Tag: 17p deletion

FAT1 Mutations Influence Time to First Treatment in Untreated CLL

john-allan-mdBy John Allan, M.D.

Despite recent strides in mapping the mutational landscape of chronic lymphocytic leukemia (CLL) there is still limited information regarding the clinical impact of some less common gene mutations in the treatment of CLL. As next generation sequencing (NGS) has become more readily available physicians have more information about their patient’s genome, but this information is often lacking in context.

Using a commercially available NGS platform researchers from Weill Cornell Medicine identified a high prevalence of mutations in the FAT1 gene in people with CLL. FAT1 plays a role in regulating WNT signaling and tumor suppression and mutations have previously been associated with leukemia. Given the prevalence of FAT1 mutations in our CLL database and evidence suggesting FAT1 contributes to tumor growth, researchers investigated the clinical impact of FAT1 mutations.

Altogether 172 patients were included in the study. Nineteen (11%) patients were found to have a FAT1 mutation and 153 (89%) were lacking the mutation. In total 21 mutations were identified with 17 being unique. No significant differences were found between groups based on age or co-occurrence of high risk mutations, although 17p deletions occurred significantly more in mutated FAT1 patients (24%) compared to people lacking the mutation (7%). Mutated FAT1 patients had a significantly shorter TTFT at 50 months compared to 143 months for people lacking the mutation.

Researchers identified a higher prevalence of FAT1 mutations in untreated CLL patients than previously reported. FAT1 was found to associate with the 17p deletion, but no other high-risk mutations. We also found a vast difference in TTFT between mutated FAT1 and those lacking the mutation, although there was no difference in response rates when treated with novel agents.

These findings suggest that FAT1 mutations may be more common in patients, who have yet to receive treatment than commonly supposed. Results warrant additional research to investigate the influence of FAT1 mutations and association with the 17p deletion.

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: Phase 2 Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia with 17p Deletion

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with chronic lymphocytic leukemia. The study sponsor is Gilead Sciences, Inc., and the principal investigator at Weill Cornell is Richard Furman, M.D..  For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older
  • Diagnosis of CLL with 17p deletion
  • No prior therapy for CLL other than corticosteroids for disease complications
  • Detailed eligibility reviewed when you contact the study team

Study Details

This clinical trial is for men and women with previously untreated CLL with 17p Deletion.

Patients with 17p deleted CLL have particularly aggressive courses characterized by a lack of response to chemotherapy.  Standard treatment for patients who are previously untreated is chemotherapy that carries significant risks without the likelihood of significant benefit. Idelalisib has demonstrated excellent activity and tolerability in patients with relapsed and refractory 17p deleted CLL. This study will provide more information about whether giving rituximab and idelalisib together can benefit patients with previously untreated CLL who have a 17p deletion.

Subjects will receive rituximab for 8 weeks and Idelalisib continuously throughout the study (up to 10 years) as long as they are responding to therapy and not experiencing unacceptable side effects. Rituximab is administered intravenously once weekly. Idelalisib is administered orally twice daily. After discontinuing treatment, follow-up information will be collected once every year throughout the study (up to 10 years) at clinic visits or through telephone calls.

Subjects will be provided a stipend for each study visit to reimburse the cost of travel and other expenses.

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