DA-EPOCH-R Induction Followed by Nivolumab Consolidation in Newly Diagnosed MYC BCL2 and/or BCL6 Rearranged HGBL

  • STATUS
    Recruiting
  • End date
    Aug 26, 2026
  • participants needed
    97
  • sponsor
    Stichting Hemato-Oncologie voor Volwassenen Nederland
Updated on 26 January 2021
Investigator
M. ED Chamuleau, MD PhD
Primary Contact
MST (0.0 mi away) Contact
+25 other location
cyclophosphamide
rituximab
vincristine
prednisone
measurable disease
etoposide
consolidation therapy
doxorubicin
nivolumab
diffuse large b-cell lymphoma
b-cell lymphoma
avid
r-chop
high grade b-cell lymphoma
fludeoxyglucose f-18
chop regimen
r-chop regimen

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.

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.

Details
Condition Lymphoma, Lymphoma, B-Cell Lymphoma, Non-Hodgkin's Lymphoma, Lymphoma, B-Cell, High-grade B-cell Lymphoma, MYC Translocation, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, High-grade B-cell Lymphoma, BCL-2 Translocation, non-hodgkin's lymphoma (nhl), b-cell lymphomas, b cell lymphomas, b cell lymphoma, High-grade B-cell Lymphoma, BCL-2 Translocation
Treatment DA-EPOCH-R followed by Nivolumab
Clinical Study IdentifierNCT03620578
SponsorStichting Hemato-Oncologie voor Volwassenen Nederland
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

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
F-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

Exclusion Criteria

Exclusion Criteria for DA-EPOCH-R induction
All histopathological diagnoses other than DH/TH-HGBL (like testicular large B-cell lymphoma or primary mediastinal B-cell lymphoma) according to WHO 2016 classification
Known history of indolent lymphoma previously treated with immunochemotherapy
Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration). Creatinine clearance (CrCl) may be calculated by Cockcroft -Gault formula: CrCl = (140
age [in years]) x weight [kg] (x 0.85 for females) (0.815 x serum creatinine [mol/L])
Inadequate hepatic function: bilirubin > 3 times upper limit of normal (ULN) (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin
Inadequate hematological function: absolute neutrophil count (ANC) < 1.0x109/L or platelets < 75x109 /L before R-CHOP unless lymphoma related
Central nervous system (CNS) localization of the lymphoma. Cerebrospinal fluid (CSF) analysis before start of treatment is only necessary in case of suspicion of CNS localization
Female subject pregnant or breast-feeding
History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma
Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. In case of cardiac history, an echo or multigated acquisition (MUGA) should be obtained and left ventricular ejection fraction (LVEF) should exceed 40% to be eligible
Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.) that would jeopardize the patient's ability to receive the regimen with reasonable safety
HIV positivity
Active Hepatitis B or C infection as defined by positive serology and transaminitis. Non-active Hepatitis B carriers may be included if protected
Severe pulmonary dysfunction (CTCAE grade III-IV)
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
Prior treatment with an anti-PD1, anti-PDL1, anti-PDL2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
Severe neurological or psychiatric disease
Current participation in another clinical trial interfering with this trial
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Claustrophobia precluding PET-CT
Exclusion criteria for Nivolumab consolidation
Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration). Creatinine clearance may be calculated by Cockcroft -Gault formula: CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females) (0.815 x serum creatinine [mol/L])
Inadequate hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
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