New Investigational Agent Targets Gene Signaling Pathways to Improve Therapeutic Response for Patients with Chronic Lymphocytic Leukemia

ATLANTA, Dec. 8, 2012 /PRNewswire-USNewswire/ -- The promising investigational targeted therapy ibrutinib and its mechanism of silencing gene communication pathways critical to the development of cancer may be an effective way to combat chronic lymphocytic leukemia (CLL), according to studies presented today at the 54th Annual Meeting of the American Society of Hematology (ASH).

CLL is a blood cancer that causes abnormal white blood cells called lymphocytes to accumulate in the blood, bone marrow, and in the lymph nodes or other organs, causing these organs to enlarge. Approximately 15,000 Americans are diagnosed with CLL every year; nearly 70 percent of those affected are 65 and older.^{[1], [2]} For some patients with slower growing disease, physicians employ "watch and wait" strategies to minimize unnecessary treatment. However, patients with high-risk features such as rapidly progressing disease require prompt treatment to manage symptoms and reduce organ damage.

Ibrutinib is a specialized anti-cancer therapy that targets the Bruton's tyrosine kinase (BTK, an enzyme important in the development of CLL). As an inhibitor of BTK, ibrutinib selectively targets leukemia cells, promoting their death and preventing them from growing while leaving normal cells unharmed. Studies suggest this design allows the drug to more effectively treat the disease, with encouraging early results in harder-to-treat patient groups such as elderly untreated patients and those whose disease has become resistant to other therapies or those who have experienced disease recurrence after receiving other therapies. Two studies will present efficacy and safety results testing the compound alone and in combination with other currently used therapies for CLL.

"The evidence collected to date on ibrutinib demonstrates that it may have the potential to improve long-term prognosis for patients who are not sensitive to standard treatment," said Claire E. Dearden, MD, moderator of the press conference, Consultant Hematologist and Head of the CLL Unit at The Royal Marsden NHS Foundation Trust in London. "Equally important, the exciting efficacy and safety data that we are seeing for this drug in these studies underscore the significant progress we are making in our quest to better understand and attack the specific cellular targets responsible for CLL, particularly in these vulnerable patient populations."

This press conference will take place on Saturday, December 8, at 8:00 a.m. EST.

The Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and is Tolerable in Treatment Naive (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 Phase Ib/II Study [Abstract 189]

New research demonstrates that a novel investigational therapeutic agent called ibrutinib may be an effective and safe targeted treatment option for previously untreated, hard-to-treat, and relapsed patients with chronic lymphocytic leukemia (CLL). 

Primary treatment for CLL includes a combined chemotherapy-based regimen with fludarabine and cyclophosphamide, along with the immune therapy rituximab. While rituximab is effective, it is generally not well tolerated among elderly patients. Treatment with this drug also compromises the immune system by attacking both cancerous and normal cells, putting patients at risk for a range of infections and increasing their risk of developing treatment-related acute myeloid leukemia.

To understand if ibrutinib may be effective for elderly CLL patients and to identify which patients might benefit most from the drug, researchers enrolled 116 CLL patient participants in several treatment cohorts: patients who were never treated (the treatment-naive group), those who had received two or more prior therapies (the relapsed/refractory group), those who had relapsed within two years of treatment (the high-risk group), and those over age 65. Two oral dosing regimens (420 mg or 840 mg daily) of ibrutinib were used. The primary goal of the study was to determine the safety of the low and high doses; secondary objectives included efficacy, measures of the intensity of the drug's effect in the body, and the long-term safety of administering this therapy continuously until relapse.

The study found that response to therapy was high across the cohorts, with largely manageable toxicities.  Previously untreated elderly patients responded best to the agent, with 71 percent experiencing a complete or partial response at either treatment dose. The same response was observed in 67 percent of the relapsed patients and 50 percent of the high-risk patient cohort. After 22 months of follow-up, the disease had not progressed in 96 percent of previously untreated patients and 76 percent of relapsed and high-risk patients.

The treatment regimen was generally well-tolerated, as only non-severe side effects were observed, including diarrhea, fatigue, chest infection, rash, nausea, joint pain, and infrequent and transient low blood counts. Investigators found no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months for treated patients. These results demonstrate ibrutinib's potential as a highly active, well-tolerated first-line therapy for CLL.

"As we learn more about how to target specific essential survival signals and communications pathways in cancer, we are improving our ability to effectively treat the disease while avoiding the toxicities of chemotherapy and potential relapse," said John C. Byrd, MD, lead author and Director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute in Columbus. "If we can replicate these high survival rates and good tolerability with ibrutinib through larger scale Phase III studies, we may find it to be an extremely valuable new therapy for not just elderly, but for all CLL patients."   

Dr. Byrd will present this study in an oral presentation on Sunday, December 9, at 5:00 p.m. EST at the Georgia World Congress Center in Thomas Murphy Ballroom 4, Level 5, Building B.

The BTK Inhibitor Ibrutinib (PCI-32765) in Combination with Rituximab is Well−Tolerated and Displays Profound Activity in High-Risk Chronic Lymphocytic Leukemia (CLL) Patients

[Abstract 187]

The combination of the novel investigational agent ibrutinib with an established therapeutic antibody, rituximab, may present a safer and more effective option than the current standard chemotherapy-based treatment regimen for patients with high-risk CLL.

While current chemotherapy-based treatment options for CLL patients are effective, they come with toxic side effects that are challenging for elderly patients. Physicians have long awaited new options that offer better tolerability. Ibrutinib is designed to selectively target leukemia cell growth, with the aim of effectively treating the disease without the toxicities of chemotherapy. Data from earlier studies of ibrutinib have shown it to be equally effective in both low- and high-risk CLL.

High-risk CLL patients typically have unfavorable responses to standard CLL therapies and a dismal outcome. Such patients are characterized by presence of chromosomal abnormalities (i.e., deletions of chromosome 17p or 11q) or short remissions (less than 3 years) after standard chemo-immunotherapy. To develop an alternative therapy regimen for this patient population, researchers explored the combination of ibrutinib and the anti-CD20 antibody rituximab in high-risk CLL.

In this Phase II study conducted at The University of Texas MD Anderson Cancer Center in Houston, ibrutinib was given in combination with rituximab to evaluate its potential to accelerate and improve CLL patient responses. Forty patients were treated with 420 mg of ibrutinib daily in combination with weekly rituximab for four weeks, followed by ibrutinib daily plus monthly rituximab until month six, followed by single-agent ibrutinib.

Positive responses to therapy were shown among the vast majority of treated patients. At four months of follow-up, the overall response rate was 85 percent and almost all (38 of 40) patients continued on therapy without disease progression. Of the 20 patients evaluable for early response, 17 achieved a partial remission. Patient health questionnaires also noted improvements in health and the quality of life of all treated patients. 

Overall, the regimen was well-tolerated among participants, with little severe toxicity that was largely unrelated and short in duration. After treatment with ibrutinib-rituximab (iR) combination therapy, most cases of early lymphocytosis (increase in white blood cells that is a sign of infection), due to the ibrutinib-induced shift of CLL cells from lymph node tissues into the blood, peaked early and resolved; at four months of follow-up, only three treated patients had lymphocytosis that had not yet resolved. This shorter lymphocytosis duration, when compared to single-agent use of ibrutinib, is presumably related to the addition of rituximab.

"We know that high-risk CLL patients struggle with the effects of standard chemo-immunotherapy and eventually become resistant. For these harder-to-treat patients, ibrutinib in combination with rituximab appears to be a safer option with high efficacy and without the related risks," said Jan Burger, MD, PhD, lead author and Associate Professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. "Based on these promising results, we need larger-scale studies of ibrutinib-rituximab in high-risk CLL, with the goal of accelerating the development of this therapy for patients who most urgently need better options."

Dr. Burger will present this study in an oral presentation on Sunday, December 9, at 4:30 p.m. EST at the Georgia World Congress Center in Thomas Murphy Ballroom 4, Level 5, Building B.

American Society of Hematology 54th Annual Meeting

The study authors and moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on efforts to reduce toxicity and improve survival for blood cancer therapy, strategies to increase the efficacy and safety of treatments for bleeding and clotting disorders, new targeted treatment for hard-to-treat blood disorders, and advances in stem cell technology and transplant strategies. For the complete annual meeting program and abstracts, visit www.hematology.org/2012abstracts. Follow ASH (@ASH_hematology) on Twitter (use the hashtag #ASH12 when posting tweets about the meeting) and on Facebook at www.facebook.com/AmericanSocietyofHematology for the most up-to-date information about the 2012 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[1] National Cancer Institute, "SEER Stat Fact Sheets: Chronic Lymphocytic Leukemia," http://seer.cancer.gov/statfacts/html/clyl.html (Accessed October 2012).

[2] Gribben, J.G., "How I treat CLL up front," Blood 115, no. 2 (2009): 187-197.

SOURCE American Society of Hematology