Frontline Therapy of CLL—Changing Treatment Paradigms

Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164–74.

Article  CAS  PubMed  Google Scholar 

Eichhorst B, Fink A-M, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928–42.

Article  CAS  PubMed  Google Scholar 

International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779–90.

Article  Google Scholar 

Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.

Article  PubMed  Google Scholar 

Kittai AS, Miller C, Goldstein D, Huang Y, Abruzzo LV, Beckwith K, et al. The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib. Blood. 2021;138(23):2372–82.

Article  CAS  PubMed  Google Scholar 

Fürstenau M, Thus YJ, Robrecht S, Mellink CHM, van der Kevie-Kersemaekers A-MF, Dubois J, et al. High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations. Blood. 2023;142(5):446–59.

Rigolin GM, Cavallari M, Quaglia FM, Formigaro L, Lista E, Urso A, et al. In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood. 2017;129(26):3495–8.

Article  CAS  PubMed  Google Scholar 

Baliakas P, Espinet B, Mellink C, Jarosova M, Athanasiadou A, Ghia P, et al. Cytogenetics in chronic lymphocytic leukemia: ERIC perspectives and recommendations. HemaSphere. 2022;6(4): e707.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28(29):4473–9.

Article  PubMed  Google Scholar 

Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112(8):3322–9.

Article  CAS  PubMed  Google Scholar 

Parikh SA, Rabe KG, Kay NE, Call TG, Ding W, Leis JF, et al. The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL. Blood. 2021;138(2):149–59.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, et al. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022;139(2):177–87.

Article  CAS  PubMed  Google Scholar 

Langerbeins P, Robrecht S, Nieper P, Cramer P, Fürstenau M, Al-Sawaf O, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naive early stage chronic lympho- cytic leukemia (CLL): final results of the phase 3, double- blind, placebo controlled CLL12 trial. Hematol Oncol. 2023;41(S2):56–8.

Article  Google Scholar 

Stephens DM, Moseley A, Hill BT, Pagel JM, Shadman M, Fisch MJ, et al. Randomized, phase III study of early intervention with venetoclax and obinutuzumab versus delayed therapy with venetoclax and obinutuzumab in newly diagnosed asymptomatic high-risk patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): EVOLVE CLL/SLL study (SWOG S1925, NCT#04269902). JCO. 2021;39(15_suppl):TPS7567.

Article  Google Scholar 

Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–15.

Article  CAS  PubMed  Google Scholar 

Thompson PA, Tam CS, O’Brien SM, Wierda WG, Stingo F, Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. 2015;56(6):1643–50.

Article  CAS  PubMed  Google Scholar 

Carney DA, Westerman DA, Tam CS, Milner A, Prince HM, Kenealy M, et al. Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia. 2010;24(12):2056–62.

Article  CAS  PubMed  Google Scholar 

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440–50.

Article  CAS  PubMed  PubMed Central  Google Scholar 

• Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–43 This trial demonstrated an overall survival advantage for patients receiving ibrutinib with rituximab as compared to the FCR regimen.

•• Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O’Brien S, Barrientos J, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140(2):112–20 Longer-term follow-up of the E1912 trial of ibrutinib with rituximab versus FCR confirmed the overall survival advantage and also demonstrated a progression-free survival advantage for both mutated and unmutated IGHV patients.

Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535–52.

Article  CAS  PubMed  Google Scholar 

Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–28.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

•• Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–91 This trial demonstrated superior progression-free survival for frontline use of acalabrutinib (alone or with obinutuzumab) as compared to chlorambucil with obinutuzumab.

Sharman JP, Egyed M, Jurczak W, Skarbnik AP, Kamdar MK, Munir T, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: five-year follow-up of ELEVATE-TN. JCO. 2022;40(16_suppl):7539–7539.

Article  Google Scholar 

Shadman M, Munir T, Roback T, Brown JR, Kahl BS, Ghia P, et al. Zanubrutinib (ZANU) versus bendamustine + rituximab (BR) in patients (PTS) with treatment naïve (TN) CLL/SLL: extended follow up of the SEQUOIA study. Hematol Oncol. 2023;41(S2):235–8.

Article  Google Scholar 

Gordon MJ, Jones JE, George B, Peterson C, Burger JA, Jain N, et al. Long-term outcomes in patients with chronic lymphocytic leukemia treated with ibrutinib: focus on hypertension and cardiovascular toxicity. Cancer. 2023;129(14):2192–200.

Article  CAS  PubMed  Google Scholar 

Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441–52.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Seymour JF, Byrd JC, Ghia P, Kater AP, Chanan-Khan AA, 645 Furman RR, et al. Detailed safety profile of acalabrutinib vs 646 ibrutinib in previously treated chronic lymphocytic leukemia in 647 ELEVATE-RR. Blood 2023;142(8):687–699.

Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319–32.

Article  CAS  PubMed  Google Scholar 

•• Fischer K, Al-Sawaf O, Bahlo J, Fink A-M, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225–36 This trial demonstrated superior progression-free survival for frontline use of time-limited venetoclax with obinutuzumab as compared to chlorambucil with obinutuzumab.

Al-Sawaf O, Zhang C, Jin HY, Robrecht S, Choi Y, Balasubramanian S, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14(1):2147.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

•• Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739–54 This trial demonstrated superior progression-free survival for frontline use of time-limited venetoclax with obinutuzumab as compared to chemoimmunotherapy regimens (FCR and BR).

Huang Q, Deering KL, Harshaw Q, Leslie LA. Real-world clinical outcomes of first-line ibrutinib or chemoimmunotherapy in patients with chronic lymphocytic leukemia by risk status. Adv Ther. 2022;39(7):3292–307.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brown JR, Hallek MJ, Pagel JM. Chemoimmunotherapy versus targeted treatment in chronic lymphocytic leukemia: when, how long, how much, and in which combination? Am Soc Clin Oncol Educ Book. 2016;35:e387–98.

Article  PubMed  Google Scholar 

•• Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031–43 This trial demonstrated superior progression-free survival for zanubrutinib as compared to BR regimen.

Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink 52. A-M, et al. Venetoclax obinuzutuab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. HemaSphere | 2023;7(S3).

Mato AR, Roeker LE, Allan JN, Pagel JM, Brander DM, Hill BT, et al. Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. Am J Hematol. 2018;93(11):1394–401.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rigolin GM, Olimpieri PP, Summa V, Celant S, Scarfò L, Tognolo L, et al. Outcomes in patients w

Comments (0)

No login
gif