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 low-risk 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, cyclophosphamide- fractionated, 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: non- germinal 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 high- risk 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]. García-Suárez 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 evaluation in a large randomized trial against R-CHOP sponsored by CALGB, which is nearing completion of accrual (NCT00118209). However, the study has broad eligibility not restricted to any specific risk stratum, and it is not certain that it will have adequate power to specifically address potential risk/benefit in perceived “high-risk” subsets, although laudably, there is well-integrated biological specimen collection and translation studies focused on molecular disease subtypes that will be very informative.

The reported improved outcome of R-HCVAD in comparison with other dose intensification strategies (rituximab–high-dose cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone [R-MegaCHOEP] and upfront rituximab–high-dose therapy with autologous stem cell transplant) investigated in patients with high-risk DLBCL points toward the potential contribution of fractionated delivery of high-dose alkylating agents and high-dose antimetabolites in these often rapidly proliferative lymphomas [9,13]. A significant proportion of these high- risk patients are also at a higher risk of central nervous system (CNS) disease, and this regimen provides excellent CNS penetration of methotrexate and cytarabine [14].

Improving the chemotherapy backbone is only half the answer to improving outcomes for poor-risk lymphoma. Targeted therapy with incorporation of novel agents specifically addressing the high-risk biology mediated through unique pathways (e.g. the proteasome inhibitors in nuclear factor κB [NFκB] activated DLBCL or BCL2 inhibitors such as ABT199 in double-hit lymphomas) plays a vital role in allowing us to selectively hit the malignant cell, with minimal damage to normal tissues [15,16]. Such therapies in combination with the conventional intensive chemotherapy regimens like R-HCVAD conceptually provide the most promising approach in this unfavorable subgroup of lymphomas, and should be the focus of future clinical trials. With the availability of whole genome sequencing techniques and other directed cancer diagnostics, personalized risk-adapted anti-lymphoma therapy is not far from reality.

Potential conflict of interest

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