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R-CODOX-M/R-IVAC VERSUS DOSE-ADJUSTED(DA)-EPOCH-R IN PATIENTS WITH NEWLY DIAGNOSED HIGH-RISK BURKITT LYMPHOMA; FIRST RESULTS OF A MULTI-CENTER RANDOMIZED HOVON/SAKK TRIAL.
Author(s): ,
Martine Chamuleau
Affiliations:
Hematology, Cancer Center Amsterdam,Amsterdam UMC, location VU,Amsterdam,Netherlands
,
Frank Stenner
Affiliations:
Oncology,University Hospital Basel and SAKK,Basel,Switzerland
,
Dana Chitu
Affiliations:
Hematology, HOVON Data Center,Erasmus MC Cancer Institute,Rotterdam,Netherlands
,
Urban Novak
Affiliations:
Medical Oncology,Inselspital /Bern University Hospital and SAKK,Bern,Switzerland
,
Monique Minnema
Affiliations:
Hematology,UMC Utrecht,Utrecht,Netherlands
,
Otto Visser
Affiliations:
Hematology,Isala Clinics,Zwolle,Netherlands
,
Wendy Stevens
Affiliations:
Hematology,Radboud UMC,Nijmegen,Netherlands
,
Thorsten Zenz
Affiliations:
Medical Oncology and Hematology,University Hospital Zurich and SAKK,Zurich,Switzerland
,
Gustaaf van Imhoff
Affiliations:
Hematology,University Medical Center Groningen,Groningen,Netherlands
,
Ka Lung Wu
Affiliations:
Hematology,ZNA Stuivenberg,Antwerpen,Belgium
,
Astrid Demandt
Affiliations:
Internal Medicine, Division of Hematology, GROW,Maastricht University Medical Center,Maastricht,Netherlands
,
Marie-Jose Kersten
Affiliations:
Hematology,Amsterdam UMC, location AMC,Amsterdam,Netherlands
,
Wim Terpstra
Affiliations:
Hematology,OLVG,Amsterdam,Netherlands
,
Lidwine Tick
Affiliations:
Internal Medicine,Máxima Medical Center,Eindhoven,Netherlands
,
Dries Deeren
Affiliations:
Hematology,AZ Delta,Roeselare,Belgium
,
Eric van de Neste
Affiliations:
Hematology,Cliniques universitaires UCL ,Saint-Luc,Belgium
,
Michael Gregor
Affiliations:
Hematology,Luzerner Kantonsspital and SAKK,Luzern,Switzerland
,
Hendrik Veelken
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
,
Lara Bohmer
Affiliations:
Hematology,Haga Tecahing Hospital,The Hague,Netherlands
,
Clemens Caspar
Affiliations:
Department of Internal Medicine, Division of Medical Oncology and Hematology,Kantonsspital Baden and SAKK,Baden,Switzerland
,
Stefan Dirnhofer
Affiliations:
Institute of Medical Genetics and Pathology,University Hospital Basel,Basel,Switzerland
,
Michiel van de Brand
Affiliations:
Pathology,Radboud UMC,Nijmegen,Netherlands
,
Daphne de Jong
Affiliations:
Pathology,Amsterdam UMC, location VU,Amsterdam,Netherlands
,
Marcel Nijland
Affiliations:
Haematology,University Medical Center Groningen,Groningen,Netherlands
Elly (Petronella) Lugtenburg
Affiliations:
Hematology,Erasmus MC Cancer Institute, University Medical Center Rotterdam,Rotterdam,Netherlands
(Abstract release date: 06/02/22) EHA Library. Chamuleau M. 06/12/22; 366213; LB2370
Dr. MED Chamuleau
Dr. MED Chamuleau
Contributions
Abstract
Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2370

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Optimal first-line treatment for patients with high-risk Burkitt lymphoma (BL) remains to be defined. Treatment with high dose multi-agent chemotherapy such as R-CODOX-M/R-IVAC is effective (2 yr PFS 64-71%) at the cost of significant toxicity and long hospitalization. DA-EPOCH-R has demonstrated favorable 2 yr PFS of 85% and less toxicity in a phase II study. Here, we present the first results of a randomized trial comparing R-CODOX-M/R-IVAC with DA-EPOCH-R (EudraCT2013-004394-27).

Aims
The trial was designed to demonstrate an improvement of 2 yr PFS (primary endpoint) from 70% with R-CODOX-M/R-IVAC (arm A) to 85% with DA-EPOCH-R (arm B) in patients with newly diagnosed BL.

Methods
Patients (18-75 yr) with newly diagnosed (sporadic and HIV-associated), high-risk BL were eligible. High-risk was defined as any of: elevated LDH, WHO PS ≥ 2, stage III/IV, mass ≥ 10 cm. Central nervous system (CNS) involvement was excluded. After obtaining informed consent, patients were randomly assigned to treatment with 2 cycles of R-CODOX-M/R-IVAC or 6 cycles of DA-EPOCH-R. All patients received intrathecal CNS prophylaxis. EOT response was assessed by PET-CT scan. Complete Metabolic Remission (CMR) was defined as Deauville score 1-3. To confirm the hypothesis, 260 patients were needed. Due to slow accrual rate and the inability of another cooperative group to participate, the trial was closed prematurely. Data cut off for analysis was April 16, 2022.

Results
Between 2014 and 2021, 89 patients were enrolled. Five patients were excluded (3 CNS involvement, 2 no BL), 84 patients were randomized (n=43 arm A, n=41 arm B). Median follow-up is 19.1 (0.03-88.4) months. Baseline characteristics were well balanced between both arms (median age 50 yr (18-75) vs 56 yr (22-74, p=0.30), stage III/IV 88% vs 92% (p=0.62) in arm A and B respectively. Central pathology review was performed in 89% of patients. R-CODOX-M/R-IVAC was fully dosed in 92% of cycles (range 86-95% for different components). Maximum dose level (DL) of DA-EPOCH-R was DL1 in 35%, DL2 in 19%, DL3 in 24%, and DL4 in 22% of patients. In arm A 9/43 (21%) patients discontinued treatment (reason: 4 excessive toxicity, 3 progression, 1 refusal, 2 death (1 BL, 1 sepsis)) vs 4/41 (10%, reason: none excessive toxicity, 3 progression, 1 death (COVID)) in arm B. All other patients completed planned treatment. In arm A 28/43 (65%) patients achieved CMR and in arm B 27/41 (66%). In arm A 34/43 patients (79%) experienced AE grade (G) 3-5 (one G5: sepsis) and 30 SAE were reported in 21 patients, vs 30/41 (73%) patients with AE G3-5 (one G5: COVID) and 28 SAE in 20 patients in arm B. Most common SAE were infectious complications (infections and febrile neutropenia), 22/30 SAE (73%) in arm A vs 13/28 SAE (46%) in arm B (p=0.04). In arm A patients received a median of 2 (0-37) platelet transfusions and 5 (0-28) red blood cell transfusions vs 0 (0-6) and 1 (0-17) in arm B (p<0.01 for both). In arm A patients were hospitalized 46 nights (mean, 1-99) vs 25 nights (4-78) in arm B (p<0.01). Preliminary survival analysis demonstrated comparable estimated 2 yr OS rates of 75% in arm A and 76% in arm B. Causes of death were refractory/relapsed BL in 8 and 7 patients (arm A and B respectively), see Figure 1.

Conclusion
This is the first multi-center randomized trial comparing two different chemotherapy regimens in BL. The trial was closed prematurely. Treatment with DA-EPOCH-R resulted in comparable CMR and survival rates as R-CODOX-M/R-IVAC, but was associated with significant less infectious complications, transfusions and hospitalization days.

Keyword(s): Burkitt's lymphoma, Randomized, Clinical trial, Non-Hodgkin's lymphoma

Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2370

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Optimal first-line treatment for patients with high-risk Burkitt lymphoma (BL) remains to be defined. Treatment with high dose multi-agent chemotherapy such as R-CODOX-M/R-IVAC is effective (2 yr PFS 64-71%) at the cost of significant toxicity and long hospitalization. DA-EPOCH-R has demonstrated favorable 2 yr PFS of 85% and less toxicity in a phase II study. Here, we present the first results of a randomized trial comparing R-CODOX-M/R-IVAC with DA-EPOCH-R (EudraCT2013-004394-27).

Aims
The trial was designed to demonstrate an improvement of 2 yr PFS (primary endpoint) from 70% with R-CODOX-M/R-IVAC (arm A) to 85% with DA-EPOCH-R (arm B) in patients with newly diagnosed BL.

Methods
Patients (18-75 yr) with newly diagnosed (sporadic and HIV-associated), high-risk BL were eligible. High-risk was defined as any of: elevated LDH, WHO PS ≥ 2, stage III/IV, mass ≥ 10 cm. Central nervous system (CNS) involvement was excluded. After obtaining informed consent, patients were randomly assigned to treatment with 2 cycles of R-CODOX-M/R-IVAC or 6 cycles of DA-EPOCH-R. All patients received intrathecal CNS prophylaxis. EOT response was assessed by PET-CT scan. Complete Metabolic Remission (CMR) was defined as Deauville score 1-3. To confirm the hypothesis, 260 patients were needed. Due to slow accrual rate and the inability of another cooperative group to participate, the trial was closed prematurely. Data cut off for analysis was April 16, 2022.

Results
Between 2014 and 2021, 89 patients were enrolled. Five patients were excluded (3 CNS involvement, 2 no BL), 84 patients were randomized (n=43 arm A, n=41 arm B). Median follow-up is 19.1 (0.03-88.4) months. Baseline characteristics were well balanced between both arms (median age 50 yr (18-75) vs 56 yr (22-74, p=0.30), stage III/IV 88% vs 92% (p=0.62) in arm A and B respectively. Central pathology review was performed in 89% of patients. R-CODOX-M/R-IVAC was fully dosed in 92% of cycles (range 86-95% for different components). Maximum dose level (DL) of DA-EPOCH-R was DL1 in 35%, DL2 in 19%, DL3 in 24%, and DL4 in 22% of patients. In arm A 9/43 (21%) patients discontinued treatment (reason: 4 excessive toxicity, 3 progression, 1 refusal, 2 death (1 BL, 1 sepsis)) vs 4/41 (10%, reason: none excessive toxicity, 3 progression, 1 death (COVID)) in arm B. All other patients completed planned treatment. In arm A 28/43 (65%) patients achieved CMR and in arm B 27/41 (66%). In arm A 34/43 patients (79%) experienced AE grade (G) 3-5 (one G5: sepsis) and 30 SAE were reported in 21 patients, vs 30/41 (73%) patients with AE G3-5 (one G5: COVID) and 28 SAE in 20 patients in arm B. Most common SAE were infectious complications (infections and febrile neutropenia), 22/30 SAE (73%) in arm A vs 13/28 SAE (46%) in arm B (p=0.04). In arm A patients received a median of 2 (0-37) platelet transfusions and 5 (0-28) red blood cell transfusions vs 0 (0-6) and 1 (0-17) in arm B (p<0.01 for both). In arm A patients were hospitalized 46 nights (mean, 1-99) vs 25 nights (4-78) in arm B (p<0.01). Preliminary survival analysis demonstrated comparable estimated 2 yr OS rates of 75% in arm A and 76% in arm B. Causes of death were refractory/relapsed BL in 8 and 7 patients (arm A and B respectively), see Figure 1.

Conclusion
This is the first multi-center randomized trial comparing two different chemotherapy regimens in BL. The trial was closed prematurely. Treatment with DA-EPOCH-R resulted in comparable CMR and survival rates as R-CODOX-M/R-IVAC, but was associated with significant less infectious complications, transfusions and hospitalization days.

Keyword(s): Burkitt's lymphoma, Randomized, Clinical trial, Non-Hodgkin's lymphoma

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