In the treatment of chronic lymphocytic leukemia the combination of a small molecule inhibitor with monoclonal antibody immunotherapy. The results support the practice of fixed duration therapy for a treatment based venetoclax in LLC, according to Shuo Ma, MD, ’00 Ph.D., associate professor of Medicine in the Division of Hematology and Oncology and co-first author of the study.
There Research was published in the scientific journal Blood.
Chronic lymphocytic leukemia: this is how the new therapy works
Chronic lymphocytic leukemia is a type of leukemia which occurs particularly in elderly patientsi, when B lymphocytes, a type of white blood cell, develop into cancer cells in the bone marrow, blood and lymphatic system. In general, those affected do not experience symptoms at initial diagnosis, but over time, cancer cells proliferate and can cause symptoms or impaired bone marrow function, requiring treatment.
Conventional chemoimmunotherapy has long been the therapeutic orientation for the treatment of the disease, but in recent years, therapeutic strategies have mainly focused on small molecule inhibitors that target enzymes in the B cell receptor (BCR) signaling pathway or the apoptosis pathway. Inhibitors of the BCR pathway prevent the proliferation and growth of cancer cells by blocking communication between leukemia cells and the tumor microenvironment.
“These inhibitors require continuous and indefinite treatment“, he has declared But, who is also a member of the Robert H. Lurie Comprehensive Cancer Center from the Northwestern University. The other class of targeted therapy, represented by venetoclax, targets the protective BCL2 protein and induces rapid tumor killing by programmed cell death.
Previous work published up Lancet Oncology, of which Ma was also a co-first author, reported a phase 1b study of a new combination treatment of venetoclax and a monoclonal antibody immunotherapy called rituximab was highly effective for patients with relapsed or refractory CLL.
For the study, participants received 200 to 600 milligrams of venetoclax per day and rituximab for six months, followed by venetoclax alone. Rituximab, which targets the CD20 molecule expressed on the surface of B cells, is currently widely used for various types of B-cell lymphomas and leukemias, including CLL, in combination with chemotherapy or other targeted therapies.
Ma and collaborators showed that venetoclax-rituximab combination therapy was particularly effective in producing a rapid reduction in the leukemia burden, with most of those involved achieving a profound response with no minimal residual disease. Patients who achieved profound response to venetoclax-rituximab treatment also had the option to continue with venetoclax alone or to stop treatment altogether.
In the current follow-up report, Ma and colleagues evaluated patient outcomes at five years for the combined venetoclax-rituximab treatment. Overall patient survival, progression-free survival, and duration of treatment response after five years were 86 percent, 56 percent, and 58 percent, respectively.. In addition, according to the authors, 74% of patients who achieved a profound response to combination therapy and who chose to stop treatment had prolonged remission, which was also similar to patients who chose to continue treatment.
The findings support the fixed-duration venetoclax-based therapy, which has now become the standard of care, according to Ma: “We also reported the efficacy of the new venetoclax-rituximab treatment for those patients who progressed after completing the course of treatment. initial, further extending the clinical benefit of venetoclax-based therapy, ”concluded Ma.
Chronic lymphatic leukemia: it is the combined targeted therapy that has proved successful
The results of a Phase II research conducted by a single institution were published today at JAMA Oncology , they demonstrated as a combination of ibrutinib And venetoclax provides a lasting remission of the disease in patients with chronic lymphocytic leukemia. Principal investigators on the study are Nitin Jain, MD, associate professor of leukemia; William Wierda, MD, Ph.D., professor of leukemia; and Varsha Gandhi, Ph.D., chair of the interim department of Experimental Therapy.
MD Anderson’s experts previously reported the results of this study showing that ibrutinib and venetoclax are effective when co-administered to elderly and high-risk patients with the disease. This report offers an additional two years of follow-up data and statistics on measurable residual bone marrow disease (U-MRD) after therapy. Overall, three-year progression-free survival was 93% and three-year overall survival was 96%. Response rates were the same for the subgroup of high-risk patients.
“Chronic lymphocytic leukemia is the most common leukemia in the United States and was originally treated with chemoimmunotherapy”, Jain said. “These long-term results show that two years of oral targeted therapy can achieve lasting remission of the disease for CLL patients ”.
The researchers followed 80 previously untreated patients with an average age of 65, 30% of whom were over 70. Overall, 92% had high-risk genetic abnormalities. The median follow-up for all 80 patients was 38.5 months. Participants in the study were 94% white, 4% other, 1% American Indian or Alaskan natives, and 1% unknown.
U-MRD responses improved with the continuous combination of ibrutinib plus venetoclax. After 12 cycles of combination therapy, 56% of patients achieved bone marrow U-MRD and after 24 cycles of combination therapy, 66% of patients achieved bone marrow U-MRD remission. A total of 75% of patients achieved bone marrow U-MRD remission at any time during the study.
“MRD is one of the most important prognostic markers at the end of leukemia treatment”, Jain said. “Most patients achieved remission of bone marrow MRD and none of the patients in the study had progression of CLL disease. “
The research team continues to monitor patients’ MRD every six months and is working on further related studies. Treatment was well tolerated and the toxicity profile of both drugs was consistent with other studies, with no additional toxicities observed with the combination.
Several ongoing studies are investigating BTK inhibitors combined with venetoclax, including the CAPTIVATE study, which reported the results at the recent American Society of Clinical Oncology (ASCO) annual meeting, the FLAIR study in the UK, the CLL17 study and the study CLL GLOW, which will report Phase III results at the Virtual Congress of the European Hematology Association (EHA). Data from these and other studies will clarify the duration and role of this treatment regimen.
“I think this will be one of several standard treatments available for CLL patients “concluded Jain. “There are pros and cons to each of these approaches and doctors will have to decide which option is best for their patient. “
According to the airc: “In Italy, about 15 new cases are diagnosed per 100,000 people per year (16.9 cases per 100,000 males and 12.8 per 100,000 females) which translate into an estimated number of 5,300 new cases every year among men and slightly less of 3,900 among women“.
“Based on the AIRTUM data (Italian Association of Cancer Registers), in our country the most frequent forms of leukemia are chronic lymphatic (33.5 percent of total leukemia), the acute myeloid (26.4 per cent), la chronic myeloid (14.1 per cent) and the acute lymphatic (9.5 per cent) “.
Most leukemias are related to DNA abnormalities in chromosomes or individual genes. In particular: ” Chronic myeloid leukemia is caused by the so-called “Philadelphia” chromosome which contains a gene (BCR-ABL) formed by the fusion of two portions of DNA which, under normal conditions, are found on two different chromosomes, 9 and 22 ″.
Always according to the Airc: “Some genetic diseases, like Down syndrome, are associated with a 10 to 20 times higher risk of developing leukemia in the first ten years of life. As for adults, there is a link between exposure to massive doses of radiation and some types of leukemia “.
“There is also an association with exposure to chemicals such as benzene, a natural component of petroleum, and the formaldehyde, a naturally occurring organic compound used in the chemical industry. Even one radiotherapy or one previously performed chemotherapy to treat other forms of cancer may increase the risk of some types of leukemia “.
“Finally, some non-modifiable risk factors have been identified, that is, on which it is not possible to intervene to reduce the risk, such asold age and the male sex“.