Primair mediastinaal B-cel lymfoom
Algemeen
The World Health Organization now recognizes primary mediastinal B-cell lymphoma (PMBCL) as a unique clinical and biologic entity. PMBCL is distinct from other B-cell non-Hodgkin lymphoma subtypes and has features that overlap with classical Hodgkin lymphoma, including a peak incidence in the adolescent and young adult population, mediastinal presentation of disease, and molecular alterations in JAK2 and programmed death ligands. Because PMBCL is rare, there are few prospective clinical trials to guide therapy, resulting in no single standard of care
PMBCL is a rare subtype of non-Hodgkin lymphoma that predominantly occurs in adolescents and young adults. The diagnosis of PMBCL can present a challenge because the histologic features overlap with nodular sclerosing Hodgkin lymphoma. The malignant cells express B-cell markers (CD19, CD20, CD22, CD79a) but not surface immunoglobulin. CD30 is expression is weak (vs strong in nodular sclerosing Hodgkin lymphoma), and CD15 is negative. B-cell transcription factors are often positive, including PAX5, OCT2, BCL6, and BOB1.
Clinically, PMBCL typically presents as a bulky mediastinal mass. Local infiltration to the lung, chest wall, pleura, or pericardium is common. Unlike other non-Hodgkin lymphoma (NHL) subtypes, PMBCL has a female predominance.
Overlap tussen Hogdkin lymfoom, PMBCL en gray zone lymfoom
Behandeling
Retrospective studies in the pre-rituximab era suggest that outcomes with V/MACOP-B are superior to CHOP; however, the addition of rituximab to CHOP may mitigate this effect. The largest comparison of CHOP and V/MACOP-B ( (etoposide or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) was a retrospective series that observed superior outcome among patients treated with a MACOP-B–like regimen over a CHOP-like regimen (10-year survival, 67% vs 35%; P = .0003). However, the addition of rituximab to CHOP has likely improved outcomes, making the distinction between R-CHOP and V/MACOP-B less clear. Although there are no randomized trials of R-CHOP vs CHOP specifically in PMBCL, data from prospective and retrospective series suggest an advantage to R-CHOP. A subgroup analysis of the Mabthera International Trial compared patients with PMBCL who were treated with CHOP-like chemotherapy with or without rituximab.
Among 86 patients, the 3-year event-free survival (EFS) in the R-CHOP and CHOP groups was 78% and 52%, respectively (P = .012). Similar findings were observed in a large retrospective series (5-year PFS with R-CHOP and historic CHOP was 81% vs 47%, P < .0001). Rituximab has also been added to V/MACOP-B, but the benefit in this setting is less clear. Zinzani et al reported a 5-year PFS of 84% among 45 patients treated with rituximab + V/MACOP-B (R-V/MACOP-B), which was not statistically different from historic controls without rituximab. Comparisons among CHOP, R-CHOP, and R-V/MACOP-B have also been performed in retrospective studies. The British Columbia Cancer Agency (BCCA) reported their 5-year overall survival (OS) with V/MACOP-B, CHOP-like treatment, and R-CHOP to be 87%, 71%, and 82% respectively. In pairwise comparisons, the only 2 groups that were significantly different were V/MACOP-B and CHOP, suggesting that V/MACOP-B is superior to CHOP but not R-CHOP. In conclusion, R-CHOP and (R-)V/MACOP-B result in favorable outcomes for the majority of patients; however, they are usually given in combination with radiotherapy.
More recently, dose-intensive regimens without radiation have been investigated. Reducing the exposure to radiation is of particular interest in the AYA population given the risk for late effects, including breast cancer and cardiovascular disease. The National Cancer Institute (NCI) recently conducted a phase 2 trial of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) without radiation in PMBCL. A 5-year EFS of 93% was observed among 51 patients. Similar results were observed in a single-center retrospective series of 16 patients, with no events reported. Our group recently conducted a multicenter retrospective study of DA-EPOCH-R in adults and children with PMBCL. Among 118 adults, the 3-year EFS was 87%. Of note, in our retrospective series, 15% of patients received consolidative radiotherapy. Based on encouraging results with DA-EPOCH-R, many centers in the United States consider this to be the standard of care for PMBCL; however, prospective multicenter studies are needed to validate the existing data.
R/R PMBCL
Review Ann Transl Med 2020 Aug
Overall, 20% of subjects with PMBCL will fail first-line therapy and more than half of them will also be refractory to second-line chemotherapy, and therefore an unmet clinical need exists for this setting of patients.
Checkpoint inhibitors in R/R PMBCL
Review Ann Transl Med 2020 Aug
CPis are a new revolutionary class of drugs, which act on PD-L1. The activation of PD-1/PD-L1 signaling let tumor cells evade the antigen-specific T-cell immunologic response. Therefore, blocking this checkpoint signaling may represent an effective cancer therapy. Pembrolizumab and nivolumab, the two leading drugs of the first CPi generation, have demonstrated substantial activity in several solid and hematological tumors and are now approved for the treatment of several malignancies.
Allogenic SCT in R/R PMBCL
Herrera et al. Biology of Blood and Marrow Transplantation 2019
N=28 patiënten met PMBCL.
At the time of alloHSCT, 1 patient (4%) was in complete response (CR), 21 patients (75%) were in partial response (PR), and 6 (21%) were refractory to pretransplantation therapy.
Conditionering: 86% received reduced-intensity conditioning.
Hele groep: 5-year PFS 34%, 5-y OS 45%. Non-relapse mortality 32% relapse mortality 33%
In refractaire ptn: 2y PFS en OS 0%
In responsieve (CR/PR) groep: 5y PFS 44%.
Take home: alleen bij tenminste PR door gaan voor allogene SCT, PFS van 44%.
N=33 patiënten met R/R PMBCL, gemiddeld reeds 3 behandellijnen voorafgaand aan allogene SCT.
At time of transplant, 50% of patients were in CR, 40% in PR, and 10% had a progressive disease.
Conditioning regimen was reduced intensity regimen in 63%. Stem cell source was PBSC in 88%. Donors were sibling in 42% or matched related donor in 39%. An alternative donor was chosen in 18%. GVHD prophylaxis included antithymocyte globulin in 61%, and calcineurin inhibitor in 97%.
Median follow up was 6y.
Hele groep: 2y OS 48%, DFS 60%, NRM 18%, and cumulative incidence of relapse 34%
Patients with progressive disease at transplantation had worst 2y PFS and OS (PFS: HR: 6.12, 95%CI: 1.32-28.31, p=0.02 and OS: HR: 7.04, 95%CI: 1.52-32.75, p=0.013).