A Phase I–II Study To Determine the Maximum Tolerated Infusion-Rate of Rituximab, with a Special Emphasis on Monitoring the Effect of Rituximab on Cardiac Function.

We conducted an infusion rate-escalation trial to evaluate the maximum rate at which rituximab (R) can be administered without steroid pre-medication in patients (pts) having received at least 1 infusion of R in the previous 3 months. The main eligibility criteria was a normal cardiac function. Cohorts of 3 pts were assigned to receive R (375mg/m²) ± concomitant chemotherapy (CT), at a given initial infusion rate of 200mg/hr in the first cohort and increased by 100mg/hr in each subsequent cohort. All pts received standard anti-histamines and paracetamol pre-medication. The rate was increased by 100mg/hr every 30min within each cycle to the prescribed total dose. In each subsequent R administrations the initial rate was increased by 100mg/hr to a maximal predefined infusion-rate of 700mg/hr. Pts were monitored every 15min for symptoms, blood pressure (BP) and heart rate (HR), hourly for temperature and an ECG was performed before and after treatment. An echocardiography was performed at baseline and within 1 month from the last infusion. Additional CT was administered the same day after R. In the first part of the study (21 pts) 2 previously well tolerated R administrations had to be given, while in second part of the study (11 pts) the maximum infusion-rate (700mg/hr) was applied after only 1 previous infusion of R. In this last cohort cardiac monitoring included also an ECG during infusion, troponin I and brain natriuretic peptide (BNP) measurements before and 24hrs after administration, echocardiography within 1 month from the last infusion. Holter ECG’s were performed at baseline and during the first administration of R. A total of 32 pts with lymphoma were included with a median age of 57,5 years (range 24–77). The histological subtypes comprised diffuse large B cell (18 pts), follicular (7 pts), other indolent (3 pts) and other aggressive lymphomas (4 pts). Four pts were treated with single agent R and 28 in combination with CT. A total of 128 cycles were completed. Three cycles were given at a starting infusion speed of 200mg/hr, 7 cycles at 300mg/hr, 11 cycles at 400mg/hr, at 500mg/hr and at 600mg/hr and 85 cycles at 700mg/hr. All pts tolerated the increased infusion-rate without major side effects. Mean systolic and diastolic BP and HR did not change significantly. Body temperature was always ≤37.1°C. Grade I headache and dyspnoea were observed in 4 and 1 pts respectively. Three pts experienced asthenia grade I–II. One pt had grade I hypotension. There were no new clinically relevant ECG alterations. One patient showed repeatedly ST-segment and T-wave alterations (T-flattening) over V2 and V3 under maximal infusion-rate requiring a reduction of the rate. Troponin levels remained within normal range (<0.1ng/l). The mean baseline cardiac ejection-fraction of 65.5% (±5.4) remained unchanged; mean BNP baseline level was 30.4 ng/l (±20.8) and increased to 64.1ng/l (±41.2) but still remained within a normal range (<73μg/l) 24hrs after R administration (p<0.0001). Holter ECG’s showed no pathological changes compared to baseline. We conclude that R can be administered safely as 1h infusion without steroid pre-medication in pts with a normal cardiac function who already received at least 1 R dose in the previous 3 months.