학술논문
Infuzní toxicita rituximabu u nemocných s chronickou lymfocytární leukemiíRituximab infusion-related toxicity in patients with chronic lymphocytic leukemia
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Abstract
Úvod: Kombinace monoklonální antiCD20 protilátky rituximabu s chemoterapií je vysoce účinná v léčbě chronické lymfocytární leukemie (CLL). Hlavním nežádoucím účinkem rituximabu jsou infuzní reakce, např. syndrom uvolnění cytokinů (cytokine release syndrome – CRS), který zpravidla doprovází první podání rituximabu. Cílem naší retrospektivní analýzy bylo zhodnotit četnost výskytu infuzních reakcí v rutinní klinické praxi, jejich vztah k parametrům nádorové nálože a zjistit možnou spojitost infuzních reakcí s účinností léčby. Dále byla posouzena bezpečnost rychlé infuze s rituximabem u nemocných s CLL. Charakteristika souboru: Hodnoceno bylo 108 nemocných s CLL léčených chemoimunoterapií s rituximabem od května roku 2005 do března roku 2011 v našem centru. V rámci 1. linie (n = 66, 71 % mužů, věkový medián 63 let) byly použity tyto léčebné režimy: fludarabin, cyklofosfamid, rituximab – FCR (n = 43) a nízkodávkovaný FCR (n = 13); 10 nemocných bylo léčeno jinými protokoly. 42 nemocných (76 % mužů, věkový medián 65 let) podstoupilo 2. linii: rituximab-dexametazon (n = 18), FCR/nízkodávkované FCR (n = 14) a 10 nemocných jiný režim. Součástí premedikace před infuzí rituximabu byl metylprednisolon 80 mg i.v., paracetamol 1 000 mg p. o. a bisulepin 1 mg i. v., všichni nemocní měli nitrožilní hydrataci minimálně 2 000 ml/den a alopurinol 300–600 mg/den. V 1. cyklu byl rituximab podáván frakcionovaně v celkové dávce 375 mg/m2 a od 2. cyklu formou rychlé infuze v dávce 500 mg/m2. Výsledky: K rozvoji infuzní reakce po rituximabu došlo u 32 % nemocných v 1. linii a 19 % v 2. linii. Jednalo se převážně o mírné reakce a k závažné toxicitě (stupeň III/IV dle NCI CTCAE – National Cancer Institute – The Common Terminology Criteria for Adverse Events) došlo výjimečně (3 % nemocných v 1. linii a 2 % v 2. linii). Reakce se nejčastěji projevila třesavkou, zimnicí, dušností, horečkou či hypotenzí. U všech nemocných bylo možné dokončit infuzi rituximabu v plánované dávce ve stejný den. Hodnocení léčebné odezvy (overall response rate – ORR) neprokázalo statisticky významné rozdíly mezi nemocnými s reakcí či bez infuzní reakce. Nemocní s infuzní toxicitou měli vyšší absolutní počet lymfocytů (1. linie, 87 vs 56 × 109/l, p = 0,21; 2. linie, 101 vs 14 × 109/l, p = 0,043). Při mediánu sledování 36 měsíců nebyl prokázán statisticky významný rozdíl v PFS (doba přežití bez progrese – progression-free survival) a OS (celkové přežití – overall survival) mezi oběma skupinami. Závěry: Výskyt infuzních reakcí u nemocných s CLL léčených rituximabem je poměrně běžný (32 %), avšak při pečlivé premedikaci jsou reakce velmi dobře zvladatelné a těžká forma je vzácná. Potvrdili jsme velmi dobrou snášenlivost rychlé infuze rituximabu. Naše data neprokázala statisticky významnou souvislost mezi výskytem infuzních reakcí a efektem léčby.
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. Results: 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. Conclusions: 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.
Martin Šimkovič, Pavel Vodárek, Monika Motyčková, Pavel Žák, Lukáš Smolej
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. Results: 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. Conclusions: 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.
Martin Šimkovič, Pavel Vodárek, Monika Motyčková, Pavel Žák, Lukáš Smolej