Suboptimal dosing of rituximab in male and female patients with DLBCL

Abstract

Key Points• Elderly females have a better outcome than elderly males and a more favorable rituximab pharmacokinetics than all other patients with DLBCL.• Prospective trials aiming at optimizing rituximab dose and schedule are warranted in all DLBCL patients.To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HR PFS-male ) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients (MapThera International Trial study), HR PFS-male was 1.3 (P 5 .092) without and 1.1 (P 5 .660) with rituximab. In elderly patients (RICOVER-60 study), HR PFS-male was 1.1 (P 5 .348) with CHOP but increased to 1.6 (P 5 .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P 5 .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P 5 .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P 5 .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m 2 . Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients. (Blood. 2014;123(5):640-646)

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

“…This is in contrast to a better outcome of female patients with diffuse large B-cell lymphoma treated with rituximab plus CHOP, where the explanation is a prolonged half-life of rituximab in elderly female patients. 26,27 In our Burkitt lymphoma/leukemia cohort, reasons for the inferior outcome of the female patients are as yet unclear.…”

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas

“…Data were collected from the following 11 consecutive prospective DSHNHL trials (see supplemental Table 1 on the Blood Web site) with a median follow-up .3 years): the randomized NHL-B1, 15 which compared CHOP given every 3 weeks, CHOP given every 3 weeks with the addition of etoposide (CHOEP-21), CHOP given every 2 weeks (CHOP- 14), and CHOEP-14 in a 2 3 2 factorial design in young (18 to 60 years of age) patients with good prognosis (normal lactate dehydrogenase [LDH]); the NHL-B2 trial, which addressed the same question in elderly patients 16 ; the High-CHOEP phase 1/2 trial, a randomized dose-escalation study of CHOEP-21 and CHOEP-14 in young good-prognosis (normal LDH) patients 17 ; the High-CHOEP phase 3 study, 18 which compared dose-escalated CHOEP-21 with standard CHOEP-21 in young good-prognosis (normal LDH) patients; and 2 Mega-CHOEP phase 2 studies 19,20 without and 1 21 with rituximab, which evaluated dose-escalated CHOP plus etoposide followed by repetitive autologous stem cell transplantations in young poor-prognosis patients without and with rituximab; the MabThera International Trial (MInT) study, 2 which compared CHOP-like chemotherapy regimens with and without rituximab in young (18 to 60 years of age) good-prognosis DLBCL (age-adjusted International Prognostic Index [IPI] 5 0, 1; except for stage I without bulky disease) patients; the Rituximab with CHOP over Age 60 Years (RICOVER-60) 3 trial, which compared 6 vs 8 cycles of CHOP-14 with and without rituximab in elderly (61 to 80 years of age) patients, the Pegfilgrastim study, 22 which addressed the same question as the RICOVER-60 trial in 99 elderly patients, but where patients had an additional randomization into pegfilgrastim given on day 2 vs day 4; and the Conventional Chemo Vs HD Chemo Followed by Auto SCT in Younger Patients With Aggressive Non-Hodgkin's Lymphoma (Mega-CHOEP) phase 3 study, 23 which compared 8 cycles of CHOEP with added rituximab every 2 weeks with 4 cycles of maximally doseescalated Mega-CHOEP with added rituximab requiring 3 autologous stem cell supports in young poor-prognosis patients. In total, 4155 patients were included in this study.…”

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

“…10 These results are attributed to higher rituximab clearance in males who are undertreated without rituximab maintenance. 11 The risk of relapse at onset (age-adjusted International Prognostic Index) or disease status after induction (CR or PR) would also affect the applicability of rituximab maintenance and should be clarified.…”