On September 24, 2018, the U.S. Food and Drug Administration (FDA) approved a new targeted drug for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic The FDA approved the indication for duvelisib (trade name Copiktra, manufactured by Verastem), a new targeted agent for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
This is an oral tyrosine kinase inhibitor for the treatment of adult patients who have relapsed or are refractory after receiving at least two prior systemic treatments. In addition, duvelisib is also approved for the treatment of adult patients with follicular lymphoma (FL) who have relapsed or are refractory after receiving at least two prior systemic therapies.
What are CLL and SLL?
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are inert B-cell lymphomas, and chronic lymphocytic leukemia and small lymphocytic lymphoma are different presentations of the same disease, with small lymphocytic lymphoma usually having no leukemia-like presentation and chronic lymphocytic leukemia with bone marrow and peripheral blood involvement. Chronic lymphocytic leukemia is characterized by bone marrow and peripheral blood involvement. Chronic lymphocytic leukemia is a clonal proliferative neoplasm of mature B lymphocytes with a specific immunophenotype characterized by the accumulation of lymphocytes in the peripheral blood, bone marrow, spleen and lymph nodes. The International Workshop on Chronic Lymphocytic Leukemia (IWCLL) defines small lymphocytic lymphoma as the presence of enlarged lymph nodes and/or splenomegaly, absence of hematocrit due to bone marrow invasion, and a peripheral blood B-cell count <5× 10e9/L.
Chronic lymphocytic leukemia and small lymphocytic lymphoma both arise from a type of CD5-expressing B cell (B1 cell) that is no longer made by the bone marrow in adulthood, and these cells rely entirely on self-replication to maintain cell numbers.B1 cells sometimes go awry when they replicate and proliferate, resulting in cell Infinite proliferation. If the extra cells accumulate in the lymph nodes, there will be enlargement of the lymph nodes, which in turn affects nearby organs, which is small lymphocytic lymphoma; if the cells accumulate in the bone marrow, it is chronic lymphocytic leukemia.
What is duvelisib?
Duvelisib inhibits both phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ. Both enzymes promote the proliferation of malignant B cells and T cells, and may also play a role in the formation and maintenance of the tumor microenvironment.
Duvelisib not only inhibits kinases that contribute to the growth and survival of malignant B cells, but also acts by disrupting the microenvironment that supports tumor growth. It is this dual inhibition that makes the drug effective in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Evidence of efficacy: 78% of patients in remission, with a PFS of 16.4 months
The approval of Duvelisib for the indication of chronic lymphocytic leukemia or small lymphocytic lymphoma was based primarily on a multicenter, open-label randomized controlled clinical trial (NCT02004522). A total of 196 patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma were enrolled in the study and randomized to duvelisib treatment or Ofatumumab treatment. The results showed that the median progression-free survival (PFS) period after duvelisib treatment was longer (16.4 months vs 9.1 months) and the overall remission rate (ORR) was better (78% vs 39%) than with Ofatumumab treatment.
The approval of Duvelisib for the indication of follicular lymphoma was primarily based on a single-arm multicenter trial (NCT02204982). The study included 83 patients with follicular lymphoma who had not previously responded to rituximab, chemotherapy or radioimmunotherapy. The overall remission rate after duvelisib treatment was found to be 42%. Of the 35 patients who achieved remission, remission was maintained for at least 6 months in 15 (43%) and for at least 12 months in 6 (17%).
Black box warning: need to be alert for lethal infections, diarrhea, colitis, skin reactions, and pneumonia
Common adverse reactions to Duvelisib include mainly diarrhea or colitis, neutropenia, rash, fatigue, fever, cough, nausea, upper respiratory tract infection, pneumonia, musculoskeletal pain, and anemia.
It is important to note that the instructions for duvelisib include a black box warning that the drug may cause lethal infections, diarrhea, colitis, skin reactions, and pneumonia.
In addition, duvelisib may cause severe hepatotoxicity, neutropenia, and may be harmful to the fetus when taken by women during pregnancy. In studies of duvelisib for chronic lymphocytic leukemia or small lymphocytic lymphoma, 35% of patients permanently discontinued duvelisib due to treatment-related adverse reactions and 24% had their treatment dose reduced.
How is duvelisib used?
According to the approved product insert, the recommended use and dosage of duvelisib is as follows:
- Recommended dose: 25 mg orally twice daily in 28-day cycles.
- Pneumocystis jirovecii (PJP) prophylaxis is required during duvelisib treatment; prophylaxis is also required after completion of treatment until CD4+ T-cell counts are >200cells/μL.
- Prophylactic antiviral therapy is required during duvelisib treatment to prevent cytomegalovirus (CMV) infection or reactivation.
duvelisib is not yet available in China, but it has shown promising efficacy in a variety of hematologic malignancies, and it is hoped that clinical trials for Chinese patients will be conducted soon to verify that the drug is equally effective in Chinese patients.