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    Home > Active Ingredient News > Blood System > What needs to be clarified before treatment for CLL patients in the new drug era?

    What needs to be clarified before treatment for CLL patients in the new drug era?

    • Last Update: 2021-03-24
    • Source: Internet
    • Author: User
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    Author: This article is the author's permission Chunlan Qiugui NMT Medical publish, please do not reprint without authorization.

    In recent years, with the application of new drugs such as BTK inhibitors (BTKi) and BCL-2 inhibitors in patients with chronic lymphocytic leukemia (CLL), the treatment pattern of CLL has undergone a landmark change.

    Compared with traditional immunochemotherapy (CIT), the new drug has greatly improved the efficacy of CLL patients and improved the clinical outcome.

    But at the same time, the unique side effects of new drugs also need our attention.

    So in the era of new drugs, what needs to be clarified before treatment for CLL patients? This article has carried out an inventory summary on this, I hope it will be helpful to everyone.

    Clarify the prognosis stratification The CLL prognostic risk stratification model provides the basis for stratified treatment for patients, and can provide appropriate targeted treatment for CLL patients according to the clinical factors, comorbidities, genetic factors, etc.
    of CLL.

    The two staging systems, Rai and Binet, are widely used in clinical practice because of their simplicity and accuracy of predicting results.

    Patients in the high-risk group (Rai III/IV, Binet C) have a more aggressive clinical course and a shorter survival period.

    Prognostic stratification model based on molecular and genomic research, IGHV mutation status and cytogenetic characteristics (analyzed by FISH, including del17p, del11q, trisomy 12, del13q and complex karyotype [defined as ≥3-5 Chromosomal abnormalities]) are all associated with a worse prognosis of CLL.

    Genomic mutations, especially TP53 gene mutations, indicate that the disease is more aggressive.

    The 2016 CLL International Prognostic Index (CLL-IPI) combines important genomic factors (IGHV, TP53 mutation status) with Rai / Binet staging, β-2 microglobulin level and age to predict the survival rate of CLL patients.

    The accuracy of the CLL-IPI model has been confirmed in multiple studies, including most young patients receiving CIT treatment.

    Nevertheless, the value of CLL-IPI in predicting the prognosis of CLL patients receiving targeted therapy is still unclear [1].

    Choosing the right time for treatment The consensus guidelines of the International Chronic Lymphocytic Leukemia Working Group (iWCLL) [2] recommend that patients with CLL start treatment only when they are indicated for treatment.

    In 2019, a clinical study for early intervention of the new drug ibrutinib vs.
    placebo for patients with high-risk CLL without indications for treatment is underway [3].

    The median follow-up time was 31 months, the median event-free survival (EFS) of the placebo group was 47.
    8 months, and the ibrutinib group had not yet reached (hazard ratio [HR] of 0.
    25; 95% confidence interval [CI ] Is 0.
    14-0.
    43; P<0.
    0001).

    The median progression-free survival (PFS) of the placebo group was 14.
    8 months, while the ibrutinib group had not yet reached (HR 0.
    18; 95% CI 0.
    12-0.
    27).

    Patients in the ibrutinib group took longer to the next treatment.

    Until the data of a complete survival analysis is obtained, patients with high-risk CLL who are not indicated for treatment should continue to be closely monitored until treatment is indicated.

    Matters needing attention before treatment for newly diagnosed CLL patients When determining the first-line treatment plan for CLL, several factors are more important, including age, prognostic factors of CLL, comorbidities, concomitant medications, and the patient’s preference for the duration of treatment (patient choice) intention).

    Data from a number of phase III trials show that CLL patients with high-risk characteristics and IGHV not mutated can benefit from “chemical-free” first-line treatment; while IGHV-mutated CLL patients without del17p or TP53 mutations can still benefit from the FCR regimen or Benefit from BR regimen treatment [4].

    The side effects of BTKi are mainly non-hematological toxicity, especially atrial fibrillation, bleeding risk and hypertension [5-7].
    It is important to consider the patient’s age and cardiac risk factors (atrial fibrillation history, high risk of multiple drug Blood pressure) and bleeding risk (with anticoagulation, history of severe bleeding).

    The risks of potential side effects and the benefits of treatment must be carefully weighed according to the specific situation.

    Although BTKi has a strong clinical effect, the complete remission (CR) rate of its monotherapy is low.

    Therefore, in the absence of intolerable toxicity, continuous treatment is recommended to prevent disease progression.

    In the E1912 trial [8], more than half of the patients discontinued the use of ibrutinib due to adverse events, and real-world data also confirmed this finding; however, compared with patients who discontinued treatment due to disease progression, Patients who discontinued treatment due to adverse events had longer PFS.

    If patients with newly diagnosed CLL are at risk of serious cardiovascular adverse events, it is recommended that the treatment plan based on venacola is the first choice, and the adverse events of tumor lysis syndrome (TLS) should be paid attention to, and real-time monitoring during treatment is also required.

    The treatment plan of Venecla combined with the new CD20 monoclonal antibody is expected to be discontinued.

    The combined regimen of BTKi and Venecla seems to have a higher incidence of cytopenias than any of the single drugs, and care should be taken in clinical decision-making.

    The optimal treatment strategy for patients with del17p/TP53 mutations remains unknown.

    Compared with CIT, both Venecla and BTKi regimens showed improved clinical outcomes.

    In the CLL14 study, most progression events occurred in patients with del17p/TP53 mutations [9].
    Therefore, it is not clear whether time-limited treatment can provide the same benefits for this group of patients. Ongoing clinical trials with time-bound therapies will answer this question in the future.

    In addition, the first-line "no chemotherapy" program has become the new standard of treatment for CLL patients.

    However, there are currently no head-to-head data available to determine which chemotherapy-free first-line treatment option provides a better overall response rate (ORR), PFS, and/or overall survival (OS).

    References: [1].
    Molica S, Giannarelli D, Mirabelli R, Levato L, Shanafelt TD.
    Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) in patients receiving chemoimmuno or targeted therapy: a systematic review and meta-analysis.
    Ann Hematol .
    2018;97(10):2005-2008.
    [2].
    Hallek M, Cheson BD, Catovsky D, et al.
    iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.
    Blood.
    2018; 131(25):2745-2760.
    [3].
    Langerbeins P, Bahlo J, Rhein C, et al.
    Ibrutinib versus placebo in patients with asymptomatic treatment-naive early stage CLL: primary endpoint results of the phase 3 double-blind randomized CLL12 trial.
    Hematol Oncol.
    2019;37(suppl 2):38-40.
    [4].
    Joanna M Rhodes, Jacqueline C Barrientos.
    Chemotherapy-free frontline therapy for CLL: is it worth it? Hematology Am Soc Hematol Educ Program.
    2020 Dec 4;2020(1):24-32.
    [5].
    Brown JR, Moslehi J, O'Brien S, et al.
    Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials.
    Haematologica.
    2017;102 (10):1796-1805.
    [6].
    Caron F, Leong DP, Hillis C, Fraser G, Siegal D.
    Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis.
    Blood Adv.
    2017;1( 12):772-778.
    [7].
    Roeker LE, Sarraf Yazdy M, Rhodes J, et al.
    Hypertension in patients treated with ibrutinib for chronic lymphocytic leukemia.
    JAMA Netw Open.
    2019;2(12):e1916326.
    [8 ].
    Mato AR, Nabhan C, Thompson MC, et al.
    Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.
    Haematologica.
    2018;103(5):874-879.
    [9] .
    Fischer K, Al-Sawaf O, Bahlo J, et al.
    Venetoclax and obinutuzumab in patients with CLL and coexisting conditions.
    N Engl J Med.
    2019;380(23): 2225-2236.
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