Chronic Lymphocytic Leukemia: 2013 Update

Kanti R. Rai, MD

Clinical study results presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting may offer new hope for patients with chronic lymphocytic leukemia (CLL). Kanti R. Rai, MD, chief of the Division of Hematology and Oncology at Long Island Jewish Medical Center, and professor of Medicine at Albert Einstein College of Medicine, Bronx, New York, noted that the recent advances in CLL “provide the hope and the methods to change CLL into a treatable disease,” adding that “the new treatment options promise to change the course of this disease for large numbers of patients.” Rai credits researchers and drug developers for supporting the use of a hypothesis-driven approach in developing the agents and clinical protocols.

CLL is the most common form of lymphoid malignancy, accounting for 25% of all forms of leukemia diagnosed in the Western world and causing about 75,000 deaths worldwide each year.¹Because CLL often grows slowly, treatment may be delayed. Treatment regimens often include a combined approach using chemotherapies, such as fludarabine and alemtuzumab, and monoclonal antibodies, such as rituximab and ofatumumab.²

Ofatumumab is a type I human monoclonal antibody approved by the FDA in 2009 for the treatment of B-cell CLL refractory to both fludarabine and alemtuzumab.³Significant response rates during a phase II study in treatment-refractory patients placed this drug in the FDA’s accelerated approval process. Ofatumumab continues to be evaluated in clinical trials and has demonstrated prolonged progression-free survival (PFS) and overall survival (OS) rates in patients with refractory CLL and is also showing efficacy in the treatment of malignant and nonmalignant diseases, such as non-Hodgkin lymphoma, rheumatoid arthritis, and multiple sclerosis.⁴Higher dosages of ofatumumab may result in higher rates of complete response as compared with a lower-dose regimen, with complete response rates of 50% and 32%, respectively.⁵Comparative trials are ongoing.

At ASCO 2013, results were presented on a phase III study in patients with previously untreated CLL evaluating the safety and efficacy of ofatumumab plus chlorambucil versus chlorambucil alone.6 Patients receiving ofatumumab plus chlorambucil demonstrated a 9.3-month improvement in PFS versus chlorambucil alone (22.4 months vs 13.1 months, respectively; HR = 0.57;P< .001). Safety data were consistent with those of previous studies.

Encouraging initial results from a phase III study of the investigational drug GA101 (now known as obinutuzumab) were also presented at ASCO 2013.⁷CLL11 is a multicenter, open-label, randomized, three-arm study evaluating the safety and efficacy of GA101 in 781 patients with previously untreated CLL. The study included elderly patients and patients with comorbidities with previously untreated CLL. The comorbidities allowed by the study design included disease states such as hypertension, cardiovascular disease, and renal disease. According to Rai, effective treatment of CLL in otherwise healthy individuals has historically been challenging, but treatment of the elderly and patients with comorbid conditions represents an even greater challenge.

GA101 is the first type II anti-CD20 antibody that has been developed using GlycoMab technology, or glycoengineering. The technology is designed to strengthen the body&rsquo;s own immune responses, with anti-CD20 binding directly with CD20 to enhance killing of invading cancer cells. The primary endpoint of the CLL11 study was PFS, with secondary endpoints including overall response rate (ORR), OS, disease-free survival (DFS), minimal residual disease (MRD), and safety. The patients were randomized to one of three arms: GA101 plus chlorambucil, rituximab plus chlorambucil, or chlorambucil alone.

Study results to date are impressive. A statistically significant reduction of 86% in the risk of disease progression or death was demonstrated in the GA101-plus-chlorambucil arm versus the chlorambucil- alone arm. The GA101-plus-chlorambucil arm also demonstrated a median PFS of 23 months versus 10.9 months with chlorambucil alone (HR = 0.14; 95% CI, 0.09-0.21;P<.0001).⁷In the rituximab-plus-chlorambucil arm, the risk of disease progression or death was reduced by 68%. The median PFS in the rituximab-pluschlorambucil arm was 15.7 months compared with 10.8 months for chlorambucil alone.

Toxicity was as expected. The most common adverse events (AEs) in the GA101 arm involved infusion-related reactions during the first infusion and neutropenia. The most common AEs in the rituximab arm were infections and neutropenia.^7,8The FDA recently granted obinutuzumab priority review for previously untreated CLL.

Jennifer R. Brown, MD, PhD

Another agent, ibrutinib, although not yet approved by the FDA, is designed to selectively inhibit the enzyme Bruton&rsquo;s tyrosine kinase (BTK). This enzyme is a key mediator in multiple B-cell survival mechanisms, thereby making it an important target. The FDA announced in May that ibrutinib was awarded Breakthrough Therapy designation for CLL with 17p deletions, placing ibrutinib in the FDA&rsquo;s accelerated approval process. Ibrutinib has demonstrated sustained inhibition of Bcell receptor signaling and nuclear factor kappa B signaling in lymph nodes and in peripheral blood. This agent is proving to be highly effective, even in difficult-to-treat populations, and possibly may be used as single-agent treatment against CLL.⁹

Manipulation of the BTK enzyme is an area of much recent research. The integration of BTK manipulation with other treatment options is also anticipated to be an area of ongoing research. Ibrutinib is the primary agent in the ongoing RESONATE phase III clinical trial and SPARK phase II clinical trial. In addition, ClinicalTrials.gov currently reports five active phase III trials under way for ibrutinib.¹⁰

Inhibition of PI3K is another approach in CLL. A phase I study of the novel selective PI3K-delta inhibitor idelalisib (formerly known as GS-1101) presented at ASCO 2013 found that idelalisib produced rapid and prolonged tumor shrinkage in half of patients with relapsed or refractory CLL who received the drug as monotherapy.11

The PI3K pathway is hyperactive in CLL, and the PI3K-delta isoform is the predominant hyperactive subtype. Idelalisib is the first drug that selectively inhibits this PI3K subtype and is designed to reduce proliferation, enhance apoptosis, and inhibit homing and retention of malignant B cells.

In the phase I study, 54 patients with relapsed or refractory CLL were treated continuously for up to 48 weeks with idelalisib as a single agent, with dosages ranging from 50 mg to 350 mg twice daily in 28-day cycles, although 10 patients received the 300-mg dosage once daily in 28-day cycles. Patients had received a median of five prior therapies (range, 2-14), and 70% of patients were refractory to their most recent prior regimen. Patients were exposed to idelalisib for a median of 9 months (range, 0-41+ months), with 25 patients (46%) completing the primary study and 23 patients (43%) enrolling in an extension study.¹¹

The median time to first response was 1.9 months (range, 0.9-12.9 months). The median PFS was 17 months and the median duration of response was 18 months. The PFS was better than what is typically expected for a sixth-line therapy, where the benefit might last for between 6 and 12 months.¹¹

Idelalisib was generally well tolerated. Adverse events associated with the drug included elevated liver function tests that were asymptomatic and resolved, diarrhea, and rash. Low neutrophil counts and infections, particularly pneumonia, were also observed.

Role of Older Therapies

&ldquo;The substantial clinical activity of idelalisib that we observed justifies its further clinical development in CLL,&rdquo; said Jennifer R. Brown, MD, PhD, director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts, and lead author of the study. Three phase III trials of idelalisib are currently enrolling patients with previously treated CLL; the studies will test idelalisib in combination with other agents: with ofatumumab (ClinicalTrials.gov Identifier NCT01659021), rituximab (NCT01539512), and a combination of rituximab and bendamustine (NCT01569295).Rai recognizes the importance of the recent advancements and the potential value of drugs currently in clinical trials and in the pipeline. He adds that there is a need to incorporate the older medications into new treatment regimens. &ldquo;Understanding the mechanisms of the newer and older drugs provides the treating physician with the ability to control, or traffic, the treatment of each patient, thereby making chemotherapy as effective as possible,&rdquo; he said.

Many older agents remain important for optimizing efficacy in treatment regimens for patients with CLL, and will likely continue to be used in combination with the newer drugs. Lenalidomide is FDA-approved as an orphan drug in the treatment of CLL.¹²This medication carries multiple warnings and requires cautious use in specified patient populations. Black box warnings for lenalidomide include risks of embryo-fetal toxicity, hematologic toxicity, and deep venous thromboembolism and pulmonary embolism.¹³

Bendamustine is an older agent and works primarily by controlling cellular proliferation. It is indicated for use in the treatment of CLL and indolent B-cell non-Hodgkin lymphoma that has progressed under defined treatment regimens. FDA approval for the use of bendamustine in patients with CLL and recent research labels this medication as a &ldquo;rediscovered&rdquo; drug, showing evidence of improved OS rates in study populations.^14,15

Susan M. O&rsquo;Brien, MD

Although drug therapy is key to the treatment of CLL, other areas are also being explored. Abstracts were presented at ASCO 2013 on areas of research involving monoclonal antibodies, combination treatments, pipeline agents, CLL genetics, stem cell research, and tumor genomic profiling. In-depth genetic work is being done to consider different avenues of treatment for different patient populations.

In order to diagnose CLL, at least 5000 clonal B cells/&mu;L must be present in the peripheral blood. Confirmation of the CLL diagnosis requires adequate immunophenotyping using flow cytometry of peripheral blood for the following cell surface markers: kappa/lambda, CD19, CD20, CD5, CD23, and CD10. Alternatively, paraffin-section immunohistochemistry can be used to confirm the diagnosis with the following markers: CD3, CD5, CD10, CD20, CD23, and cyclin D1.^2,16

Fluorescence in situ hybridization (FISH) can be used to evaluate prognosis, and it is recommended that FISH be re-evaluated periodically due to the ability of cytogenetic abnormalities to evolve over time.^2,16Other tests that may be performed at diagnosis include the evaluation of the mutational status of IgVH, VH3.21 usage, and expression of ZAP-70 or CD38. Serum markers that may be evaluated to predict survival or PFS include CD23, thymidine kinase, and &beta;2-microglobulin. A bone marrow aspirate and biopsy, while not required, may provide information to help evaluate factors that contribute to cytopenias that may or may not be related to leukemia cell infiltration of the marrow.¹⁶

When asked how to effectively assign patients to the various emerging novel treatments, Susan M. O&rsquo;Brien, MD, Ashbel Smith Professor, Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, replied at this year&rsquo;s ASCO meeting, &ldquo;We don&rsquo;t yet know enough in terms of biomarkers&hellip; I think a lot of this will come out with further trial data and further information. I think we&rsquo;re not quite there yet.&rdquo;

According to Rai, the recent treatment advances in CLL and the greater understanding of the disease itself provides an expectation that CLL will soon become a uniquely different disease and one that is treatable, even in the difficult-to-treat patient population. The recent treatment advances offer new hope to patients with CLL.

References

1. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukemia.Cochrane Database Syst Rev. 2012;11:CD008079.
2. National Comprehensive Cancer Network. NCNN Clinical Practice Guidelines in Oncology: Non-Hodgkin&rsquo;s Lymphomas. Version 1.2013. Available at: www.nccn.org. Accessed July 8, 2013.
3. American Society of Health System Pharmacists, Inc. Ofatumumab. Updated July 1, 2010. www.drugs.com/monograph/ofatumumab. html. Accessed July 15, 2013.
4. Nightingale G. Ofatumumab: a novel anti-CD20 monoclonal antibody for treatment of refractory chronic lymphocytic leukemia.Ann Pharmacother. 2011;45(10);1248-1255.
5. Tsimberidou AM. Ofatumumab in the treatment of chronic lymphocytic leukemia.Drugs Today, (Barc). 2010;46(7):451-461.
6. The ASCO Post website. Ofatumumab plus chlorambucil improves progression-free survival in patients with previously untreated CLL. May 30, 2013. http://www.ascopost.com/ViewNews.aspx?nid=4177. Accessed July 15, 2013.
7. Roche Pharmaceuticals. Roche&rsquo;s obinutuzumab (GA101) significantly reduced the risk of disease progression or death in people with one of the most common forms of blood cancer. Roche Pharmaceuticals website. May 16, 2013.. http://www.roche.com/media/media_ releases/med-cor-2013-05-16.htm. Accessed July 15, 2013.
8. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus chlorambucil 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. Presented at: ASCO 2013 Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract 7004.
9. Goodman A. Promising phase II results continue to support ibrutinib in CLL. The ASCO Post website. May 15, 2013. http://www.ascopost. com/issues/may-15,-2013/promising-phase-ii-results-continue-tosupport- ibrutinib-in-cll.aspx. Accessed July 15, 2013.
10. Pharmacyclics Inc. Pharmacyclics completes enrollment of first phase III ibrutinib CLL study- RESONATE and announces completion of enrollment of phase II ibrutinib MCL study- SPARK. Pharmacyclics website. April 18, 2013. http://ir.pharmacyclics.com/releasedetail. cfm?releaseid=757619. Accessed July 15, 2013.
11. Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3K&delta;, in patients with relapsed or refractory CLL.J Clin Oncol. 2013;31(suppl; abstr 7003).
12. Medscape Reference. Lenalidomide. Available at http://reference. medscape.com/drug/revlimid-lenalidomide-342200. Accessed July 15, 2013.
13. American Society of Clinical Oncology. FDA approves lenalidomide for mantle cell lymphoma. ASCO in Action website. June 6, 2013. http://ascoaction.asco.org/Home/tabid/41/articleType/ArticleView/ articleId/489/FDA-Approves-Lenalidomide-for-Mantle-Cell- Lymphoma.aspx. Accessed July 15, 2013.
14. Abou-Nassar K, Brown JR. Novel agents for the treatment of chronic lymphocytic leukemia.Clin Adv Hematol Oncol. 2010;8(12):886-895.
15. Mundell EJ. &lsquo;Rediscovered&rsquo; lymphoma drug helps double survival: study.US News & World Report. June 3, 2012. Available at http:// health.usnews.com/health-news/news/articles/2012/06/03/ rediscovered-lymphoma-drug-helps-double-survival-study. Accessed July 15, 2013.
16. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 Guidelines.Blood. 2008;111(12):5446-5456.