hematology and oncology
Chronic Lymphocytic Leukemia (CLL)
Treatment of CLL
Chemoimmunotherapy, targeted therapy, and sometimes radiation therapy Supportive care Chronic lymphocytic leukemia is considered incurable with the current standard of care; treatment is aimed at symptom amelioration. Thus, treatment is withheld until patients have one of the following: Symptoms attributed to CLL Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period Lymphocyte doubling time (increase of ≥ 100%) < 6 months Symptoms that prompt treatment in patients with CLL include Constitutional symptoms (fever, night sweats, extreme fatigue, weight loss) Significant hepatomegaly, splenomegaly, or lymphadenopathy Recurrent infections Symptomatic anemia and/or thrombocytopenia Disease-directed treatmentoptions include Chemoimmunotherapy Targeted therapy Radiation therapy Supportive careincludes Transfusion of packed red blood cells for anemia Platelet transfusions for bleeding associated with thrombocytopenia Antimicrobials for bacterial, fungal, or viral infections Because neutropenia and hypogammaglobulinemia limit bacterial killing, antibiotic therapy should be bactericidal. Gamma-globulin infusions should be considered for treatment in patients with hypogammaglobulinemia and refractory infections or for prophylaxis when≥2 severe infections occur within 6 months. The intent of initial therapy is to Relieve symptoms Induce durable remissions Prolong survival Patients are observed until symptoms develop at which point treatment consists of a targeted therapy in combination with a monoclonal antibody directed against B cells. Studies have suggested that targeted therapy is as efficacious if not superior to upfront chemoimmunotherapy for most patients. Selection of initial therapy depends on patient characteristics, disease-specific features such as presence of del(17p), and the overarching goals of therapy. as this regimen was easier to tolerate ( Treatment references ). The landmark E1912 study examined the efficacy of treatment with FCR versus the novel combination of , a glycoengineered monoclonal antibody against CD20, is as efficacious and potentially better tolerated than conventional chemoimmunotherapy ( Treatment references ). Given the advent of targeted therapy for use in upfront treatment of CLL, several studies have examined a "time limited" approach to treatment. The oral Bcl2 inhibitor Relapsed or refractory CLL should be confirmed histologically before restarting treatment. Transformation to large cell lymphoma (Richter's transformation) should be specifically excluded. Asymptomatic patients with recurrent CLL are monitored closely for symptoms that warrant treatment. Factors that influence choice of treatment at relapse include Initial therapy used Initial duration of response In patients who received upfront chemoimmunotherapy, treatment with a Btk inhibitor can improve response rate and progression-free survival in relapsed or refractory CLL. Btk inhibitors are continued until toxicity develops or disease progresses. Other effective targeted therapies for relapsed CLL includedidelalisib(an oral inhibitor of phosphoinositide 3'-kinase [PI3K] delta) andvenetoclax.Venetoclaxcan be used for patients with del(17p) who have received at least one prior therapy. The advent of upfront targeted therapy may make selection of optimal therapy challenging in patients with relapsed CLL. When applicable, clinical trial enrollment is encouraged. Monotherapy with an anti-CD20 monoclonal antibody (rituximab,ofatumumab,obinutuzumab) may transiently palliate symptoms. ( Treatment references ) and is a selective and non-covalent Btk inhibitor with efficacy in such patients ( Treatment references ). Hematopoietic Stem Cell Transplantation should be considered for patients who are fit and whose leukemia is refractory to novel combinations of targeted therapies with immunotherapies and emerging cellular therapies. Palliative irradiation may be given to areas of lymphadenopathy or for liver and spleen involvement that does not respond to chemotherapy. Total body irradiation in small doses is occasionally successful in temporarily relieving symptoms. 1.Eichhorst B, Fink AM, Bahlo J et al: First-line chemoimmunotherapy withbendamustineandrituximabversusfludarabine,cyclophosphamide, andrituximabin patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial.Lancet Oncol17:928–942, 2016. 2.Shanafelt TD, Wang XV, Kay NE, et al:Ibrutinib-rituximabor chemoimmunotherapy for chronic lymphocytic leukemia.N Engl J Med381:432–443, 2019. doi: 10.1056/NEJMoa1817073 3.Sharman JP, Egyed M, Jurczak W, et al:Acalabrutinibwith or withoutobinutuzumabversuschlorambucilandobinutuzmabfor treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial.Lancet395(10232):1278–1291, 2020. doi: 10.1016/S0140-6736(20)30262-2 4.Fischer K, Al-Sawaf O, Bahlo J, et al:Venetoclaxandobinutuzumabin patients with CLL and coexisting conditions.N Engl J Med380(23):2225–2236, 2019. doi: 10.1056/NEJMoa1815281 5.Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial ofacalabrutinibversusidelalisibplusrituximaborbendamustineplusrituximabin relapsed or refractory chronic lymphocytic leukemia.J Clin Oncol38(25):2849–2861, 2020. doi:10.1200/JCO.19.03355 6.Brown JR, Eichhorst B, Hillmen P, et al:Zanubrutiniboribrutinibin relapsed or refractory chronic lymphocytic leukemia.N Engl J Med388(4):319–332, 2023. doi:10.1056/NEJMoa2211582 7.Hillmen P, Eichhorst B, Brown JR, et al:Zanubrutinibversusibrutinibin relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Interim analysis of a randomized phase III trial.J Clin Oncol41(5):1035–1045, 2023. doi:10.1200/JCO.22.00510 8.Mato AR, Woyach JA, Brown JR, et al:Pirtobrutinibafter a covalent BTK inhibitor in chronic lymphocytic leukemia.N Engl J Med389(1):33–44, 2023. doi:10.1056/NEJMoa2300696 9.Siddiqi T, Maloney DG, Kenderian SS, et al:Lisocabtagene maraleucelin chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.Lancet402(10402):641–654, 2023. doi:10.1016/S0140-6736(23)01052-8 