Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic
Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data

Objective: This study aimed to retrospectively evaluate the efficacy, safety, and survival outcome of single-agent ibrutinib therapy in chronic lymphocytic leukemia patients. Materials and Methods: A total of 136 patients (mean age ± standard deviation: 64.6±10.3 years, 66.9% males) who had received at least one dose of ibrutinib were included in this retrospective multicenter, noninterventional hospital-registry study conducted at 33 centers across Turkey. Data on patient demographics, baseline characteristics, laboratory findings, and leukemia-cell cytogenetics were retrieved. Treatment response, survival outcome including overall survival (OS) and progression-free survival (PFS), and safety data were analyzed. Results: Overall, 36.7% of patients were categorized as Eastern Cooperative Oncology Group (ECOG) class 2-3, while 44.9% were in Rai stage 4. Fluorescence in situ hybridization revealed the presence of del(17p) in 39.8% of the patients. Patients received a median of 2.0 (range: 0-7) lines of pre-ibrutinib therapy. Median duration of therapy was 8.8 months (range: 0.4-58.0 months). The 1-year PFS and OS rates were 82.2% and 84.6%, respectively, while median PFS time was 30.0 (standard error, 95% confidence interval: 5.1, 20.0-40.0) months and median OS time was 37.9 (3.2, 31.5-44.2) months. Treatment response (complete or partial response), PFS time, and OS time were better with 0-2 lines versus 3-7 lines of prior therapy (p<0.001, p=0.001, and p<0.001, respectively), with ECOG class 0-1 versus class 2-3 (p=0.006, p=0.011, and p=0.001, respectively), and with Rai stage 0-2 versus 3-4 (p=0.002, p=0.001, and p=0.002, respectively). No significant difference was noted in treatment response rates or survival outcome with respect to the presence of comorbidity, bulky disease, or del(17p). While 176 adverse events (AEs) were reported in 74 (54.4%) patients, 46 of those 176 AEs were grade 3-4, including pneumonia (n=12), neutropenia (n=11), anemia (n=5), thrombocytopenia (n=5), and fever (n=5). Conclusion: This real-life analysis confirms the favorable efficacy and safety profile of long-term ibrutinib treatment while emphasizing the potential adverse impacts of poorer ECOG performance status, heavy treatment prior to ibrutinib, and advanced Rai stage on patient compliance, treatment response, and survival outcomes.

Anahtar Kelime:

Kronik Lenfositik Lösemili Hastalarda İbrutinib Tedavisinin Etkililiği ve Güvenilirliği: Gerçek Hayat Verilerinin Retrospektif Analizi

Öz:

Amaç: Kronik lenfositik lösemi hastalarında tek ajan ibrutinib tedavisinin etkinliğini, güvenliğini ve sağkalım sonuçlarını geriye dönük olarak değerlendirmek. Gereç ve Yöntemler: Otuz üç merkezde yapılan bu retrospektif, çok merkezli, girişimsel olmayan hastane kayıt çalışmasına en az bir doz ibrutinib uygulanan 136 hasta (ortalama ± standart sapma yaş 64,6 10,3, % 66,9’u erkek) dahil edildi. Hastaların demografik verileri, bazal karakteristikleri, laboratuvar bulguları, lösemi hücre sitogenetiği ile ilgili veriler kaydedildi. Tedavi yanıtı, genel sağkalım (OS), progresyonsuz sağkalım (PFS) ve güvenlik verileri analiz edildi. Bulgular: Hastaların %36,7’sinde ECOG 2-3, % 44,9’u Rai evre 4 idi. FISH ile hastaların %39,8’inde del(17p) varlığını gösterdi. Hastalar medyan 2 (0 ila 7 arasında) sıra pre-ibrutinib tedavisi aldı. Medyan tedavi süresi 8,8 aydı (0,4-58 ay). Bir yıllık PFS ve OS oranları sırasıyla %82,2 ve %84,6, medyan (SE, %95 güven aralığı) PFS süresi 30 (5,1, 20-40) ay ve OS süresi 37,9 (3,2, 31,5-44,2) aydı. Tedavi yanıtı (CR veya PR), PFS ve OS süreleri; ibrutinib öncesi 3-7 basamak tedaviye karşı 0-2 basamak tedavi alanlarda (p<0,001, p=0,001 ve p<0,001, sırayla), ECOG 2-3’e göre ECOG 0-2 olanlarda (p=0,006, p=0,011 ve p=0,001, sırasıyla), Rai evre 0-2 olanlarda Rai evre 3-4 olanlara göre (p=0,002, p=0,001 and p=0,002, sırasıyla) daha iyiydi. Komorbidite, hacimli hastalık veya del(17p) varlığına göre tedaviye yanıt oranlarında veya sağkalım sonuçlarında önemli bir fark kaydedilmedi. 74 hastada (%54,4) 176 advers olay (AE) saptandı; 176 AE’nin 46’sı derece 3-4 idi. Bunlar; pnömoni (n=12), nötropeni (n=11), anemi (n=5), trombositopeni (n=5) ve ateş (n=5) idi. Sonuç: Bu gerçek hayat analizi, uzun vadeli ibrutinib tedavisinin olumlu etkililiğini ve güvenlik profilini doğrularken, kötü ECOG performans durumunun, ibrutinib’den önce ağır şekilde tedavi verilmiş olmasının ve ileri evre hastalığın, hasta uyumu, tedavi yanıtı ve sağkalım üzerindeki potansiyel olumsuz etkilerini ortaya koymuştur.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Catovsky D, Richards S, Matutes E, Oscier D, Dyer M, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230-239.
2. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793-798.
3. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-1174.
4. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; German CLL Study Group (GCLLSG). 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;17:928-942.
5. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208-215.
6. Zenz T, Busch R, Fink A, Winkler D, Fischer K, Bühler A, Hoth P, Fingerle- Rowson GR, Kneba M, Boettcher S, Jäger U, Mendila M, Wenger M, Lichter L, Hallek M, Döhner H, Stilgenbauer S. Genetics of patients with F-refractory CLL or early relapse after FC or FCR: results from the CLL8 trial of the GCLLSG. Blood 2010;116:2427.
7. Tam CS, O’Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, Do KA, Cortes J, Khouri I, Kantarjian H, Lerner S, Keating MJ. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059-3064.
8. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101-1110.
9. Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, Lotter J, Housel S, Stetler-Stevenson M, Yuan CM, Maric I, Calvo KR, Nierman P, Hughes TE, Saba NS, Marti GE, Pittaluga S, Herman SEM, Niemann CU, Pedersen LB, Geisler CH, Childs R, Aue G, Wiestner A. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood 2018;131:2357-2366.
10. Huang SJ, Gerrie AS, Young S, Tucker T, Bruyere H, Hrynchak M, Galbraith P, Al Tourah AJ, Dueck G, Noble MC, Ramadan KM, Tsang P, Hardy E, Sehn L, Toze CL. Comparison of real-world treatment patterns in chronic lymphocytic leukemia management before and after availability of ibrutinib in the province of British Columbia, Canada. Leuk Res 2020;91:106335.
11. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O’Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42.
12. Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 2019;381:432-443.
13. Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 2020;34:787-798.
14. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018;379:2517-2528.
15. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-223.
16. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/ refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910-1919.
17. Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O’Brien S, Wierda WG, Ferrajoli A, Keating MJ. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019;133:1011-1019. 18. Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 2018;103:1502-1510.
19. Dutch/Belgium HOVON CLL Working Group. Dutch guidelines for the diagnosis and treatment of chronic lymphocytic leukaemia. Neth J Med 2016;74:68-74.
20. Follows GA, Bloor A, Dearden C, Devereux S, Fox CP, Hillmen P, Kennedy B, McCarthy H, Parry-Jones N, Patten PEM, Schuh A, Walewska R. Interim Statement from the BCSH CLL Guidelines Panel. London, British Society [no date]. Available from: https://b-s-h.org.uk/media/13488/interimstatement- cll-guidelines-version6.pdf.
21. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Byrd JC, Czuczman MS, Fayad LE, Fisher RI, Glenn MJ, Habermann TM, Harris NL, Hoppe RT, Horwitz SM, Kelsey CR, Kim YH, Krivacic S, LaCasce AS, Nademanee A, Porcu P, Press O, Rabinovitch R, Reddy N, Reid E, Saad AA, Sokol L, Swinnen LJ, Tsien C, Vose JM, Wilson L, Yahalom J, Zafar N, Dwyer M, Sundar H; National Comprehensive Cancer Network. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. J Natl Compr Canc Netw 2015;13:326-362.
22. UK CLL Forum. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica 2016;101:1563-1572.
23. Winqvist M, Asklid A, Andersson PO, Karlsson K, Karlsson C, Lauri B, Lundin J, Mattsson M, Norin S, Sandstedt A, Hansson L, Österborg A. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica 2016;101:1573-1580.
24. Wierda WG, Byrd JC, Abramson JS, Bilgrami SF, Bociek G, Brander D, Brown J, Chanan-Khan AA, Chavez JC, Coutre SE, Davis RS, Fletcher CD, Hill B, Kahl BS, Kamdar M, Kaplan LD, Khan N, Kipps TJ, Ma S, Malek S, Mato A, Mosse C, Neppalli VT, Shadman M, Siddiqi T, Stephens D, Wagner N, Dwyer MA, Sundar H. NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019. J Natl Compr Canc Netw 2019;17:12-20.
25. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O’Brien S, Robak T, Seymour JF, Kipps TJ. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745-2760.
26. Göçer M, Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world data from a singlecenter study in Turkey. Blood Res 2020;55:206-212.
27. Quinquenel A, Fornecker LM, Letestu R, Ysebaert L, Fleury C, Lazarian G, Dilhuydy MS, Nollet D, Guieze R, Feugier P, Roos-Weil D, Willems L, Michallet AS, Delmer A, Hormigos K, Levy V, Cymbalista F, Baran-Marszak F; French Innovative Leukemia Organization (FILO) CLL Group. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood 2019;134:641-644.
28. Del Poeta G, Biagi A, Laurenti L, Chiarenza A, Pozzo F, Innocenti I, Postorino M, Rossi FM, Del Principe MI, Bomben R, de Fabritiis P, Bruno A, Cantonetti M, Di Raimondo F, Zucchetto A, Gattei V. Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia. Haematologica 2021;106:2345-2353.
29. Machnicki MM, Górniak P, Pępek M, Szymczyk A, Iskierka-Jażdżewska E, Steckiewicz P, Bluszcz A, Rydzanicz M, Hus M, Płoski R, Makuch-Łasica H, Nowak G, Juszczyński P, Jamroziak K, Stokłosa T, Puła B. Predictive significance of selected gene mutations in relapsed and refractory chronic lymphocytic leukemia patients treated with ibrutinib. Eur J Haematol 2021;106:320-326.
30. Ysebaert L, Aurran-Schleinitz T, Dartigeas C, Dilhuydy MS, Feugier P, Michallet AS, Tournilhac O, Dupuis J, Sinet P, Albrecht C, Cymbalista F. Realworld results of ibrutinib in relapsed/refractory CLL in France: early results on a large series of 428 patients. Am J Hematol 2017;92:E166e8.
31. Ysebaert L, Quinquenel A, Bijou F, Ferrant E, Michallet AS; French Innovative Leukemia Organization (FiLO) CLL Group. Overall survival benefit of symptom monitoring in real-world patients with chronic lymphocytic leukaemia treated with ibrutinib: a FiLO group study. Eur J Cancer 2020;135:170-172.
32. Mato AR, Nabhan C, Barr PM, Ujjani CS, Hill BT, Lamanna N, Skarbnik AP, Howlett C, Pu JJ, Sehgal AR, Strelec LE, Vandegrift A, Fitzpatrick DM, Zent CS, Feldman T, Goy A, Claxton DF, Bachow SH, Kaur G, Svoboda J, Nasta SD, Porter D, Landsburg DJ, Schuster SJ, Cheson BD, Kiselev P, Evens AM. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood 2016;128:2199e205.
33. Allouchery M, Tomowiak C, Guidez S, Delwail V, Delaunay P, Lafay- Chebassier C, Salvo F, Pérault-Pochat MC. Patterns of use and safety of ibrutinib in real-life practice. Br J Clin Pharmacol 2021;87:895-904.
34. Dimou M, Iliakis T, Pardalis V, Bitsani C, Vassilakopoulos TP, Angelopoulou M, Tsaftaridis P, Papaioannou P, Koudouna A, Kalyva S, Kyrtsonis MC, Panayiotidis P. Safety and efficacy analysis of long-term follow up realworld data with ibrutinib monotherapy in 58 patients with CLL treated in a single-center in Greece. Leuk Lymphoma 2019;60:2939-2945.
35. Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, DeVos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia 2018;32:83-91.
36. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O’Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 2015;373:2425-2437.
37. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O’Brien S. Three-year follow-up of treatment-naive and previously treated patients with CLL and S LL receiving single-agent ibrutnib. Blood 2015;125:2497-2506.
38. Munir T, Brown JR, O’Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. 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;94:1353-1363.
39. O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 2016;17:1409-1418.
40. Byrd J, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan S, Jäger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Pagel JM, Burger JA, Jones JA, Dai S, Vezan RN, James DF, Brown JR. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): up to four years follow-up of the RESONATE study. J Clin Oncol 2017;35(15 Suppl):7510-7510.
41. Gordon MJ, Sitlinger A, Salous T, Alqahtani H, Churnetski M, Rivera X, Wisniewski P, Cohen J, Patel K, Shadman M, Choi M, Hill B, Stephens D, Persky D, Brander D, Danilov AV. A simplified prognostic index for chronic lymphocytic leukemia treated with ibrutinib: results from a multicenter retrospective cohort study. Leuk Res 2020;89:106302.
42. Kittai AS, Lunning M, Danilov AV. Relevance of prognostic factors in the era of targeted therapies in CLL. Curr Hematol Malig Rep 2019;14:302-309.
43. Brander DM, Rhodes J, Pagel JM, Nabhan C, Tam CS, Jacobs R, Hill BT, Lamanna N, Lansigan F, Shadman M, Ujjani CS, Skarbnik AP, Cheson BD, Pu JJ, Sehgal AR, Barr PM, Allan JN, Beach DF, Bhavisha Patel B, Pickens PV, Dwivedy Nasta S, Kennard K, Tuncer HD, Koch B, Furman RR, Mato AR. Applicability of the chronic lymphocytic leukemia (CLL)-IPI on patients treated with front-line ibrutinib in the real world: the case for new prognostic models. Blood 2017;130(Suppl 1):1719.
44. Soumerai JD, Ni A, Darif M, Londhe A, Xing G, Mun Y, Kay NE, Shanafelt TD, Rabe KG, Byrd JC, Chanan-Khan AA, Furman RR, Hillmen P, Jones J, Seymour JF, Sharman JP, Ferrante L, Mobasher M, Stark T, Reddy V, Dreiling LK, Bhargava P, Howes A, James DF, Zelenetz AD. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol 2019;6:e366-e374.
45. Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS, Lucas D, Williams K, Zhao W, Rassenti L, Ghia E, Kipps TJ, Mantel R, Jones J, Flynn J, Maddocks K, O’Brien S, Furman RR, James DF, Clow F, Lozanski G, Johnson AJ, Byrd JC. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014;123:1810-1817.
46. Ball S, Das A, Vutthikraivit W, Edwards PJ, Hardwicke F, Short NJ, Borthakur G, Maiti A. Risk of infection associated with ibrutinib in patients with B-cell malignancies: a systematic review and meta-analysis of randomized

APA	TOMBAK A, TANRIKULU F, DURUSOY S, Dinçyürek H, KAYA E, ÜMİT E, YAVAŞOĞLU İ, MEHTAP Ö, deveci B, ÖZCAN M, Terzi H, OKAY M, Sayınalp N, YILMAZ M, OKAN V, KIZIKLI A, ÖZCAN Ö, Çetin G, Demircioğlu S, AYDOGDU I, SAYDAM G, ARSLAN DAVULCU E, ILHAN G, UÇAR M, SELİM BATUR D, YILDIRIM R, ÖZKOCAMAZ V, GÜNEŞ A, SAHİP B, ERTOP Ş, AKAY O, BAŞTÜRK A, DOĞU M, AKDENİZ A, ÜNAL A, SEYHANLI A, GURKAN E, ÇEKDEMIR D, Ferhanoğlu B (2021). Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. , 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
Chicago	TOMBAK ANIL,TANRIKULU Funda Pepedil,DURUSOY Salih Sertaç,Dinçyürek Hüseyin Derya,KAYA Emin,ÜMİT Elif Gülsüm,YAVAŞOĞLU İrfan,MEHTAP Özgür,deveci BURAK,ÖZCAN MEHMET ALİ,Terzi Hatice,OKAY Müfide,Sayınalp Nilgün,YILMAZ MEHMET,OKAN Vahap,KIZIKLI Alperen,ÖZCAN Ömer,Çetin Güven,Demircioğlu Sinan,AYDOGDU ISMET,SAYDAM Güray,ARSLAN DAVULCU EREN,ILHAN GÜL,UÇAR Mehmet Ali,SELİM BATUR Derya,YILDIRIM Rahşan,ÖZKOCAMAZ Vildan,GÜNEŞ Ahmet Kürşad,SAHİP Birsen,ERTOP Şehmus,AKAY Olga Meltem,BAŞTÜRK Abdülkadir,DOĞU Mehmet Hilmi,AKDENİZ Aydan,ÜNAL Ali,SEYHANLI Ahmet,GURKAN EMEL,ÇEKDEMIR DEMET,Ferhanoğlu Burhan Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. (2021): 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
MLA	TOMBAK ANIL,TANRIKULU Funda Pepedil,DURUSOY Salih Sertaç,Dinçyürek Hüseyin Derya,KAYA Emin,ÜMİT Elif Gülsüm,YAVAŞOĞLU İrfan,MEHTAP Özgür,deveci BURAK,ÖZCAN MEHMET ALİ,Terzi Hatice,OKAY Müfide,Sayınalp Nilgün,YILMAZ MEHMET,OKAN Vahap,KIZIKLI Alperen,ÖZCAN Ömer,Çetin Güven,Demircioğlu Sinan,AYDOGDU ISMET,SAYDAM Güray,ARSLAN DAVULCU EREN,ILHAN GÜL,UÇAR Mehmet Ali,SELİM BATUR Derya,YILDIRIM Rahşan,ÖZKOCAMAZ Vildan,GÜNEŞ Ahmet Kürşad,SAHİP Birsen,ERTOP Şehmus,AKAY Olga Meltem,BAŞTÜRK Abdülkadir,DOĞU Mehmet Hilmi,AKDENİZ Aydan,ÜNAL Ali,SEYHANLI Ahmet,GURKAN EMEL,ÇEKDEMIR DEMET,Ferhanoğlu Burhan Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. , 2021, ss.273 - 285. 10.4274/tjh.galenos.2021.2021.0007
AMA	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. . 2021; 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
Vancouver	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. . 2021; 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
IEEE	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B "Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data." , ss.273 - 285, 2021. 10.4274/tjh.galenos.2021.2021.0007
ISNAD	TOMBAK, ANIL vd. "Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data". (2021), 273-285. https://doi.org/10.4274/tjh.galenos.2021.2021.0007

APA	TOMBAK A, TANRIKULU F, DURUSOY S, Dinçyürek H, KAYA E, ÜMİT E, YAVAŞOĞLU İ, MEHTAP Ö, deveci B, ÖZCAN M, Terzi H, OKAY M, Sayınalp N, YILMAZ M, OKAN V, KIZIKLI A, ÖZCAN Ö, Çetin G, Demircioğlu S, AYDOGDU I, SAYDAM G, ARSLAN DAVULCU E, ILHAN G, UÇAR M, SELİM BATUR D, YILDIRIM R, ÖZKOCAMAZ V, GÜNEŞ A, SAHİP B, ERTOP Ş, AKAY O, BAŞTÜRK A, DOĞU M, AKDENİZ A, ÜNAL A, SEYHANLI A, GURKAN E, ÇEKDEMIR D, Ferhanoğlu B (2021). Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. Turkish Journal of Hematology, 38(4), 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
Chicago	TOMBAK ANIL,TANRIKULU Funda Pepedil,DURUSOY Salih Sertaç,Dinçyürek Hüseyin Derya,KAYA Emin,ÜMİT Elif Gülsüm,YAVAŞOĞLU İrfan,MEHTAP Özgür,deveci BURAK,ÖZCAN MEHMET ALİ,Terzi Hatice,OKAY Müfide,Sayınalp Nilgün,YILMAZ MEHMET,OKAN Vahap,KIZIKLI Alperen,ÖZCAN Ömer,Çetin Güven,Demircioğlu Sinan,AYDOGDU ISMET,SAYDAM Güray,ARSLAN DAVULCU EREN,ILHAN GÜL,UÇAR Mehmet Ali,SELİM BATUR Derya,YILDIRIM Rahşan,ÖZKOCAMAZ Vildan,GÜNEŞ Ahmet Kürşad,SAHİP Birsen,ERTOP Şehmus,AKAY Olga Meltem,BAŞTÜRK Abdülkadir,DOĞU Mehmet Hilmi,AKDENİZ Aydan,ÜNAL Ali,SEYHANLI Ahmet,GURKAN EMEL,ÇEKDEMIR DEMET,Ferhanoğlu Burhan Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. Turkish Journal of Hematology 38, no.4 (2021): 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
MLA	TOMBAK ANIL,TANRIKULU Funda Pepedil,DURUSOY Salih Sertaç,Dinçyürek Hüseyin Derya,KAYA Emin,ÜMİT Elif Gülsüm,YAVAŞOĞLU İrfan,MEHTAP Özgür,deveci BURAK,ÖZCAN MEHMET ALİ,Terzi Hatice,OKAY Müfide,Sayınalp Nilgün,YILMAZ MEHMET,OKAN Vahap,KIZIKLI Alperen,ÖZCAN Ömer,Çetin Güven,Demircioğlu Sinan,AYDOGDU ISMET,SAYDAM Güray,ARSLAN DAVULCU EREN,ILHAN GÜL,UÇAR Mehmet Ali,SELİM BATUR Derya,YILDIRIM Rahşan,ÖZKOCAMAZ Vildan,GÜNEŞ Ahmet Kürşad,SAHİP Birsen,ERTOP Şehmus,AKAY Olga Meltem,BAŞTÜRK Abdülkadir,DOĞU Mehmet Hilmi,AKDENİZ Aydan,ÜNAL Ali,SEYHANLI Ahmet,GURKAN EMEL,ÇEKDEMIR DEMET,Ferhanoğlu Burhan Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. Turkish Journal of Hematology, vol.38, no.4, 2021, ss.273 - 285. 10.4274/tjh.galenos.2021.2021.0007
AMA	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. Turkish Journal of Hematology. 2021; 38(4): 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
Vancouver	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data. Turkish Journal of Hematology. 2021; 38(4): 273 - 285. 10.4274/tjh.galenos.2021.2021.0007
IEEE	TOMBAK A,TANRIKULU F,DURUSOY S,Dinçyürek H,KAYA E,ÜMİT E,YAVAŞOĞLU İ,MEHTAP Ö,deveci B,ÖZCAN M,Terzi H,OKAY M,Sayınalp N,YILMAZ M,OKAN V,KIZIKLI A,ÖZCAN Ö,Çetin G,Demircioğlu S,AYDOGDU I,SAYDAM G,ARSLAN DAVULCU E,ILHAN G,UÇAR M,SELİM BATUR D,YILDIRIM R,ÖZKOCAMAZ V,GÜNEŞ A,SAHİP B,ERTOP Ş,AKAY O,BAŞTÜRK A,DOĞU M,AKDENİZ A,ÜNAL A,SEYHANLI A,GURKAN E,ÇEKDEMIR D,Ferhanoğlu B "Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data." Turkish Journal of Hematology, 38, ss.273 - 285, 2021. 10.4274/tjh.galenos.2021.2021.0007
ISNAD	TOMBAK, ANIL vd. "Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data". Turkish Journal of Hematology 38/4 (2021), 273-285. https://doi.org/10.4274/tjh.galenos.2021.2021.0007