1. CALGB/Alliance 50303: R-CHOP vs DA-EPOCH-R in Newly Diagnosed Diffuse Large B-Cell Lymphoma
New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

2. CALGB/Alliance 50303: Background
DLBCL: disease with clinically and molecularly different subtypes[1]
GCB subtype
ABC subtype
R-CHOP: standard of care for DLBCL[2]
Multicenter phase III trial found 5-yr PFS of approximately 65%[3]
DA-EPOCH-R: dose-intensive treatment alternative
Multicenter phase II trial found 5-yr TTP of 81% and 5-yr OS of 84% with DA-EPOCH- R[4]
Current CALGB/Alliance compared R-CHOP vs DA-EPOCH-R in pts with untreated stage II-IV DLBCL (subtypes GCB and ABC)[5]
ABC, activated B-cell–like; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell–like; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; TTP, time to progression.
1. Lenz G, et al. N Engl J Med. 2008;359: Sehn LH, et al. Blood. 2015;125: Cunningham et al. Lancet. 2013;381: Wilson WH, et al. Haematologica. 2012;97: Wilson WH, et al. ASH Abstract 469.
Slide credit: clinicaloptions.com

3. CALGB/Alliance 50303: Study Design
Untreated, newly diagnosed stage II-IV DLBCL (stage I PMBCL), ECOG PS 0-2, LVEF > 45%, tumor biopsies available, no CNS disease
(N = 465)
DA-EPOCH-R*
Rituximab 375 mg/m2 IV
Cyclophosphamide† 750 mg/m2 IV
Doxorubicin† 10 mg/m2 IV on Days 1-4
Etoposide† 50 mg/m2 IV on Days 1-4
Vincristine 0.4 mg/m2 IV on Days 1-4
Prednisone 60 mg/m2 BID on Days 1-5
G-CSF as needed SC on Days 6-12
(n = 232)
R-CHOP*
Cyclophosphamide 750 mg/m2 IV
Doxorubicin 50 mg/m2 IV
Vincristine 1.4 mg/m2 IV (max 2 mg)
Prednisone 40 mg/m2 PO on Days 1-5
G-CSF as needed SC
(n = 233)
*Included CNS prophylaxis if BM/testicular involvement or elevated LDH plus ≥ 2 extranodal sites. Prophylaxis: MTX IT x 4 doses on Day 1 of Cycles 3-6. †Increased 20% if ANC nadir > 0.5. De-escalated if ANC < 0.5 for > 3 days.
6 cycles
Randomized phase III study
Primary endpoint: EFS
Secondary endpoints: RR OS
Safety
ANC, absolute neutrophil count; BM, bone marrow; CNS, central nervous system; Cr, creatinine; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; EFS, event-free survival; G-CSF, granulocyte-colony stimulating factor; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MTX, methotrexate; PMBCL, primary mediastinal large B-cell lymphoma; PS, performance status; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RR, response rate.
Wilson WH, et al. ASH Abstract 469.
Wilson WH, et al. Blood. 2002;99:
Slide credit: clinicaloptions.com

4. CALGB/Alliance 50303: Baseline Characteristics
R-CHOP
DA-EPOCH-R
P Value
Median age, yrs (range)
58 (18-86)
57 (19-84)
.677
ECOG PS, %
0/1 2 88 12 87 13
.518
Stage, %
1 (PMBCL) 3 4 21 28 45 17 25 52
.641
IPI criteria, %
4/5 26 39 8 36
.405
DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; ECOG, Eastern Cooperative oncology Group; IPI, International Prognostic Index; PMBCL, primary mediastinal large B-cell lymphoma; PS, performance status; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
No significant differences in characteristics between treatment arms
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

5. CALGB/Alliance 50303: Response Outcomes
R-CHOP
DA-EPOCH-R
P Value
ORR
CR/CRu PR SD PD
89.3
62.3
27.0
2.6
1.7
88.8
61.1
27.2
3.5
< 1.0
.983
Missing data
6.4
6.9 --
No significant difference in response rates between treatment arms
CRu, unconfirmed CR; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; PD, progressive disease; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SD, stable disease.
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

6. CALGB/Alliance 50303: Event-Free Survival and OS
EFS OS 80 80 60 60
HR: 1.14 (95% CI: ; P = .4386)
HR: 1.18 (95% CI: ; P = .42)
EFS (%)
OS (%) 40 40 20
R-CHOP DA-EPOCH-R 20
R-CHOP DA-EPOCH-R
DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. 1 2 3 4 5 1 2 3 4 5
Yrs
Yrs
Arm N
Events, n
3 Yrs (95% CI)
5 Yrs (95% CI)
R-CHOP
233 64
0.81 ( )
0.69 ( )
DA-EPOCH-R
232 70
0.79 ( )
0.66 ( )
Arm N
Events, n
3 Yrs (95% CI)
5 Yrs (95% CI)
R-CHOP
233 44
0.85 ( )
0.80 ( )
DA-EPOCH-R
232 50
0.85 ( )
0.76 ( )
*Median follow-up 5 yrs
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

7. CALGB/Alliance 50303: EFS by Age and IPI Score
5-Yr EFS by Subgroup, %
Pts
ALL
R-CHOP
DA-EPOCH-R
P Value
Age
≤ 60 yrs
> 60 yrs 59 41 71 63 73 65 70 61
.073
IPI criteria
0/1 2 3
4/5 27 38 25 10 82 55 53 90 72 50 40 68 60
< .001
DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; EFS, event-free survival; IPI, International Prognostic Index; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
Posttreatment substudy (n = 171) using PET found no significant difference in 3-yr EFS between PET-positive and PET-negative subsets (80% vs 72%; P = .057)
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

8. CALGB/Alliance 50303: AEs AEs Grade 3-5, % R-CHOP DA-EPOCH-R P Value
Treatment-related deaths* 2
.975
All grade 3-5 AEs
Hematologic
Nonhematologic
76.3
73.1
41.3
96.5
97.7
70.9
< .001
ANC 68 96
Platelets 11 65
Febrile neutropenia 17 35
Infection 14
.169
Mucositis 6
.011
Neuropathy
Sensory
Motor 1 8
AE, adverse event; ANC, absolute neutrophil count; CNS, central nervous system; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
*5 deaths per arm. R-CHOP: congestive heart failure, 1; CNS bleed, 1; infection, 1; febrile neutropenia, 1; unknown, 1. DA-EPOCH-R: infection, 2; myocardial infarction, 1; unknown, 2.
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

9. CALGB/Alliance 50303: Conclusions
No differences between R-CHOP vs DA-EPOCH-R for EFS and OS with 5-yr follow-up
No benefit with DA-EPOCH-R identified among clinical subgroups defined by age and IPI criteria
Moderately increased rates of grade 3-5 AEs in the DA-EPOCH-R arm vs R-CHOP arm (cytopenias, febrile neutropenia, neuropathy)
Investigators plan to perform future correlative analyses to potentially identify prognostic subsets, novel treatment targets, and new response or toxicity biomarkers
AE, adverse event; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab; EFS, event-free survival; IPI, International Prognostic Index; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
Slide credit: clinicaloptions.com
Wilson WH, et al. ASH Abstract 469.

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