Dose adjusted (DA) chemotherapy in the form of DA-EPOCH was first explored in the pre-rituximab era in an effort to improve survival in aggressive non-Hodgkin lymphomas by utilising the principles of dose intensification.r At this time, CHOP chemotherapy was the standard of care, and resulted in long term cure in only about 30 - 40% of patients.
Because of both its single agent action and synergy, etoposide was added to the other drugs from the CHOP regimen, and a regimen involving infusional etoposide, vincristine and doxorubicin plus bolus cyclophosphamide was developed. Dose modifications were made in subsequent cycles based on toxicity and nadir neutrophil counts. A phase II multi-institutional study in 50 patients showed excellent results of 70% progression free survival (PFS) and 73% overall survival (OS) at 62 months.r
It should be noted that the most notable evidence for this regimen comes from a single centre. DA-R-EPOCH was prospectively compared to R-CHOP for unselected DLBCL patients in a CALGB trial.r This showed more early discontinuations in the DA-R-EPOCH arm, with no difference in survival (85%) in both arms.
Currently, some of the main areas of interest include: (1) improvement of cure rates in poorer prognosis disease, (2) improving outcomes in primary mediastinal B cell lymphoma (3) the treatment of Burkitt lymphoma (4) the treatment of aggressive non-hodgkin lymphomas in HIV-infected individuals.
High grade B-cell lymphoma (including DLBCL) with MYC and BCL-2 or BCL-6 translocations (WHO 2016)
Jermann et alr examined DA-R-EPOCH in 50 patients (from 5 institutions in Switzerland) with relapsed or refractory diffuse large B cell lymphoma or mantle cell lymphoma. They found an overall response rate (ORR) of 68%, with 28% complete response (CR) and 40% partial response (PR), at 33 months follow up.
Garcia-Suarez et alr studied 33 patients with poor prognosis previously untreated diffuse large B cell lymphoma who received DA-R-EPOCH. All patients had at least 2 adverse prognostic factors on the IPI (International Prognostic Index). 24% had bulky disease. ORR was 97%, with CR 81% and 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 down regulate bcl6 expression.
Wilson et alr looked at 69 patients with previously untreated DLBCL, who received DA-R-EPOCH, and compared outcomes between different prognostic groups according to IPI and to germinal centre (GC) vs non-GC phenotype. High risk by IPI had 54% event free survival (EFS) at 62 months compared with 92% and 87% in the high-intermediate and low-intermediate groups respectively. EFS was 94% vs 58% for GC vs non-GC phenotype respectively.
Outcomes in Germinal centre B cell (GCB) type DLBCL over two trials show 100% EFS at 5 years in HIV negative GCB DLBCL,r and 95% EFS at 5 years in HIV positive GCB DLBCL. A modification of DA-EPOCH regime substituting high dose dexamethasone for prednisolone, and administering cycles at 14 day intervals, also achieved encouraging PFS and OS rates, especially in high risk disease.r
Friedbergr summarises the treatment of Double and Triple Hit Lymphomas 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. It is felt that there will be insufficient numbers of Double/Triple Hit Lymphomas for post-hoc subset analysis in the CALGB study (Clinicaltrials.gov NCT00118209) to definitively state superiority of DA-R-EPOCH over R-CHOP for unselected DLBCL, however, there are some datar to suggest superior response rates (improved PFS) of “intensive” immunochemotheapy regimens over R-CHOP. This 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.
Oki et alrhave published the largest case series of Double Hit Lymphoma. This included 129 patients with DHL confirmed by FISH and retrospective analysis was undertaken. Similar to the Petrichrdata, 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 therefore be considered. CNS relapse occurred in 10-15%, highlighting the need for CNS prophylaxis with DHL.
© British Journal of Haematology 2014
Primary mediastinal diffuse large B cell lymphoma.
A recent studyr 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.
If these results are repeatable, it represents a significant advance in that radiotherapy can be safely omitted without compromising cure rates for the majority of patients, particularly given that most patients are young women (median age 30 years, 59% female). Furthermore, Martelli et alr showed that patients who achieve a PET CR after initial anthracycline/Rituximab containing regimen have a better survival compared to those who do not. Using liver uptake as a cut-off, they demonstrated 5-year PFS of 99% versus 68% (P<.001) and 5-year OS of 100% versus 83%. These data suggest that some patients may not require radiotherapy.
A randomized, open label, multi-centre 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
In a phase II single arm study of 19 HIV negative patients with Burkitt lymphoma, DA-R-EPOCH achieved 95% freedom from progression and 100% EFS.r A modified (reduced intensity chemotherapy with double-dose Rituximab) "short course" regimen was given to 11 HIV patients, achieving 100% FFP and 90% OS. Patients received 2 cycles following CR, for a total of 6-8 cycles. It should be noted that this study involved small numbers of patients with CNS disease, and these patients received IT methotrexate.
Aggressive non-hodgkin lymphoma in HIV infected individuals.
A recent pooled analysis of aggressive lymphomas in the HIV population compared treatment using DA-R-EPOCH with R-CHOP,r and found improved EFS and OS with DA-R-EPOCH (hazard ratios 0.4 [95% CI 0.23-0.69] and 0.38 [95%CI 0.21-0.69] respectively). CD4 counts of < 50/µL or aaIPI (age adjusted International Prognostic Index) were markers of poor outcome.
Earlier studiesr evaluated DA-EPOCH in this setting. This prospective single arm trial evaluated DA-EPOCH in 39 patients with newly diagnosed AIDS-related lymphoma (80% DLBCL). ART was deferred until completion of chemotherapy. Results showed CR in 74% and at median follow-up 53 months, estimated PFS was 73% and OS 60%. 5 year OS for patients with CD4 counts >100/microL and ≤100/micro were 87 and 16% respectively.
While there is clear evidence for activity of this regimen in aggressive subtypes of Non-Hodgkin Lymphoma, the role of DA-R-EPOCH remains unclear. A search of the literature did not find strong evidence to support the use of DA-R-EPOCH over alternative options in the treatment of NHL, however the use of R-CHOP alone for "High grade B-cell lymphoma with translocations involving myc and bcl-2 or bcl-6" (per WHO Revised classification 2016) remains associated with a poor outcome and remains an area of unmet need in DLBCL management. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II studies in the table below, and published expert opinion.
Published studies to date have only compared to historical controls or to other trials, but these have shown at least comparable efficacy.
© British Journal of Haematology 2007
© Haematologica 2012
DA-R-EPOCH is generally well tolerated, with the major toxicities being neutropenia, febrile neutropenia and thrombocytopenia. Toxic deaths have been rarely reported, and secondary AML has also been rarely reported, usually in pre-treated patients.r
© British Journal of Haematology 2007