High-grade B-cell lymphoma (including DLBCL) with MYC and BCL-2 or BCL-6 translocations (WHO 2016)
Garcia-Suarez et al.r studied 33 patients with poor prognosis previously untreated DLBCL who received DA-R-EPOCH. All patients had at least 2 adverse prognostic factors on the IPI (International Prognostic Index). 24% had bulky disease. Overall response rate (ORR) was 97%, with CR 81% and partial response (PR) 16%. Long-term follow up of this study demonstrated 10-year EFS and OS rates of 47.8% and 63.6% respectively.r Patients with bcl6 rearrangement had an OS of 100%, with the authors postulating that the addition of etoposide may downregulate bcl6 expression.
Friedbergr summarises the treatment of Double and Triple Hit Lymphomas (DHL/THL) in this manuscript. The utility of “aggressive” chemoimmunotherapy regimens is broadly supported in view of the poor outcomes of such patients with R-CHOP alone. There were insufficient numbers of DHL/THLs for post-hoc subset analysis in the CALGB study to assess superiority of DA-R-EPOCH over R-CHOP for unselected DLBCL,r however, there are some datar to suggest superior response rates (improved PFS) of “intensive” immunochemotherapy regimens over R-CHOP. These retrospective, pooled data appears to support a more intensive regimen, however, utility of one (DA-R-EPOCH, HyperCVAD/MA, R-CODOX-M/IVAC) regimen over others is not suggested, and difference in results may be attributed to other issues studied, e.g. patient population. Consolidation with AutoSCT appears not to improve survival in the de novo setting.
Dunleavy et al. have recently published a Phase II, multicentre prospective study of DA-R-EPOCH in 53 patients with MYC rearranged DLBCL.r Of these, 19 patients had sole rearrangement of MYC, and 24 had additional rearrangement of BCL2, BCL6 or both. There were 3 treatment-related deaths. The 48-month EFS and OS were 71% and 76.7% respectively.
Oki et al.r.have published the largest case series of DHL. This included retrospective analysis of 129 patients with DHL confirmed by FISH. Similar to the Petrichr data, there is a suggestion that DA-R-EPOCH is a superior regimen to R-CHOP for DHL, certainly with respect to EFS, (see below) however, this is retrospective data, and relevant biases need to be therefore considered. CNS relapse occurred in 10 - 15%, highlighting the need for CNS prophylaxis with DHL.
Howlett et al. published a systematic review and meta-analysis of the use of R-CHOP, DA-R-EPOCH and intensive dose chemotherapy protocols such as CODOX-M/R-IVAC, R-HyperCVAD/R-M/C. They included 394 patients from 11 studies in the analysis of which 180 received R-CHOP, 91 received DA-R-EPOCH and 123 received dose-intensive protocols. The median PFS for the groups was 12.1, 22.2 and 18.9 months respectively, with a significant improvement in PFS with DA-R-EPOCH compared to R-CHOP, however, there was no significant improvement in OS.r
Of note, on immunohistochemistry, tumours may demonstrate high levels of expression of MYC, BCL-6 and BCL-2. While in many cases this corresponds to findings of gene rearrangements on FISH analysis, this is not always the case. Whether the use of dose escalation in these so-called double- or triple-expressors also confers an advantage is the source of interest, however the studies to date have failed to clearly demonstrate an advantage, and recommendations therefore remain to dose escalate in the case demonstrated MYC, BCL2 and/or BCL6 rearrangements only.
CNS disease poses a particular challenge in patients with DLBCL, including patients with CNS involvement at the time of presentation, as well as the risk of CNS relapse. Patients who experience CNS relapse have very poor prognosis, however, the risk of CNS relapse is less than that seen in other types of high-grade lymphoma such as Burkitt Lymphoma.r Higher risk patients include those with a greater burden of extranodal disease, increased age, high LDH and unfavourable tumour biology, including double and triple hit disease.r Of note, DA-R-EPOCH does not have good CNS penetration, and so patients with CNS involvement, or deemed to be at high risk of CNS involvement, require additional measures to be taken. Several strategies have been explored, including use of intrathecal methotrexate incorporated into the DA-R-EPOCH protocol, and use of high dose methotrexate given in between cycles.rrr
When considering addition of CNS prophylaxis, the toxicity of the approaches needs to be considered, particularly for patients with other co-morbidities, such as baseline renal dysfunction, who may be at increased risk of toxicity due to reduced clearance. Furthermore, protocols incorporating high dose methotrexate are usually given as an inpatient and therefore require planned admissions for administration, hydration and monitoring of clearance. It is of note that investigations into the use of intrathecal methotrexate have shown variability in CSF concentrations, and appear to have sufficient dose concentration in the leptomeninges, but do not appear to have sufficient penetration for parenchymal disease. This is of particular importance given that, in the rituximab era, the majority of CNS relapses are intraparenchymal.rr Conversely, use of systemic methotrexate requires a sufficient dose concentration to ensure appropriate CNS penetration, requiring rapid infusions at sufficient doses.r
There is a paucity of prospective randomised control trials looking at CNS prophylaxis in DLBCL, particularly looking at IT methotrexate vs systemic therapy. Several retrospective and prospective studies have been done looking at various strategies, although many of these used combined modalities.
CNS prophylaxis with high dose methotrexate is supported by several studies, showing decreased risk of CNS relapse albeit at the expense of increased toxicity. Ferreri et al. showed a risk of relapse in high-risk patients treated with high dose methotrexate of 2.5% vs 12% in those either not receiving CNS prophylaxis, or receiving intrathecal therapy alone.r There is minimal evidence to suggest safety of DA-R-EPOCH with intravenous methotrexate to date. A small case series of 5 patients looked at the use of a combination of DA-R-EPOCH and high dose methotrexate with no treatment-related deaths.r
(A) Progression-free and (B) overall survival curves estimated from the meta-analysis r
© British Journal of Haematology 2015
Primary mediastinal diffuse large B cell lymphoma.
A single-arm, Phase II study showed excellent outcomes using DA-R-EPOCH for 51 patients with newly diagnosed primary mediastinal B cell lymphoma, with the aim of being able to omit adjuvant mediastinal radiotherapy. OS was 97% at 5 years, with 1 death due to secondary acute myeloid leukaemia. EFS was 93%. Only 2 patients did not achieve CR, and these subsequently entered CR after receiving radiotherapy.r
A subsequent multicentre, retrospective analysis with propensity scoring of 56 patients receiving R-CHOP and 76 receiving DA-R-EPOCH revealed similar 2-year OS (89% vs 91%). Fewer patients receiving DA-R-EPOCH were given consolidative radiotherapy (13.2% versus 58.9% for R-CHOP, p<0.001).r
A randomised, open-label, multicentre trial to assess the role of radiotherapy in patients achieving a PET CR post at least 6 cycles of chemoimmunotherapy (R-CHOP, DA-R-EPOCH and others) is ongoing (Clinicaltrials.gov NCT01599559). The potential to omit radiotherapy is appealing, particularly in younger female patients.
Treatment of Burkitt lymphoma
DA-R-EPOCH has been utilised in the treatment of Burkitt lymphoma in both HIV positive and HIV negative patients. Compared to many other Burkitt lymphoma protocols, DA-R-EPOCH is less toxic and shows excellent response rates regardless of HIV status, age or disseminated disease. A single-arm Phase II study by Dunleavy et al. of 19 HIV negative patients using DA-R-EPOCH demonstrated 95% FFP and 100% EFS.r
CNS disease is of concern in Burkitt given a high risk of CNS relapse, even in those with negative findings at time of diagnosis. There have been various strategies for managing this. The Roschewski trial did not use CNS prophylaxis in patients who were classified as having low-risk disease, and no patients had progression. Other strategies have included the use of CNS prophylaxis with IT methotrexate at varying frequencies, however, this remains an area requiring more study.r
PFS, OS and PFS by subset in the Phase III Intergroup Trial Alliance/CALGB 50303r
@Journal of Clinical Oncology 2019