaction, the cells essentially go out into circulation and then they die. So if you have a patient on ibrutinib, for example, what you see initially on treatment is a rise in the white blood cell count. If you have a patient with a 200,000/mcL white blood cell count, it may go up to 300,000/mcL initially. In addition to this rise in leukemia count, one of the indicators that the drug is working to treat the disease is that patients typically will have a rapid improvement in their disease-related symptoms. Their fatigue improves. Their night sweats improve. Within 4 weeks to 6 weeks, there should be marked reduction in lymph node size. There haven’t been any significant complications related to a rising white blood cell count in the CLL population. We don’t see leukostasis, for example, or respiratory problems or stroke, when the white count goes up. It’s these features that are a little bit unique to these compounds, whether they’re the tyrosine kinase inhibitors or PI3 kinase inhibitors. Those are the things that we expect to see and look for, and are the indicators that the drug has activity in treating disease. I think it’s just a matter of the physicians being aware of that and gaining some experience when they put patients on treatment.

Key Elements of the B-Cell Receptor Pathway

Image redesigned from: Brown JR. Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway. Presented at 11th International Congress on Targeted Therapies; August 16-17, 2013; Washington, DC.

We do not see the lymphocytosis for patients who are initiated on BCL2 inhibitor therapy; in this case, there is typically rapid reduction in leukemia count in responding patients. Is there a framework in development for assessing response that incorporates elements unique to a targeted therapy in CLL? I think of response in terms of a patient’s “best response.” The elements of response for these agents may require patients to be past this period where they get the lymphocytosis, and you see their best reduction in leukemia counts, lymph node size, improvement in bone marrow, and elimination of disease-related symptoms. That may not be for 6 months to even a year after they’ve been on the treatment.

What else should clinicians know about ibrutinib?

What are the challenges of introducing oral targeted therapies that patients would be taking for the rest of their lives?

When you look at what their best response is, that’s really the only feature that’s distinguishing of this group of compounds (BTK, PI3K, and Syk inhibitors) compared with what we evaluate response with for chemoimmunotherapy— the fact that when patients have their best response, they still may have a lymphocytosis. It most likely will be less than what it was when they started treatment, but it will be over 7000/mcL or 10,000/mcL. There still will be a circulating population of leukemia cells. That was consistent with partial remission in the old guidelines.The side effect profile of ibrutinib is excellent. Perhaps there might be some GI intolerance such as nausea or loose stools. Ibrutinib is not myelosuppressive, so I don’t worry about making neutropenia worse when I put patients on ibrutinib monotherapy or having worsening anemia or thrombocytopenia. Those are things that I don’t worry about and I expect for them to improve as the patients stay on the treatment and respond. We do still see a risk of infection in this population. If they have been treated previously, their immune system is not normal because of the disease and prior treatments, so you have to be vigilant about the risk for infections and proactive about the use of antibiotics.That’s one of the discussions that I have with patients, and I think it’s something that’s going to be more relevant as we move forward. Patients will say, “Well, this is great, but do I have to take it every day for the rest of my life?” And the answer so far is, “Yes, you do, because we don’t have any data that indicate that patients are getting a molecular remission—MRD [minimal residual disease]—negative status— with ibrutinib, for example. The majority of patients aren’t getting an MRD-negative remission as their best response with ibrutinib, and we know that if we stop the drug, the disease will likely progress. So with that agent, we are essentially committing patients to an indefinite period of treatment.

What impact do you think the emerging targeted therapies will have on the role of stem cell transplant in patients with CLL?

We also worry about development of resistance, as we’ve seen with other TKIs. We haven’t had enough follow-up to have a good concept of how that’s going to look in the future with ibrutinib.The clinical decision of when to go to a transplant is becoming more challenging. For example, for the high-risk patients, the patients with a 17p deletion or those who have developed fludarabine refractory-ness, we could easily make an argument for them to go to transplant, whether it was with an unrelated donor or a matched related sibling donor. Our efforts were all aimed at getting them to transplant. Now we have patients with high-risk features who may have several different options, and they also may have a matched related donor.

What do you think the role of transplants should be?

You struggle with the concept. You have the knowledge of the availability of these agents that can control their disease, so the urgency for the patient to go to transplant isn’t like it used to be.I think an overall goal is to get rid of transplant. My opinion is that transplant is not a good therapy. Patients many times will have a concept about transplant that you get a little chemotherapy, you get your transplant, and everything’s back to normal 3 months later. Well, that’s never the case. It’s years before they are in reasonable shape, let alone back to the shape they were before they were transplanted. We are working on strategies that may offer the advantage that you can have with the cellular therapy- based treatment without the graft-versus host effect. Strategies such as chimeric antigen receptors (CARs), engineered T cells, and training T cells to react against specific antigens found on CLL cells. Most of the work so far has been done with CAR T-cells targeting CD19. There are a number of advantages to using one’s own T cells that have been engineered to specifically react against their own leukemia cells. That’s a big area in development right now, and hopefully with time that will eliminate the need for transplants.

Reference

1. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; Horsham, PA: Janssen Biotech, Inc; 2014.