Rituximab infusion-related toxicity in patients with chronic lymphocytic leukemia

Authors: Martin Šimkovič;  Pavel Vodárek;  Monika Motyčková;  Pavel Žák;  Lukáš Smolej
Authors‘ workplace: IV. interní hematologická klinika LF UK a FN Hradec Králové, přednosta doc. MUDr. Pavel Žák, Ph. D.
Published in: Vnitř Lék 2015; 61(7-8): 626-632
Category: Original Contributions


Background and Aims:
Rituximab in combination with chemotherapy is an effective treatment of patients (pts) with chronic lymphocytic leukemia (CLL). The most frequent adverse event of rituximab is infusion-related toxicity, e.g. cytokine-release syndrome that occurs usually during the first infusion. However, there is scarce data on feasibility and tolerability of rituximab infusions in CLL outside clinical trials. Therefore, we performed a single-center retrospective analysis of the frequency of rituximab infusion-related adverse events during the first- and the second line CLL treatment administered in the routine practice. We also analyzed its relation to parameters of tumor load and possible association with treatment efficacy. The safety of rapid infusion of rituximab in CLL pts was also evaluated.

Patients and Methods:
We analyzed 108 pts with CLL treated with rituximab-containing regimens between March 2005 and May 2011 at our institution. The most common first-line regimens (n = 66, 47 males, median age 63 years) were FCR (43 pts) and low-dose FCR (13 pts); 10 pts were treated by other protocols. Forty-two pts (32 males, median age, 65 years) underwent second line treatment: 18 pts rituximab-dexamethasone, 7 pts FCR, 7 pts low-dose FCR and 10 pts other regimens. Intravenous hydration (2 000 ml daily on days 0 and 1 of cycle), allopurinol 300–600 mg p. o. daily and premedication with methylprednisolone 80 mg i. v., acetaminophen 1 000 mg p. o. and bisulepine 1 mg i. v. were administered before rituximab infusion. Rituximab was given by fractionated infusion (100 mg for 2 hours, then if tolerated well, the rest of the dose with infusion rate escalation from 100 mg/hour up to 400 mg/hour) at the dose of 375 mg/m2 in the first cycle. Subsequent doses (500 mg/m2) were administered by rapid-infusion protocol.

Rituximab infusion-related toxicity occurred in 32 % pts (n = 21) during the first line treatment and 19% pts (n = 8) during the second line treatment. Adverse events were predominantly mild and NCI CTCAE grade III/IV occurred rarely (3% in the first line, 2% in the second line). Infusion toxicity mani­fested predominantly as rigors, chills, fever and hypotension. All patients with adverse events could finish rituximab infusion as initially planned on the same day. Treatment response analysis did not demonstrate statistically significant differences between patients with and without rituximab infusion toxicity. Patients who developed rituximab infusion toxicity had higher absolute lymphocyte count (first line, 87 vs 56 × 109/l, p = 0.21; second line, 101 vs 14 × 109/l, p = 0.043). At the median follow-up of 36 months, there were no statistically significant differences in PFS or OS in both cohorts.

Rituximab infusion-related toxicity in pts with CLL is relatively frequent (32%). However, occurrence of infusion-related symptoms can be reduced by proper premedication and severe adverse events are uncommon. In our experience, all patients were able to receive the planned dose of rituximab. Subsequent doses of rituximab could be safely administered by rapid-infusion protocol. We did not find statistically significant association between rituximab infusion toxicity and effectiveness of treatment.

Key words:
chronic lymphocytic leukemia – infusion-related toxicity – rituximab


1. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346(4): 235–242.

2. Marcus R, Imrie K, Belch A et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105(4): 1417–1423.

3. Pfreundschuh M, Trumper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7(5): 379–391.

4. van Oers MH, Klasa R, Marcus RE et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108(10): 3295–3301.

5. Gurcan HM, Keskin DB, Stern JN et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009; 9(1): 10–25.

6. Klener P. Cílená léčiva a jejich přínos pro terapii vnitřních chorob. Vnitř Lék 2013; 59(1): 5–12.

7. Panovská A, Doubek M. Chronická lymfocytární leukemia – diagnostika a léčba. Onkologie 2013; 7(3): 117–120. Dostupné z WWW: < http://www.onkologiecs.cz/pdfs/xon/2013/03/04.pdf>.

8. Papajík T, Kapitáňová Y. Rituximab – mechanismus účinku u nemocných s B-buněčnými lymfoproliferacemi. Acta medicinae 2012; 7: 15–20.

9. Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005; 31(6): 456–473.

10. Winkler U, Jensen M, Manzke O et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999; 94(7): 2217–2224.

11. Goede V, Fischer K, Busch R et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014; 370(12): 1101–1110.

12. Hallek M, Fischer K, Fingerle-Rowson G 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): 1164–1174.

13. Robak T, Dmoszynska A, Solal-Celigny P et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28(10): 1756–1765.

14. Siegel RD, Castro KM, Eisenstein J et al. Quality improvement in the national cancer institute community cancer centers program: the quality oncology practice initiative experience. J Oncol Pract 2014; 11(2): e247-e254. Dostupné z DOI: <http://dx.doi.org/10.1200/JOP.2014.000703>.

15. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 2007; 12(5): 601–609.

16. Byrd JC, Murphy T, Howard RS et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19(8): 2153–2164.

17. Wing MG, Moreau T, Greenwood J et al. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest 1996; 98(12): 2819–2826.

18. Grillo-Lopez AJ, White CA, Varns C et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26(5 Suppl 14): 66–73.

19. Chung CH, Mirakhur B, Chan E et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008; 3588(11): 1109–1117.

20. Johnson P, Glennie M. The mechanisms of action of rituximab in the elimination of tumor cells. Semin Oncol 2003; 30(1 Suppl 2): 3–8.

21. Alas S, Bonavida B, Emmanouilides C. Potentiation of fludarabine cytotoxicity on non-Hodgkin‘s lymphoma by pentoxifylline and rituximab. Anticancer Res 2000; 20(5A): 2961–2966.

22. Grillo-Lopez AJ, Hedrick E, Rashford M et al. Rituximab: ongoing and future clinical development. Semin Oncol 2002; 29(1 Suppl 2): 105–112.

23. Norin S, Bjorkstrand B, Rommel F et al. Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: results from a Swedish national observational study. Leuk Res 2015; 39(1): 33–37.

24. Robak T, Lech-Maranda E, Robak P. Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. Expert Rev Anticancer Ther 2010; 10(10): 1529–1543.

25. Mabthera 100 mg and 500 mg concentrate for solution for infusion (SPC). Dostupné z WWW: <https://www.medicines.org.uk/emc/medicine/2570> (accessed 23-FEB-2015).

26. Byrd JC, Waselenko JK, Maneatis TJ et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17(3): 791–795.

27. O‘Brien SM, Kantarjian H, Thomas DA et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19(8): 2165–2170.

28. Keating MJ, O‘Brien S, Albitar M et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23(18): 4079–4088.

29. Wierda W, O‘Brien S, Wen S et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23(18): 4070–4078.

30. Hillmen P, Robak T, Janssens A et al.,Ofatumumab + Chlorambucil Versus Chlorambucil Alone In Patients With Untreated Chronic Lymphocytic Leukemia (CLL): Results Of The Phase III Study Complement 1 (OMB110911). Blood 2013; 122: 528–528..

Diabetology Endocrinology Internal medicine

Article was published in

Internal Medicine

Issue 7-8

2015 Issue 7-8

Most read in this issue

This topic is also in:

Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account