The prognosis of patients with "high-grade B cell lymphoma with cellular myelocytomatosis (MYC) and B cell lymphoma 2 (BCL2) and/or B cell lymphoma 6 (BCL6) rearrangements" (double hit (DH)/triple hit (TH)-HGBL) with rituximab-CHOP (R-CHOP) is dismal as compared to patients with diffuse large B cell lymphoma (DLBCL) without MYC, BCL2 and/or BCL6 rearrangements. Currently, there is no other standard first line treatment for these patients. Dose Adjusted - Etoposide Prednisone Vincristine Cyclophosphamide Doxorubicin - Rituximab (DA-EPOCH-R) and nivolumab are both feasible treatments. Nivolumab may induce auto-immune reactions. DA-EPOCH-R may induce more hematological toxicity than R-CHOP. The hypothesis is that addition of nivolumab to DA-EPOCH-R will contribute to increased survival.
The dismal prognosis of DH-DLBCL patients following standard therapy with R-CHOP (overall survival at 2 years 35% for MYC+ vs 61% for MYC- patients) justifies upfront new treatment approaches. Attempts have been made to improve prognosis of DH-DLBCL patients with intensified chemotherapy schemes like DA-EPOCH-R, standard treatment of Burkitt lymphoma with high dose multi-agent chemotherapy (R-CODOX-M/R-IVAC) and autologous stem cell transplantation. These treatment schedules seem to prolong disease-free survival (DFS), but relapses do often occur and improved OS has not been achieved. The investigators hypothesize to increase the number of patients in complete remission with DA-EPOCH-R to 65% as compared to 50% for R-CHOP. DA-EPOCH-R is a well-known scheme for the treatment of patients with Burkitt Lymphoma, and is one of the treatment arms of the Hemato-Oncologie voor Volwassenen Nederland (HOVON) 127 protocol. For DH-DLBCL patients the investigators expect that it will improve the complete remission (CR) rate and prolong DFS as compared to R-CHOP as has been shown in several retrospective studies. It is also clear from these studies that relapses still occur and that OS is not improved by chemotherapy only. The investigators expect to induce deeper remission with DA-EPOCH-R providing the opportunity for nivolumab to consolidate complete remission, prolong DFS, or to induce conversion of minimal residual disease (MRD) positivity to MRD negativity. A new approach underlying this proposal is to enhance anti-tumor immune responses. Malignancies with MYC aberrations were long thought to be independent of immune responses. However, recently it was shown that MYC expressing lymphoma and leukaemia mouse and human cell lines upregulate programmed death-ligand 1 (PDL1) ("don't find me" signal) and CD47 ("don't eat me" signal) expression. Inactivation of MYC enhanced tumour immune responses in vivo in mice. Moreover, a subset of DLBCL does express PDL1. No correlation with MYC rearrangements or protein expression has been described in these studies; however, these data suggest that tumours with MYC overexpression may be especially vulnerable to treatment with immune check point inhibitors, providing the rationale for treatment with nivolumab.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
97
5 induction cycles of DA-EPOCH-R protocol, for patient with Deauville imaging response criteria proven complete metabolic response followed with one year Nivolumab consolidation therapy
BE-Antwerpen-ZNASTUIVENBERG
Antwerp, Belgium
BE-Leuven-UZLEUVEN
Leuven, Belgium
NL-Den Bosch-JBZ
's-Hertogenbosch, Netherlands
NL-Almere-FLEVOZIEKENHUIS
Almere Stad, Netherlands
NL-Amersfoort-MEANDERMC
Amersfoort, Netherlands
NL-Amsterdam-AMC
Amsterdam, Netherlands
NL-Amsterdam-VUMC
Amsterdam, Netherlands
NL-Eindhoven-MAXIMAMC
Eindhoven, Netherlands
NL-Enschede-MST
Enschede, Netherlands
NL-Goes-ADRZ
Goes, Netherlands
...and 14 more locations
12 months DFS from Nivolumab consolidation registration
12 months DFS (defined as time from registration for consolidation to disease relapse or death, whichever comes first) of patients in CMR as assessed by end of DA-EPOCH-R treatment 18F-Fludeoxyglucose Positron Emission Tomography- Computed Tomography (18F-FDG PET-CT)
Time frame: 12 months
Complete metabolic response (CMR) rate on 18F-FDG PET-CT after DA-EPOCH-R
CMR rate on 18F-FDG PET-CT after DA-EPOCH-R
Time frame: at 18 weeks
18 months Progression-Free Survival (PFS)
18 months PFS (defined as time from registration to disease progression, relapse or death, whichever comes first)
Time frame: 18 months
18 months OS
18 months OS (defined as time from registration until death from any cause; patients still alive or lost to follow up are censored at the date they were last known to be alive) of all patients
Time frame: 18 months
12 months OSc
12 months overall survival under consolidation (OSc), defined as time from registration for consolidation until death from any cause. Patients still alive or lost to follow up are censored at the date they were last known to be alive
Time frame: 12 months
Rate of CTCAE grade >=2 toxicities
Rate of CTCAE grade \>=2 toxicities
Time frame: During 70 weeks treatment + 100 additional days during follow up
consolidation MRD conversion
Rate of conversion to MRD negativity during consolidation
Time frame: 12 months
predictive value of mid-treatment 18F-FDG PET-CT
Assessment of the predictive value of mid-treatment 18F-FDG PET-CT with respect to CMR at the end of DA-EPOCH-R therapy
Time frame: 2 months
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