Tag: CLL

Dr. Richard Furman Discusses Use of Ibrutinib in Treatment of CLL Patients

In this video from OncLive, Dr. Richard Furman discusses the treatment objectives he looks to achieve when treating CLL patients with ibrutinib.

Venetoclax Approved by FDA for the Treatment of CLL Patients with 17p Deletion

The Backstory

On April 11, 2016 the FDA approved venetoclax (Venclexta) for the treatment of patients with chronic lymphocytic leukemia (CLL) with the 17p deletion who have been treated with at least one prior therapy. This is the first FDA approval for venetoclax.

In addition to this recent FDA approval, venetoclax has been granted priority review for its new drug application (NDA) of venetoclax as a single agent in CLL, as well as FDA breakthrough therapy designation for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

What is venetoclax?

Venetoclax, previously known as ABT-199 is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas overexpress and are more dependent upon BCL-2 protein than normal cells. Therefore, when venetoclax inhibits the protein, the CLL cells die, while the normal cells continue unharmed.

What is the 17p deletion and how does it affect CLL?

17p deletion occurs  when part of chromosome 17 in the CLL cells is deleted in the CLL cells. This abnormality only occurs in the CLL cells, and not normal cells, and results in losing the p53 protein. The p53 protein plays an important role in enabling a cell to undergo suicide, and prevent itself from growing out of control. In CLL cells with a 17p deletion, the second genetic copy is often mutated, and as a result, these cells can grow more aggressively and are less responsive to chemotherapy. This results in worse clinical outcomes. Agents like venetoclax work independent of p53, and therefore are still effective in these cases. The 17p deletion is found in approximately 3-7% of newly diagnosed CLL patients, but increases to 30-40% in relapsed and refractory cases.

Why was venetoclax granted FDA approval?

Venetoclax was granted FDA approval based on the results from the M13-982 trial investigating venetoclax in patients with 17p deletion who had received at least one prior therapy. Venetoclax demonstrated an overall response rate of 80%, which included 8% complete response rates. Almost three quarters of patients were free from progression at one year.

Were there any side effects?

The most worrisome side effect of venetoclax is life-threatening tumor lysis syndrome. In the initial studies, when a full dose was administered on day one, two patients died as a result of tumor lysis. Since a modified weekly ramp-up starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily, no cases of clinically significant tumor lysis were seen. Common, less serious side effects included low white blood cell count, diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count, and fatigue. More serious side effects included pneumonia, fever, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome.

How can you access venetoclax now?

Venetoclax is commercially available. Clinical trials investigating the use of venetoclax in patients who are progressed after B-cell receptor (BCR) inhibitors, namely ibrutinib and idelalisib, are ongoing.

New Clinical Trial: A Phase 1 Study to Investigate the Safety & Tolerability of REGN1979 in Patients with CD20+ B-Cell Malignancies Previously Treated with CD20-Directed Antibody Therapy

The Weill Cornell Lymphoma Program has recently opened a new research study for men and women with CD20+ B-cell malignancies, including B-NHL’s and CLL. The study is sponsored by Regeneron Pharmaceuticals, Inc. and the principal investigator is John Allan, MD. For more information about the study, please call Amelyn Rodriguez at 212-746-1362 or email her at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older.
  • Diagnosis of CD20+ B-cell malignancy (B-NHL or CLL), with active disease not responsive to prior therapy.
  • Prior treatment with an anti-CD20 antibody therapy.
  • Detailed eligibility reviewed when you contact the study team.

Study Summary

This clinical trial is for men and women with CD20+ B-cell malignancies, including B-NHL and CLL.

The anti-CD20 monoclonal antibody (mAb), rituximab, has dramatically improved the prognosis for patients with NHL, and has been a mainstay of treatment since its first approval in 1997. While rituximab has single-agent activity in both indolent and aggressive NHL, and more modest activity in CLL, the standard of care is to use it in combination with chemotherapy. Response rates to conventional therapy are generally greater than 50%, but most patients will relapse. In the relapsed or salvage setting, there are no standard of care options and the choice of therapy is often guided by patient clinical factors, including performance status and the presence of comorbidities. Additionally, there is a growing body of data demonstrating the development of diminished activity of rituximab and rituximab resistance over time in multiple NHL subtypes.

REGN1979 is a bispecific (anti-CD20 and anti-CD3) monoclonal antibody, designed with a novel mechanism of action that is distinct from that of other anti-CD20 antibodies, and as such may provide a therapeutic benefit in patients who have relapsed following anti-CD20 mAb therapy. This first in human phase 1 study is designed to investigate the safety and tolerability of REGN1979.

Subjects will be assigned to a dose level cohort that will consist of an initial starting dose, followed by a higher dose for all subsequent administrations. REGN1979 will be administered as an IV infusion, weekly for the first four weeks, then monthly for five months, for a total of nine doses over six months. After completing the treatment period, subjects will have follow-up visits monthly for six months.