Idelalisib (idela), a phosphatidylinositol 3-kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R-idela) versus ibrutinib have been conducted. Therefore, we performed a real-world retrospective analysis of patients with R/R CLL treated with R-idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R-idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression-free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R-idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R-idela in patients with R/R CLL treated in routine practice. The R-idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative.

1st Department of Medicine Haematology 1st Faculty of Medicine Charles University and General University Hospital Prague Nové Město Czech Republic

4th Department of Internal Medicine Haematology University Hospital and Charles University Faculty of Medicine Hradec Králové Czech Republic

Department of Haematology 3rd Faculty of Medicine University Hospital Královské Vinohrady Praha Czech Republic

Department of Haematology and Oncology University Hospital Plzeň Pilsen Czech Republic

Department of Haematooncology University Hospital Olomouc Olomouc Czech Republic

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Internal Medicine Haematology and Oncology University Hospital Brno Czech Republic

Hospital Agel Nový Jičín Czech Republic

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

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Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus Ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-23.

Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353-63.

Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.

Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Final results of a randomized, phase III study of rituximab with or without Idelalisib followed by open-label Idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019;37:1391-402.

Coutré SE, Barrientos JC, Brown JR, De Vos S, Furman RR, Keating MJ, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56:2779-86.

Hallek M, Cheson BD, Catovsky D, Caligaris-cappio F, Dighiero G, Do H. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute - working group 1996 guidelines. Blood. 2008;111:5446-56.

Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, Morichi V, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56:1926-31.

Smolej L, Antic D, Couto ME, Alexander E, Michael G, Hoa TTT, et al. Differences in availability of targeted inhibitors and use of chemoimmunotherapy in the first-line therapy of chronic lymphocytic leukemia. A European survey. Leuk Lymphoma. 2021;62(S1):S11-3.

Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann CU, Kater AP, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32:23-33.

Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103:874-9.

Eyre TA, Preston G, Kagdi H, Islam A, Nicholson T, Smith HW, et al. A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel). Br J Haematol. 2021;194:69-77.

Rigolin GM, Cavazzini F, Piciocchi A, Arena V, Visentin A, Reda G, et al. Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema working group. Hematol Oncol. 2021;39:326-35.

Morabito F, Tripepi G, Del Poeta G, Mauro FR, Reda G, Sportoletti P, et al. Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases. Eur J Haematol. 2021;106:493-9.

Akpinar S, Dogu MH, Celik S, Ekinci O, Hindilerden IY, Dal MS, et al. The real-world experience with single agent Ibrutinib in relapsed/refractory CLL. Clin Lymphoma Myeloma Leuk. 2022;22:169-73.

Mato AR, Hill BT, Lamanna N, Barr PM, Ujjani CS, Brander DM, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28:1050-6.

Puła B, Budziszewska BK, Rybka J, Gil L, Subocz E, Długosz-Danecka M, et al. Comparable efficacy of Idelalisib plus rituximab and Ibrutinib in relapsed/refractory chronic lymphocytic leukemia: a retrospective case matched study of the polish adult leukemia group (PALG). Anticancer Res. 2018;38:3025-30.

Hoechstetter MA, Knauf W, Dambacher S, Hucke N, Höhne K, van Troostenburg A, et al. Results of a prospective non-interventional post-authorization safety study of Idelalisib in Germany. Clin Lymphoma Myeloma Leuk. 2022;22:e777-87.

Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, et al. ASCEND: phase III, randomized trial of Acalabrutinib versus Idelalisib plus rituximab or Bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38:2849-61.

Manda S, James S, Wang R, Krishnan R, Danilov AV. Impact of comorbidities on treatment outcomes in chronic lymphocytic leukemia: a retrospective analysis. Blood. 2014;124:1312-2.

Gordon MJ, Churnetski M, Alqahtani H, Rivera X, Kittai A, Amrock SM, et al. Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer. 2018;124:3192-200.

Tedeschi A, Frustaci AM, Mauro FR, Chiarenza A, Coscia M, Ciolli S, et al. Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib? Blood Adv. 2021;5:5490-500.

Gordon MJ, Huang J, Chan RJ, Bhargava P, Danilov AV. Medical comorbidities in patients with chronic lymphocytic leukaemia treated with idelalisib: analysis of two large randomised clinical trials. Br J Haematol. 2021;192(4):720-8.

Roeker LE, Thompson MC, Mato AR. Searching for a home: phosphoinositide 3-kinase inhibitors for chronic lymphocytic leukaemia in modern clinical practice. Br J Haematol. 2021;194:9-10.