Primary Mediastinal Large B-Cell Lymphoma: first-line therapy – first versus third generation chemotherapy and the addition of rituximab

On 14^th January 2017, Ferreri and Martelli published a review article on Primary Mediastinal Large B-Cell Lymphoma (PMBCL) in Critical Reviews in Oncology and Hematology.¹

First-line treatment is crucial in managing patients with PMBCL. Current salvage regimens are inefficient and so it is of utmost importance that first-line treatment results in cure, while minimizing the risk of long-term morbidity for patients.

Key Highlights:

Chemotherapy in the pre-rituximab era

• Retrospective and prospective studies suggested that superior outcomes could result from intensive third generation therapies
• Many European centers suggest that V/MACOP-B (etoposide/methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) is superior to CHOP, which is primarily used by investigators in America
• A retrospective multicenter analysis in 138 Italian patients with PMBCL found that CR in patients treated with CHOP (n=43) and MACOP-B/VACOP-B (n=95) was 51% and 80%, respectively²
• A multinational retrospective IELSG study found CR rates were similar between treatment naïve patients treated with first-generation regimens (CHOP and CHOP-like; n=105), third-generation regimens (MACOP-B, VACOP-B; n=277), and high-dose chemotherapy regimens (sequential and autologous bone marrow transplantation; n=44) ³
  • However, relapse rate at 3-yrs was significantly less in third-generation group (12% vs 23%; P = 0.02)
  • Projected 10-yr OS and PFS in third-generation compared to first-generation treated patients were 71% vs 44% (P = 0.0001) and 67% vs 34% (P = 0.0003), respectively

Chemotherapy in the post-rituximab era

• Adding rituximab to chemotherapy has been reported to significantly improve CR rates and survival for early and advanced DLBCL; it is hypothesized this effect will also occur in PMBCL
• In a BCCA population-based retrospective study of 153 PMBCL patients, 5-yr OS was significantly higher in patients treated with MACOP-B/VACOP-B (87%) than patients treated with CHOP (71%; P = 0.048)⁴
• The MiNT study in DLBCL included a subset of 87 PMBCL patients and found those treated with R-CHOP/CHOP-like regimen had higher CR (84% vs 54%; P = 0.015), lower early progression (2.5% vs 24%; P < 0.001), improved 3-yr EFS (78% vs 52%; P = 0.012), and similar OS (89% vs 78%; P = 0.158) compared to patients who were administered CHOP/CHOP-like therapy without rituximab⁵
• A retrospective study of 45 treatment naïve patients in Italy found that the projected 5-yr OS and Relapse Free Survival (RFS) were 80% and 88%, respectively, when treated with V-MACOP-B, rituximab and mediastinal RT. No significant difference was found when comparing these rates to historical data of V/MACOP-B alone
• A high primary induction failure (21%) with R-CHOP was found in a retrospective analysis of 63 patients with PMBCL; hypothesized to be due to the poor prognostic features of the patient series⁶
• In a phase 2 NCI study of 51 treatment naïve PMBCL patients, rituximab plus DA-EPOCH without radiotherapy achieved a CR in 48/51 (94%) and 3-yr OS and EFS of 97% and 93%, respectively. Moreover, after treatment only three patients showed evidence of disease; persistent focal disease (n=2) and disease progression (n=1). Results confirmed in a retrospective Stanford cohort of 16 PMBCL patients treated with DA-EPOCH-R; after median follow-up of 37 months, 100% alive and event-free⁷
• In a study of 15 pediatric patients (median age 16yrs) treated with DA-EPOCH-R, an OS of 62% was achieved⁸

Ferreri and Martelli state that it can be difficult comparing the advantages of different treatment protocols, and to explain differences achieved in CR and survival rates using similar protocols for phase 2 trials. The authors of the review also highlight that the results of the two retrospective studies in the pre-rituximab era indicate that third-generation chemotherapy regimens are superior to first generation regimens. The authors of the review also conclude that superior results are achieved when rituximab is added to chemotherapy. They hypothesize that rituximab removes the distinction between chemotherapy regimens. Lastly, the Ferreri and Martelli state that the encouraging results of DA-EPOCH-R without RT require validation in larger multicentric trials

References:

1. Ferreri & Martelli M. Primary mediastinal large B-cell lymphoma. Critical Reviews in Oncology and Hematology. 2017 Jan 14. http://dx.doi.org/10.1016/j.critrevonc.2017.01.009. [Epub ahead of print].
2. Todeschini G. et al. Primary mediastinal large B-cell lymphoma (PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B. British Journal of Cancer. 2004 Jan 26; 90(2): 372–6.
3. Zinzani P.L. et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica. 2002; 87(12): 1258–64.
4. Savage K. et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Annals of Oncology. 2006 Jan; 17(1): 123–30.
5. Pfreundschuh M. et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an openlabel randomised study of the MabThera International Trial (MInT) Group. Lancet Oncology. 2011 Oct; 12(11): 1013–22.
6. Soumerai J.D. et al. Treatment of primary mediastinal B-cell lymphoma with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone is associated with a high rate of primary refractory disease. Leukemia & Lymphoma. 2014 Mar; 55(3): 538–43.
7. Dunleavy K. et al. Dose-adjusted EPOCH-Rituximab therapy in primary mediastinal B-cell lymphoma. New England Journal of Medicine. 2013; 368(15): 1408–16.
8. Woessmann W. et al. Therapy in primary mediastinal B-cell lymphoma. New England Journal of Medicine. 2013 Jul 18; 369(3): 282.

Abstract:

Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct clinical and biological disease from other types of DLBCL. It is more frequent in young female and constitutes 6%-10% of all DLBCL. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis. Molecular analysis shows it to be a distinct entity from other DLBCL. Rituximab CHOP/MACOP-B-like regimens followed by with mediastinal radiotherapy (RT) were associated with a 5-years PFS of 75%-85%. More intensive regimens, as DA-EPOCH-R without mediastinal RT, have shown very promising results, but this therapeutic advance needs to be confirmed in further prospective trials. The role of consolidative mediastinal RT should be still better assess in prospective comparative studies. PET-CT scan is a powerful tool to define the real quality of response and it is hoped that future prospective trials may allow its role in the de-escalation of mediastinal RT.