Journal of Clinical Pathways is pleased to present a new section called “CME Corner,” which will highlight, when available, relevant continuing medical education (CME) opportunities deemed to be of use to readers. Articles will include an overview of a specific area where key opinion leaders have determined there to be an educational need, and a link to the available CME program will be provided.
The CME program titled "Advances in the Management of Chronic Lymphocytic Leukemia and Other B-Cell Lymphomas" is currently available on this topic until December 22, 2018.
Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed lymphoma in the United States, representing approximately one-third of lymphoid malignancies seen in clinical practice.1 The goal of treating DLBCL is to achieve a cure. The backbone of treatment is multiagent chemotherapy, but the number of cycles and whether radiation is added to the treatment regimen depends on stage, performance status (PS), comorbidities, and patients’ goals and beliefs.
Much progress has been gained in prognosticating DLBCL. We now know that cell of origin (COO) divides the disease into germinal center type (GCB) and non-germinal center (non-GCB or ABC), with the former having better overall survival (OS) and progression-free survival (PFS).2 COO is commonly identified using the Hans algorithm by immunohistochemistry, where the GCB subtype is CD10 positive while non-GCB is CD10- and MUM+.3 The more sophisticated gene expression profiling (GEP) identifies COO more accurately but is not always available in smaller community practices.4 For almost 3 decades, the International Prognostic Index (IPI) has helped practitioners differentiate good from poor prognosis patients. The IPI utilizes 5 readily available clinical factors (ie, age > 60 years, PS 3 or 4, high lactate dehydrogenase [LDH], advanced stage, and more than 1 extra-nodal site) where patients get 1 point for each adverse prognostic factor.5 Patients are then categorized as low (0-1 factor), low-intermediate (2 factors), high-intermediate (3 factors), and high-risk (4-5 factors) with stark OS differences.5
A recent analysis by the National Comprehensive Cancer Network (NCCN) led to the development of the NCCN-IPI where patients older than 75 years get 3 points, but those > 60 but < 75 years get 2 points.6 Also, patients with LDH levels more than 3 times the normal level get 2 points while those with 1-3 times the normal level get 1 point. The NCCN-IPI appears more robust than the IPI, but it remains unclear how often it is being incorporated in clinical practice.6 We also know that approximately 8% to 15% of DLBCL patients overexpress the c-MYC oncoprotein, which carries an adverse prognosis.7 In smaller subsets, DLBCL patients can carry the translocation of MYC and BCL2, both detected using fluorescence in-situ hybridization.8 Interestingly, GEP in DLBCL-MYC+ patients is significantly different than Burkitt lymphoma patients who carry the same exact oncoprotein. These double-hit lymphoma (DHL) patients have consistently shown worse OS and PFS when compared with other DLBCL subtypes, arguing for exploring alternative treatment regimens. 9,10
While the above highlights advances in how we prognosticate DLBCL, progress in how we treat the disease has not been significant. CHOP chemotherapy has been the standard of care in DLBCL for over 3 decades. Outcomes were significantly improved with the addition of rituximab in the early 2000s leading to R-CHOP being the standard of care for DLBCL.11 Various attempts to improve on R-CHOP took place in the preceding years, but none of them provided patients with better OS. Dose-dense R-CHOP given every 14 days showed equivalent results to standard R-CHOP every 21-days.12 Replacing rituximab with the novel anti-CD20 antibody obintuzumab did not improve OS.13 The dose-intensified regimen dose-adjusted EPOCH-R was equivalent to R-CHOP at a median follow-up of 5 years.14 Consolidated autologous stem cell transplantation (HSCT) after R-CHOP is not generally recommended.15 Maintenance lenalidomide after R-CHOP improved PFS but no OS benefit was detected.16
Despite these discouraging results, recognizing the various subtypes of DLBCL based on better prognostication and as reflected in the recent World Health Organization classification, suggest that some patients could benefit from alternative regimen. To that end, primary mediastinal large cell lymphoma (PMBCL) patients are often treated with DA-EPOCH-R to avoid radiatoin therapy (RT) to the mediastinum.17 RT to that region could lead to premature atherosclerotic disease and renders patients more prone to secondary malignancies. Ongoing studies are exploring whether non-GCB patients would benefit from the addition of lenalidomide to R-CHOP.18 Retrospective studies have demonstrated that DHL patients benefit from dose intensification such as DA-EPOCH-R or another Burkitt-like regimen.9,10 When treated with these intensified programs, patients have better outcomes compared with R-CHOP and conventional therapies. However, there remains some controversy on how best to treat patients who are double expressors. These are patients who overexpress the MYC and BCL2 proteins but do not carry either translocation that correspond to the protein.1 Whether dose-intensification is better than standard R-CHOP is unknown, but most agree that R-CHOP might suffice in this setting.19 Regardless of the treatment regimen and despite the aggressive nature of DHL, retrospective observations failed to show a survival benefit for consolidative HSCT.
Another challenging situation is older patients who are diagnosed with DLBCL. Ideally, pre-phase chemotherapy is given to improve on PS of these patients prior to administering chemotherapy.20 Most argue not to use age as a defining factor for treatment selection but rather perform a geriatric assessment to determine patients’ ability to tolerate treatment. Attenuated regimens such as the R-mini-CHOP have become popular after a French study showed promising results in DLBCL patients > 80 years.21
In summary, DLBCL is a very common lymphoma seen in clinical practice and, for the most part, R-CHOP given every 21 days remains the standard of care for most patients. DHL and PMBCL are better treated with DA-EPOCH-R. Attention to how older patients should be treated is essential to balance goals of therapy with morbidity of treatment.
The CME program titled "Advances in the Management of Chronic Lymphocytic Leukemia and Other B-Cell Lymphomas" is currently available on this topic until December 22, 2018.
References
1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.
2. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-511.
3. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
4. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-2856.
5. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329(14):987-994.
6. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-842.
7. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360-3365.
8. Cheah CY, Oki Y, Westin JR, Turturro F. A clinician’s guide to double hit lymphomas. Br J Haematol. 2015;168(6):784-795.
9. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891-901.
10. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354-2361.
11. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242.
12. Cunningham D, Smith P, Mouncey P, et al. R-CHOP14 versus R-CHOP21: Result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. J Clin Oncol 2011;29.
13. Vitolo U, Trneny M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529-3537.
14. Wilson W, sin-Ho J, Pitcher B, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. Blood. 2016;128.
15. Stiff PJ, Unger JM, Cook JR, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 2013;369(18):1681-1690.
16. Thieblemont C, Tilly H, Gomes da Silva M, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017;35(22):2473-2481.
17. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408-1416.
18. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251-257.
19. Zelenetz AD. Guidelines for NHL: updates to the management of diffuse large B-cell lymphoma and new guidelines for primary cutaneous CD30+ T-cell lymphoproliferative disorders and T-cell large granular lymphocytic leukemia. J Natl Compr Canc Netw. 2014;12(5 suppl):797-800.
20. Latta S, Cygan PH, Fried W, Nabhan C. Diffuse large B-cell non-Hodgkin lymphoma in the very elderly: challenges and solutions. Oncology (Williston Park). 2013;27(2):126-130, 132-126, 138.
21. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460-468
