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Editorials
sis from Alberta, Canada. Blood. 2020;136(Suppl 1):26-27.
2. Orellana-Noia VM, Reed DR, Sen JM, et al. CNS prophylaxis during front-line therapy in aggressive non-Hodgkin lymphomas: real- world outcomes and practice atterns from 19 US academic nstitu-
tions. Blood. 2020;136(Suppl 1):27-28.
3. Eyre TA, Djebbari F, Kirkwood AA, Collins GP. Efficacy of central
low risk of CNS recurrence in high-risk patients with diffuse large B-
cell lymphoma. Cancer. 2010;116(18):4283-4290.
13. McKay P, Wilson MR, Chaganti S, Smith J, Fox CP, Cwynarski K;
British Society of Haematology. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Br J Haematol. 2020;190(5):708-
nervous system prophylaxis with stand-alone intrathecal 714.
chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a sys- tematic review. Haematologica. 2020;105(7):1914-1924.
14. Ambady P, Holdhoff M, Bonekamp D, Wong F, Grossman SA. Late relapses in primary CNS lymphoma after complete remissions with high-dose methotrexate monotherapy. CNS Oncol. 2015;4(6):393-
4. Eyre TA, Kirkwood AA, Wolf J, et al. Stand-alone intrathecal central 398.
nervous system (CNS) prophylaxis provide unclear benefit in reduc- ing CNS relapse risk in elderly DLBCL patients treated with R- CHOP and is associated increased infection-related toxicity. Br J Haematol. 2019;187(2):185-194.
5. Cheah CY, Herbert KE, O'Rourke K, et al. A multicentre retrospec- tive comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma. Br J Cancer. 2014;111(6):1072-1079.
6. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396- 1407.
7. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of dif- fuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-690.
8. Wright GW, Huang DW, Phelan JD, et al. A probabilistic classifica- tion tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568.e14.
9. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with dif- fuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34(26):3150-3156.
10. Klanova M, Sehn LH, Bence-Bruckler I, et al. Integration of cell of ori- gin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL. Blood. 2019;133(9):919-926.
11. Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26-41.
12. Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrex- ate as central nervous system (CNS) prophylaxis is associated with a
15. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.
16. Ollila TA, Kurt H, Waroich J, et al. Genomic subtypes may predict the risk of central nervous system recurrence in diffuse large B-cell lymphoma. Blood. 2021;137(8):1120-1124.
17.Twa DDW, Lee DG, Tan KL, et al. Genomic predictors of central nervous system relapse in primary testicular diffuse large B-cell lym- phoma (DLBCL). Blood. 2021;137(9):1256-1259.
18. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833-843.e5.
19. Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017;7(9):1018-1029.
20. Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vin- cristine, and prednisone in non-germinal center B-cell diffuse large B- cell lymphoma. J Clin Oncol. 2019;37(15):1285-1295.
21. Ghesquieres H, Chevrier M, Laadhari M, et al. Lenalidomide in com- bination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multi- center prospective 'proof of concept' phase II study of the French Oculo-Cerebral Lymphoma (LOC) Network and the Lymphoma Study Association (LYSA). Ann Oncol. 2019;30(4):621-628.
22. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B- cell lymphoma in a randomized phase II US Intergroup Study ECOG-ACRIN E1412. J Clin Oncol. 2021;39(12):1329-1338.
All in the family: back-to-back kinase inhibitors for the treatment of chronic lymphocytic leukemia
Meghan C. Thompson, Lindsey E. Roeker and Anthony R. Mato
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA E-mail: ANTHONY R. MATO - matoa@mskcc.org
doi:10.3324/haematol.2021.278535
In this issue of Haematologica, Rogers et al. address a key sequencing question in the management of chronic lymphocytic leukemia (CLL) by reporting the results of the largest prospective clinical trial evaluating acalabru- tinib for the treatment of CLL following intolerance to ibrutinib.1 While the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has led to a paradigmatic shift in the treatment of CLL away from chemoimmunotherapy, high rates of ibrutinib discontinuation remain a major problem.
Real-world evidence and long-term follow-up from clinical trials of ibrutinib have established that drug intol- erance due to toxicity, rather than progressive CLL, is the most common reason for discontinuation of ibrutinib treatment.2-4 Real-world data from 616 CLL patients treat- ed with ibrutinib in clinical practice documented that 41% of patients discontinued ibrutinib (median follow-
up 17 months), and more than half of all discontinuations were due to toxicity.2 Real-world evidence from the UK documents high rates of ibrutinib discontinuation due to reasons other than disease progression (17.5%).3 Furthermore, similar patterns have emerged with longer follow-up data from clinical trials, with more patients dis- continuing ibrutinib due to toxicity than because of CLL progression. At 5 years of follow-up of the RESONATE-2 trial of ibrutinib for initial treatment of CLL, 41% of patients had discontinued ibrutinib therapy, with a 21% discontinuation rate due to adverse events including atrial fibrillation.4 Furthermore, in a pooled analysis of CLL patients treated with ibrutinib on three randomized phase III studies, 11% of patients permanently discontin- ued ibrutinib due to adverse events and 13% of patients required dose reductions due to adverse events, highlight- ing the significant impact of adverse events while on
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