Therapy for CLL: Where Are We Today? Where Will We Be Tomorrow?

Jennifer Brown MD, PhD

Targeted Oncologyinterviewed Jennifer Brown MD, PhD, director of the Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, and assistant professor of Medicine at Harvard Medical School in Boston, MA.

Targeted Oncology: What are the factors to determine whether a newly diagnosed patient requires treatment or whether the patient’s disease should be monitored at first?

Mark Weiss, MD, Comments on BTK and PI3K Inhibitors

Weiss is a professor and director in the Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation in the Department of Medical Oncology at the Kimmel Cancer Center at Thomas Jefferson University.

Dr. Brown:That decision is still based on a clinical assessment, the patient’s clinical status, and whether or not they meet clinical criteria for treatment, including presence of anemia, thrombocytopenia from the disease, or adenopathy. The majority of chronic lymphocytic leukemia (CLL) patients are diagnosed not based on symptoms but on an elevated lymphocyte count, and these patients do not need treatment.Whether a patient requires treatment is based not on symptoms, as most patients do not have CLL-specific symptoms, but on disease burden.

Are there any biomarkers that facilitate diagnosis or prognosis?

We do have a variety of biomarkers of higher-risk disease that are useful for prognosis, but if the patient has very early-stage disease, regardless of those biomarkers, those patients will still be observed initially. One is the chromosome 17p deletion, which is the highest risk marker. For patients who need treatment, this marker is associated with a poor prognosis, but for those who do not yet meet criteria for needing treatment, we still observe the patients first, as a subset of these patients may not require treatment for some time. How best to risk-stratify patients up front is still a major question, given that most patients do not have 17p deletion and the other markers are not as prognostic.

What are the first-line treatment options for CLL?

For patients who are relatively young with only a few comorbidities, chemotherapy plus antibody-based immunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) is the current standard of care (SOC) that has been shown to improve overall survival.

What about patients who are not eligible for this regimen?

Then it gets more complicated, and there is not an obvious SOC. In the United States, many of us use dose-reduced chemotherapy with rituximab, either fludarabine without cyclophosphamide or lower-dose fludarabine. Rituximab is used in combination; it is not a very effective drug as a single agent, especially in relapsed patients. There is also bendamustine with rituximab. The duration of remission appears to not be quite as good as with FCR, but it is better tolerated by older patients. For patients who cannot tolerate either of these regimens, there is chlorambucil, which has remained the standard in Europe based on a randomized trial that showed it was as effective as fludarabine in elderly patients, but it is not used very much in the United States. There also are now data that chlorambucil with rituximab is better than chlorambucil alone, again emphasizing the importance of including rituximab.

Does adding rituximab add a lot of toxicities on top of a chemotherapy regimen?

The toxicities are mostly from chemotherapy. Rituxumab adds a risk of infusion reactions at the time of treatment, but those tend to be manageable. Neutropenia induced by the chemotherapy is slightly worse when rituximab is added, but this is not a major effect.

Which patients are eligible for a stem cell transplant?

A stem cell transplant is typically considered after a patient has had several rounds of therapy or if the patient is at high risk, that is, has a 17p deletion. Allogeneic transplants have about a 15% risk of death during transplant, so we tend to hold off on a transplant until the disease poses at least that much risk. CLL patients tend to be diagnosed later in life, and so many patients are not eligible. With younger patients, up to their mid-60s, depending on their health, they would be transplant candidates, but there are also issues of getting the patient into an adequate remission state prior to a transplant.

There are several other antibodies that are also available, ofatumumab (Arzerra) and alemtuzumab (Campath)? When are these appropriate for treatment?

Alemtuzumab is approved for patients who are fludarabine-refractory and have been exposed to alkylating agents. Alemtuzumab can be effective for patients who have primarily blood and bone marrow disease, but not for patients who have disease in the lymph nodes. Most patients have disease in both lymph nodes and the blood marrow. The label for alemtuzumab was withdrawn, but it is still readily available on a compassionate-use basis. Ofatumumab is approved for patients who are refractory to both fludarabine and alemtuzumab, based on an approximate 45% response rate. The progression-free survival (PFS) is about 6 months when used as a single agent.

Let’s talk about some of the therapies that are in development for CLL. What is the rationale for these targeted agents in CLL?

Most of the newer oral agents in development are not specifically targeted against patients with chromosome 17p deletion, but the key is that these patients are typically quite resistant to chemotherapy, and they are not resistant to these targeted agents. So, these patients are a major unmet medical need that is seen to benefit from the newer agents. The overall rationale for these targeted agents is that they hit key pathways that are always turned on in CLL, keeping the cells alive when they should die. Certain pathways of great interest are the B cell receptor pathway and the BCL2 pathway.

One of these agents is ibrutinib, a Bruton's tyrosine kinase inhibitor. What is the evidence thus far in CLL?

Ibrutinib has filed [a New Drug Application] with the FDA for use in previously treated CLL patients. The data are fairly remarkable.1 The PFS at 26 months was 75% for these relapsed, refractory patients who have had a median of four prior regimens. This is very good. The drug is oral and is very well tolerated. There are also first-line data from 31 patients reported showing a high response rate with 96% of patients still in remission.2 The majority of patients seem to respond. Even the high-risk patients respond but do appear to relapse earlier than lower-risk patients.

There has been a suggestion that the frequency of transformation may be higher in patients who relapse, which is something that needs to be watched. Transformation is when CLL turns into an aggressive lymphoma such as diffuse large cell lymphoma. The typical rate of transformation is about 4%-8% in retrospective analyses, but there have not been publications on the risk of transformation among patients who relapse on a clinical trial or after a targeted agent.

What are some of the other oral agents in development?

The PI3 kinase inhibitors are also in development. Final results with a delta isoform inhibitor, idelalisib, were presented at the American Society of Clinical Oncology (ASCO) meeting this year in relapsed and refractory patients.3 The drug has quite extensive activity in heavily pretreated patients. The median PFS in the phase I, 54-patient study was about 17 months, but patients treated at the recommended phase II dose have a 29-month PFS. Another PI3K inhibitor is IPI-145 which targets both the delta and gamma isoforms. So far, data from 11 CLL patients have been reported, and the drug looks potent in inducing responses.4 The delta isoform is predominantly expressed in CLL and other hematologic malignancies. The gamma isoform is expressed in neutrophils and T-cells, and it is still unclear how much targeting the gamma isoform will add to the treatment of CLL.

What about the Bcl2 inhibitors?

The previous generation Bcl2 inhibitor, ABT-263, a Bcl2 and Bcl-xL inhibitor, had activity, about a 35% response rate, but the activity was limited by thrombocytopenia, which was due to its targeting Bcl-xL. The newer agent, ABT-199, is Bcl-2—specific but looks like it is more potent. An 80% response rate has been shown so far, and 10% of those are complete remission patients. But the phase I trial has been complicated because it causes tumor lysis, and the study was on hold but is now reopened with a new tumor lysis prophylaxis included.

Are there any antibodies in development for CLL?

There is a CD20 antibody, obinutuzumab for which there are preliminary data from the phase III trial, and more data will be reported this year.5 Of the three CD20 antibodies, the in vitro activity against CLL cells of ofatumumab is better than rituximab, and obinutuzumab is better than ofatumumab. Obinutuzumab has a slightly different mechanism that is not as dependent on the patient’s immune system to kill the CLL cells, so that is very encouraging for the likelihood of obinutuzumab to work as a single agent, more so than the other two currently available CD20 antibodies.

References

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.N Engl J Med. 2013;369(1):32-42.
2. Byrd JC, Furman RR, Coutre S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a phase Ib/II study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Blood. 2012;120(21; abstr 189).
3. Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL.J Clin Oncol. 2013;31(suppl; abstr 7003).
4. Patel MR, Kahl BS, Horwitz SM, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL.J Clin Oncol. 2013;31(suppl; abstr 7070).
5. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial.J Clin Oncol. 2013;31(suppl; abstr 7004).