More Is Not Better in Diffuse Large B-Cell Lymphoma

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younesJune11.jpgUp until now, the role of intensified therapy for newly diagnosed lymphoma in the rituximab era remained unknown. 

This week at ASCO, four independent randomized trials, looking at different strategies, reported that more intensive front-line therapy offers no added advantage over standard chemotherapy regimens in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). 

If you don't have the time to read this full report, all you need to know is that RCHOP-21 remains the standard of care.

Review of the Four Trials

RCHOP-14 and RCHOP-21 comparison by Cunningham
In the first study from the United Kingdom, Cunningham et al. compared dose dense RCHOP given every 14 days (RCHOP-14) with standard RCHOP-21 in 1,080 patients. With a median follow-up of 39 months, there was no difference in the overall response rate (88% for RCHOP-21 versus 90% for RCHOP-14), complete remission rate, progression-free survival or overall survival in the two treatment groups. 

Furthermore, in subset analysis, there was no difference in treatment outcomes in patients with high proliferating tumors, or germinal center versus non-germinal center lymphomas. Conclusion: there is no evidence that dose-dense RCHOP-14 is better than standard RCHOP-21.

RCHOP-21 x 8 and CHOP/RCHOP x 6 comparison by Stiff
Stiff et al. presented results from a randomized Phase III U.S./Canadian trial comparing CHOP-21 (or RCHOP-21) x 8 with CHOP/RCHOP x 6, followed by autologous stem cell transplant (ASCT). The study started in 1997 in the pre-rituximab era and, therefore, initially patients received CHOP. Subsequent to rituximab approval, patients received RCHOP.  
The study enrolled 397 patients with high-intermediate or high-risk (HI/H), age-adjusted (aa) international prognostic index.  Interestingly, 10% to 12% of the patients had T-cell lymphoma.

Although there was no difference in overall survival (74% for chemo + ASCT versus 71% for chemo alone), there was a trend for improved progression-free survival for the ASCT arm. Conclusion: incorporating ASCT in front-line regiment for HI/H DLBCL does not improve survival, mainly because relapsed patients can be effectively salvaged with second-line therapy and ASCT.

R-Mega-CHOEP and R-CHOEP-14 comparison by Schmitz
In a different approach, Schmitz et al. also compared intensive front-line therapy with stem cell rescue using three sequential courses of R-Mega-CHOEP with R-CHOEP-14 in young high-risk patients with aggressive B-cell lymphoma.  There were 306 patients enrolled and 262 were randomized. Approximately 90% had DLBCL histology. 

Again, there was no significant difference between the two treatment arms, although the trend was in favor of the standard RCHOEP arm, mainly due to the excessive toxicity, including death, of the intensive arm.  Conclusion: standard RCHOEP-14 is safer and as effective as intensified MegaCHOEP. Of course we don't know the contribution of etoposide to the RCHOP regimen in this patient population, and no one uses this regimen in the United States. Instead, RCHOP-21 remains the standard.

RCHOP-14 cycles by Milpied

Finally, Milpied and colleagues compared eight cycles of RCHOP-14 to a different regimen that incorporated ASCT.  The study design was a bit more complex compared to the previous studies, as it used PET results to determine subsequent therapy; some patients received BEAM/ASCT and others received RDHAP, followed by BEAM/ASCT.  Each treatment arm included 156 patients. 

To make a long story short, there was no difference between the two treatment approaches, and RCHOP-14 was as good as the ASCT-containing regimen.  Because RCHOP-14 is as good as RCHOP-21, as discussed above, the standard of care remains RCHOP-21.

What do we do now?
So how do we improve on RCHOP-21? One can say that more is not better. We need to be smarter. Incorporating novel targeted therapy with RCHOP is the way to go.

But for these trials to be successful, we need to incorporate biomarker analysis to preselect patients who are likely to benefit from these novel approaches. 

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