BCL-2 Translocation, High-grade B-cell Lymphoma, Lymphoma, B-Cell, MYC Translocation, Non Hodgkin Lymphoma
Conditions
Keywords
DLBCL, HGBL, BCL-2, BCL-6, double-hit, triple-hit, R-CHOP, DA-EPOCH-R, Nivolumab, PD1/PDL1 expression
Brief summary
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.
Detailed description
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.
Interventions
DRUGDA-EPOCH-R followed by Nivolumab
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
Sponsors
Stichting Hemato-Oncologie voor Volwassenen Nederland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial is designed as a prospective, multicenter, non-randomized phase II trial. All eligible patients will be registered during or after first R-CHOP, but before start of DA-EPOCH-R treatment and before start of nivolumab treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for DA-EPOCH-R induction: * High-grade B-cell lymphoma, with MYC in combination with BCL2 and/or BCL6 rearrangements as assessed by fluorescence in situ hybridization (FISH) according to the WHO 2016 classification including high-grade B-cell lymphoma with MYC and BCL2 rearrangements, transformed from previously untreated FL. * Age ≥ 18 year. * Patient started with or has received one course of full dose R-CHOP. \[Reversed R-CHOP (cyclophosphamide, vincristine and doxorubicin on day 5) is allowed; local radiation or short course (max 7 days) of steroids (max 100 mg/day) before R-CHOP is allowed. Mini-R-CHOP is not allowed\]. * World Health Organization (WHO) performance status 0-3 during or after the first R-CHOP cycle. * Ann Arbor stage II-IV at diagnosis. * 18F-FDG PET scan and contrast enhanced CT-scan performed within 21 days before start first cycle of R-CHOP. * Measurable disease: on contrast enhanced CT-scan at least 1 lesion/node with a long axis of \>1.5 cm and at least one 18F-FDG avid lesion. * Negative pregnancy test at study entry. * Patient is willing and able to use adequate contraception until 6 months post last treatment administration. * Written informed consent. * Patient is capable of giving informed consent. Inclusion criteria for Nivolumab consolidation: * Complete metabolic response on end of induction 18F-FDG PET-CT assessed with the Deauville response criteria * Patient has completed at least R-CHOP plus four cycles of DA-EPOCH-R induction treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12 months DFS from Nivolumab consolidation registration | 12 months | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 18 months Progression-Free Survival (PFS) | 18 months | 18 months PFS (defined as time from registration to disease progression, relapse or death, whichever comes first) |
| 18 months OS | 18 months | 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 |
| 12 months OSc | 12 months | 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 |
| Complete metabolic response (CMR) rate on 18F-FDG PET-CT after DA-EPOCH-R | at 18 weeks | CMR rate on 18F-FDG PET-CT after DA-EPOCH-R |
| consolidation MRD conversion | 12 months | Rate of conversion to MRD negativity during consolidation |
| predictive value of mid-treatment 18F-FDG PET-CT | 2 months | Assessment of the predictive value of mid-treatment 18F-FDG PET-CT with respect to CMR at the end of DA-EPOCH-R therapy |
| Rate of CTCAE grade >=2 toxicities | During 70 weeks treatment + 100 additional days during follow up | Rate of CTCAE grade \>=2 toxicities |
Countries
Belgium, Netherlands
Outcome results
None listed