Women over 60 had a slower clearance rate of rituximab, and this was felt to be the driving force as to why older women did better than older men.— Matthew A. Lunning, DO
For diffuse large B-cell lymphoma, does the dose of rituximab (Rituxan) matter? Are there patient characteristics that determine outcomes as well as the optimal dose? These questions were explored at the 2016 Pan Pacific Lymphoma Conference by Matthew A. Lunning, DO, Assistant Professor of Medicine at the University of Nebraska Medical Center, Omaha.1
Rituximab Dose: ‘An Educated Guess’
Rituximab, which targets CD20 expression on mature B-cell non-Hodgkin lymphoma, is “a smart bomb” that is widely “taken for granted,” he said. According to Dr. Lunning, the established dose of 375 mg/m2 was essentially “an educated guess,” as this particular dose was not included in the first dose-escalation studies. In fact, there is no indication as to how this dose was chosen. Perhaps it pertained to the amount of drug on hand that would satisfy the dosing needs of the planned number of clinical trial patients, he proposed.
The dose of 375 mg/m2, however, became the established dose; more recent studies have raised the issue of whether once size fits all.
Gender in Lymphoma
There is clearly a gender gap with regard to the development of lymphoma. The odds ratios for men, compared with women, are 2.7 for non-Hodgkin lymphoma, 1.7 for diffuse large B-cell lymphoma, 2.5 for peripheral T-cell lymphoma, and 4.5 for Burkitt lymphoma. Pregnancy appears to be protective, reducing the risk by up to 22%.2
Treatment effects related to rituximab also appear to be influenced by gender. Treatment with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) in the pre-rituximab era yielded a 2-year survival rate of 65%, which improved to more than 85% with rituximab and CHOP (R-CHOP; P < .0001). However, the LNH98-5 study by Ngo et al showed this improvement was greatest among females, whose complete response rate increased from 68% to 84%, compared with an increase from 64% to 77% among males (P < .001).3
With rituximab on board, the International Prognostic Index (IPI) became less useful in prognosis; instead, male gender and advanced stage of disease predicted for worse survival with R-CHOP. “This was the first signal that there may be something [prognostic] beyond IPI,” Dr. Lunning said.
A subsequent study evaluated prognostic variables in LNH98-5 and two other phase III trials of R-CHOP in diffuse large B-cell lymphoma.4 “What actually fell out in this larger dataset was gender. Women did better,” Dr. Lunning revealed.
Median progression-free survival in the combined analysis was 90.6 months for women and 55 months for men (hazard ratio [HR] = 1.237; P = .02). Overall survival was not reached for women but was 90.6 months for men (HR = 1.218; P = .0681). The difference was most significant in patients over 60 years of age.
Age and Rituximab Dose
“So gender may matter. What about age?” asked Dr. Lunning.
A review of four investigations by Pfreundschuh et al evaluated the effect of gender on outcome in diffuse large B-cell lymphoma by analyzing the male hazard ratio for progression-free survival.5 The study found no difference in outcomes by gender among persons < 60 years of age receiving rituximab plus an anthracycline-based regimen, but in persons > age 60, women benefited more than men.
The similar improvements of outcome in young patients were associated with similar rituximab clearance in young men and women, whereas the greater benefit for elderly women was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P = .005)—hence, higher serum levels and longer exposure times. This was attributable to an age-dependent (P = .004) decrease in rituximab clearance in women but not men, Dr. Lunning explained.
The authors concluded that compared with older females, all other subgroups had significantly faster rituximab clearance and therefore appeared to be suboptimally dosed with rituximab at 375 mg/m2. “Women over 60 had a slower clearance rate of rituximab, and this was felt to be the driving force as to why older women did better than older men,” he continued.
‘Smarter’ Regimen May Improve Outcomes in Men
This finding led to the recent phase II SMARTE-R trial in patients with newly diagnosed diffuse large B-cell lymphoma, in which the experimental arm received R-CHOP-14 on a unique schedule, delivering multiple doses over time for a total of 8 cycles (rituximab on days –4, 0, 10, 29, 57, 99, 155, and 239).6 The control arm was the historical cohort of the RICOVER-60 trial, which received R-CHOP-14 for 6 cycles, plus 2 additional doses of rituximab to amount to 8 as well.
In those who received extended rituximab dosing, the complete response rate was 85% overall. There were no differences in outcomes between the regimens for the overall population and for the subset of good-prognosis patients. However, in poor-prognosis patients, the longer exposure time in SMARTE-R-CHOP-14 was associated with a better 3-year event-free survival (67% vs 54%) and overall survival (80% vs 67%). In men with poor-risk features, the 3-year overall survival rate was 80% with SMARTE-R CHOP-14, vs 60% with standard treatment (P = .027).
“Perhaps by delivering a ‘smarter’ regimen, you can overcome the poor-prognosis influence of male gender,” Dr. Lunning commented.
This study was followed by the phase II SEXIE-R R-CHOP-14 study in patients aged 61 to 80, where females received rituximab at a dose of 375 mg/m2 (target 3,000 mg/m2), but men received rituximab at a dose of 500 mg/m2 (target 4,000 mg/m2).7 With this dosing strategy, there were no differences in outcomes related to gender. Three-year progression-free survival was 68% in women and 74% in men (P = .396), and overall survival was 72% and 80%, respectively (P = .111).
Dr. Lunning also noted that R-CHOP-14 seems to provide better outcomes than R-CHOP-21 in patients with diffuse large B-cell lymphoma and male patients over age 65 years, but among women, the regimens are similar. Whether such subset differences exist for the SMARTE-R regimen or for R-CHOP-21 has not been established.
What About Follicular Lymphoma?
Finally, Dr. Lunning asked whether gender differences are only seen with diffuse large B-cell lymphoma or whether they also exist in other lymphoma subtypes. In the phase II NHL-9 trial of follicular lymphoma, median levels of rituximab were higher in women treated with R-CHOP, and higher Ctrough levels were associated with deeper responses and better progression-free survival outcomes.8 “Females with follicular lymphoma [who received] higher levels of rituximab had better outcomes,” he noted. “This may not just be in diffuse large B-cell lymphoma.”
NCCN Guidelines for Dosing
The National Comprehensive Cancer Network® (NCCN®) has “acknowledged this growing dataset” and has indicated that when using R-CHOP-14 and R-CHOP-21, clinicians may consider increasing the dose of rituximab to 500 mg/m2 in men over 60 years old.
“While we await the SEXIE-R-CHOP final data, it’s becoming clear that maybe patients’ gender and age do matter,” Dr. Lunning concluded.
Meanwhile, R-CHOP-21 remains the gold standard induction regimen. Whether future trials of R-CHOP-21 will consider increasing the dose in men to 500 mg/m2 remains to be seen. “Rather than a sexier R-CHOP-21,” he said, “there is more interest in R-CHOP plus novel drug X or Y.” ■
Disclosure: Dr. Lunning has consulted for Genentech, Bristol-Myers Squibb, Gilead, Seattle Genetics, Pharmacyclics, and Celgene and has received research support from Janssen Scientific and TG Therapeutics.
4. Sarkozy C, Mounier N, Delmer A, et al: Impact of BMI and gender on outcomes in DLBCL patients treated with R-CHOP: A pooled study from the LYSA. Lymphoma. January 16, 2014. Available at http://www.hindawi.com/journals/lymph/2014/205215/abs/. Accessed August 8, 2016.
6. Preundschuh M, Poeschel V, Zeynalova S, et al: Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): Extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol 32:4127-4133, 2014.
7. Pfreundschuh M, Held G, Zeynalova S, et al: Increased rituximab doses eliminate increased risk and improve outcome of elderly male patients with aggressive CD20+ B-cell lymphomas: The SEXIE-R-CHOP-14 trial of the DSHNHL. 2014 European Hematology Association Congress. Abstract S1347.
8. Jäger U, Fridrik M, Zeitlinger M, et al: Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica 97:1431-1438, 2012.