Medical Challenge Question 11 Answer
Answer: E. Treat chronic lymphocytic leukemia with Ibrutinib
Ibrutinib was approved as a first-line treatment in elderly patients was based on the RESONATE-2 study (n=269). RESONATE-2 compared ibrutinib to chlorambucil in treatment-naïve patients with CLL who were aged 65 y or older. Statistically significant improvement in progression free survival and objective response rate were observed with ibrutinib compared with chlorambucil. Therefore, ibrutinib has become a recommended first line agent in especially in patients with chromosome p17 deletion. It is indicated for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and also indicated for CLL/SLL with 17p deletion, mantle cell lymphoma, Waldenström Macroglobulinemia, and Marginal Zone Lymphoma.
Ibrutinib is a bruton’s tyrosine kinase (BTK) inhibitor. It works by forming a covalent bond with a cysteine residue in the BTK activation site, which causes inhibition of BTK enzymatic activity. BTK is a signaling molecule related to B-cell antigen receptor (BCR) and cytokine receptor pathways and antibody response in the adaptive immune system. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.
Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy option and should be considered for a young patient with advanced chronic lymphocytic leukemia associated with a high risk of disease progression.
Hematopoietic stem cell transplantation (HSCT) is most appropriate for this patient who has aggressive B-cell chronic lymphocytic leukemia (CLL) refractory to therapy. This patient has not yet had therapy and therefore this treatment is not appropriate. CLL is the most common form of adult leukemia, accounting for 10% of all hematologic malignancies. Patients with CLL are usually diagnosed at a median age of 70 years. Many of these patients are asymptomatic at the time of diagnosis and are identified after detecting lymphocytosis on a complete blood count obtained for other purposes. The disease course is often indolent with many patients not requiring treatment. For those who do, newer therapies have improved the median survival for patients with CLL nearly to that of age-matched healthy controls. Although younger patients develop CLL less often, they usually have more aggressive disease as in this patient who had systemic symptoms at presentation in addition to significant lymphadenopathy and splenomegaly. In addition, his disease resistance to standard rituximab and multiagent chemotherapy, the presence of immune thrombocytopenia, and a 17p deletion together confer a limited likelihood of survival (median survival less than 3 years). Because of this, HSCT is the only therapeutic option for this patient that is associated with the potential for cure, and he has siblings who might serve as possible HLA-matched donors.
Leukapheresis is the selective removal of leukocytes from the blood and is typically used in patients with acute leukemias, particularly acute myelogenous leukemia, in which myeloblast counts typically exceeding 100,000/µL (100 × 109/L) result in leukostasis with resulting respiratory failure and central nervous system symptoms. Leukapheresis rapidly lowers the leukocyte count, decreasing leukostasis. However, leukostasis is rarely associated with CLL, and even with very high leukocyte counts, leukapheresis is not indicated in this patient without an extreme elevation of his leukocyte count or evidence of hyperviscosity. This patient does not meet the requirements for leukapheresis and therefore it is an inappropriate treatment.
The lymphocytes associated with CLL are usually exquisitely radiosensitive, and radiation of bulky lymph nodes may be helpful in managing symptoms associated with lymphadenopathy. It is frequently used in conjunction with other more definitive treatments or palliatively. However, this patient does not have significant symptoms related to his lymphadenopathy, and radiation therapy would also not address the underlying hematologic malignancy in this patient.
Splenectomy has been shown to be beneficial in patients with CLL who have marked splenomegaly or profound cytopenias in which splenomegaly may be a contributing factor. However, it is usually reserved for patients whose disease does not respond to chemotherapy or other treatments. Although this patient has evidence of splenomegaly and a low platelet count, he has no evidence of organ impingement from his enlarged spleen or bleeding from his thrombocytopenia. Therefore, there is no current indication for splenectomy at this time.
Referecences:
https://reference.medscape.com/drug/imbruvica-ibrutinib-999896#10
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. The New England journal of medicine. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388.
van Besien K, Keralavarma B, Devine S, Stock W. Allogeneic and autologous transplantation for chronic lymphocytic leukemia. Leukemia. 2001 Sep;15(9):1317-25. PMID: 11516091