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High-risk diffuse large B-cell lymphoma: can we do better than rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone?

Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is curative in the majority of patients with diffuse large B-cell lymphoma (DLBCL), especially in those with lowrisk disease (as assessed by an International Prognostic Index [IPI] score of 0–1 in the absence of tumor bulk) [1,2]. Improved outcomes were reported with dose intensification in patients with low-risk disease, suggesting that R-CHOP could be improved upon, albeit with substantially increased treatment-related toxicities [3]. However, the survival outcome for patients with high-risk DLBCL remains suboptimal in the age of R-CHOP chemotherapy, and approximately 50% of patients with IPI 3–5 DLBCL will ultimately manifest refractory/relapsed disease and die from their DLBCL [4]. The results of salvage chemotherapy and autologous stem cell transplant are poor in patients who experience early disease progression after primary rituximab-containing chemotherapy [5]. Thus, the logical place for intervention in these patients is to improve frontline therapy. In this regard, it is important to remember the numerous failed historical approaches to escalate frontline chemotherapy in the pre-rituximab era prior to the advent of robust risk stratification tools and our understanding of the biological classification of DLBCL [6–8]. Although more mature follow-up is needed, current evidence does not support the use of high-dose therapy and autologous stem cell transplant in first remission in these patients with high-risk disease who achieve complete remission to their initial therapy in the rituximab era [9]. Unfortunately, the current explosion in patho-biological and molecular information relevant to DLBCL comes with a cost, with no agreement on which classification system (or combination thereof ) carries the greatest clinical applicability in identifying those patients at high-risk for potentially modified therapy. For example, currently, patients may be classified as having “high-risk” disease based on clinical features (IPI), “cell-of-origin” studies, tumor proliferation index or c-MYC/BCL2 status, with little information on how the individual categories may overlap or interact to influence prognosis. In their article “Rituximab, cyclophosphamidefractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine overcomes risk features associated with inferior outcomes in treatment of newly diagnosed, high-risk diffuse large B-cell lymphoma”, Mato and colleagues describe the survival outcome of 64 patients with newly diagnosed DLBCL with high-risk features (at least one of: nongerminal center B-cell [GCB] subtype by immunohistochemistry [IHC] using the Hans algorithm, Ki-67  80%, IPI of 4 or more, or c-MYC rearrangement by fluorescence in situ hybridization [FISH]), treated with rituximab, fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-HCVAD) at the John Theurer Cancer Center, NJ [10]. With a median follow-up of 25.3 months, the authors report an encouraging overall response rate of 94%, and an estimated 3-year progression-free survival (PFS) and overall survival (OS) of 79% (95% confidence interval [CI], 65–88%) and 76% (95% CI, 61–86%), respectively. Not surprisingly, R-HCVAD was moderately toxic, with all patients requiring transfusional support, and a median of 2 episodes of neutropenic fever for each patient. This is not the first report to suggest that intensification of therapy may improve outcomes in patients with highrisk DLBCL in the R-CHOP era. Wilson et al. reported an OS of 90% at 5 years in all IPI groups except the high-risk patients, from a Cancer and Leukemia Group B (CALGB) sponsored phase II study of dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA R-EPOCH) in 69 patients with de novo DLBCL [11]. Garcia-Suarez and colleagues reported an actuarial 2-year event-free survival (EFS) and OS rates of 68% and 75%, respectively, with DA R-EPOCH, a regimen incorporating a dynamic dose-escalation strategy based on hematopoietic nadir in high-risk DLBCL (age-adjusted IPI of 2 or 3) [12]. This dose-intensive approach is under