Ibrutinib Continues to Demonstrate Viability in Treatment of CLL

Based on the results of the first in-human clinical trial of ibrutinib in chronic lymphocytic leukemia (CLL) – conducted in 2010 at Weill Cornell Medicine/NewYork-Presbyterian Hospital and other centers – researchers led in part by Dr. Richard Furman moved forward with the first phase II trial of the drug. According to a five-year follow-up study recently published in the American Society of Hematology’s Blood journal, ibrutinib continues to demonstrate excellent efficacy and tolerability as a single agent therapy for people with previously untreated and relapsed or refractory CLL.

CLL is characterized by uncontrolled growth of mature B-cells that accumulate in the blood, bone marrow, lymph nodes and spleen. As CLL cells fill these various organs, they interfere with normal cell functions. Ibrutinib is an oral treatment that inhibits Bruton’s tyrosine kinase (BTK), an enzyme involved in B-cell development that plays a critical role in CLL cell survival.

Prior to the Food and Drug Administration (FDA) approval of ibrutinib for CLL in 2014, chemoimmunotherapy (CIT), typically with fludarabine, cyclophosphamide and rituximab (FCR), was one of the only treatment options available for people with CLL. Chemoimmunotherapy often generates deep responses that last a median of five to six years, but it is associated with significant toxicities. When patients relapse after CIT, their disease becomes more resistant to subsequent treatments, and due to the accumulation of toxicities, many patients are unable to receive further CIT. Given the associated toxicities, the use of CIT is limited in older patients with comorbidities – the cohort that comprises the majority of CLL patients.

The phase II study in which Dr. Furman was involved tested ibrutinib as a single agent in over 100 patients – some of whom received no prior therapy, and others who relapsed following initial treatment. Patients received daily oral doses of ibrutinib until their disease progressed or until the presence of side-effects warranted discontinuation of therapy.

Almost 90 percent of all patient participants demonstrated a response to treatment at the five-year mark, and complete remission rates increased over time with ongoing treatment. Ninety-two percent of treatment-naive patients and 44 percent of relapsed/refractory patients remained free of disease progression five years out from the start of treatment.

Side-effects, including infections, diarrhea, bleeding and low-blood counts, were mild. They did not prevent patients from remaining on treatment long-term and often improved with continued dosing.

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Dr. Richard Furman, M.D.

“These data demonstrate the excellent long-term outcomes for CLL patients treated with ibrutinib, especially those who receive ibrutinib as their first therapy,” says Dr. Furman.

Dr. Richard Furman Examines Future of CLL Risk Assessment

At OncLive’s State of the Science Summit on Hematologic Malignancies, Dr. Richard Furman, director of the Chronic Lymphocytic Leukemia (CLL) Research Center at Weill Cornell Medicine, discussed how medical oncologists should be using prognostic markers to make risk assessments in order to determine individualized treatments for their patients with CLL.

SOSS_Richard_FurmanDr. Furman noted that current CLL therapies are effective, but they often lead to complications. CLL patients treated with standard chemotherapy drug combination fludarabine, cyclophosphamide, rituximab (FCR) are often prone to developing treatment resistance or Richter’s transformations (RT), in which their CLL transforms into a more aggressive diffuse large B-cell lymphoma (DLBCL). They may also succumb to infectious complications, adverse events, or secondary malignancies.

Because of the risks associated with FCR treatment, Dr. Furman suggested a movement toward treatment agents that are not as toxic, such as ibrutinib. But even with ibrutinib, patients can develop resistance to treatment. For example, in cysteine481-to-serine mutations, the amino acid in Bruton’s tyrosine kinase (BTK) that ibrutinib binds to is changed from a cysteine to a serine, prohibiting ibrutinib from continuing to bind. This results in inadequate ibrutinib coverage and enables CLL cells to escape treatment and survive.

According to Dr. Furman, a large number of CLL patients will have excellent responses and enjoy very long progression free survivals. What is important is to identify those who will not and to devise a treatment strategy that can improve their outcomes. Currently, interphase FISH (demonstrating deletion 11q or 17p), NOTCH1 mutation, or certain V genes help identify those patients who will progress on currently novel agents or have a risk of Richter’s transformation. In the future, stimulated karyotyping, or evaluating changes in the chromosomes after stimulation of the CLL cells, will also be of great importance.

The CLL team at Weill Cornell Medicine and NewYork-Presbyterian is currently investigating an early intervention trial in which patients at risk of developing Richter’s transformation or resistance to BTK inhibitors receive intervention before the mutations have a chance to develop. Our team is also looking into the use of combination therapies, such as ibrutinib and venetoclax, in treatment of CLL patients.

Additionally, Dr. Furman pointed out that prognostic markers are dependent upon the setting in which they’re used. Those used for FCR, such as minimal residual disease (MRD), don’t necessarily apply to ibrutinib. He said that prognostic markers are traditionally based upon responses, but we now need to start looking at them from a progression-free survival (PFS) perspective.

To hear more from Dr. Furman about the outlook of CLL prognostic markers, check out this short OncLive clip:

Targeting the Cellular Metabolism and Survival Mechanisms in CLL and Richter’s Syndrome

john-allan-mdBy John Allan M.D.

The survival of tumor cells is dependent on the tumor cells maintaining a normal interaction with the healthy microenvironment. An increasingly important strategy in the treatment of CLL is to develop new therapies that do not necessarily attack the cancerous cells themselves, but instead attack the molecular processes that allow the cancerous cells to function and thrive in the microenvironment. One potential target for treating CLL is the protein complex NF-kB, which controls important cell functions including the regulation of cell death, cell survival, and cell proliferation. If NF- kB function can be inhibited then CLL can be more easily treated.

The purpose of this recent study presented at the 2016 ASH meeting was to test the efficacy of the newly developed NF-bK inhibitor IT901 in the treatment of CLL and its aggressive transformation Richter’s Syndrome (RS).  RS is a transformation that occurs within 5-10% of CLL’s and turns the disease into a fast growing diffuse large B-cell lymphoma, an aggressive non-Hodgkin lymphoma. The treatment of RS currently represents an unmet therapeutic need.

Results from this study were confirmed in a mouse xenograft model for people with CLL and in cell samples obtained from people with RS. In both models the use of IT901 was characterized by decrease in tumor growth and Researchers found that IT901 induced death in cancerous cells within 24 hours of treatment with a minimal impact on normal B-cells.

Researchers concluded that IT901 is effective in rapidly blocking NF-kB activity by decreasing the functions that allow the cell to flourish in the microenvironment. The results from this study are encouraging and point to a potential new treatment option for patients with CLL and RS.