1. FLYER: Phase III Trial of R-CHOP x 4 Followed by Rituximab x 2 vs Standard R-CHOP x 6 in Younger Patients With Favorable-Prognosis DLBCL
Integrating New Malignant Hematology Findings Into Practice: Independent Conference Coverage of ASH 2018* December 1-4, 2018; 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.
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; R, rituximab.
Supported by educational grants from AbbVie, AstraZeneca, Celgene Corporation, Dova Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Novartis Pharmaceuticals, Pharmacyclics, Seattle Genetics, and Takeda Oncology.

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3. R-CHOP x 4 Followed by Rituximab x 2 vs R-CHOP x 6 in Favorable-Prognosis DLBCL (FLYER): Background
Addition of rituximab to 6 cycles of CHOP or CHOP-like chemotherapy significantly improved survival outcomes in younger patients with previously untreated, low- risk DLBCL[1]
3-yr PFS rate: 85% with addition of rituximab vs 68% with chemotherapy alone (log-rank P < .0001)
Benefit greatest in subgroup with favorable prognosis, defined by nonbulky disease and age-adjusted IPI = 0
Reducing number of CHOP cycles may maintain efficacy while decreasing toxicity
Current analysis evaluated noninferiority of R-CHOP x 4 cycles followed by rituximab x 2 cycles vs standard R-CHOP x 6 cycles in younger patients with aggressive B-cell NHL and favorable prognosis[2]
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; NHL, non-Hodgkin lymphoma; R, rituximab.
Slide credit: clinicaloptions.com
1. Pfreundschuh. Lancet Oncol. 2006;7: Poeschel. ASH Abstr 781.

4. FLYER: Study Design
International, randomized phase III noninferiority trial
R-CHOP x 4 cycles followed by
Rituximab x 2 cycles
(n = 293)
Patients with untreated aggressive B-cell lymphoma, aged yrs,
stage I/II disease, age-adjusted IPI = 0, no bulky disease
(maximum diameter < 7.5 cm)
(N = 588)
R-CHOP x 6 cycles
(n = 295)
Primary endpoint: PFS, 3-yr PFS rate
Assumed 3-yr PFS rate of 93% with R-CHOP x 6
Difference up to -5.5% allowed with R-CHOP x 4 → R x 2 while still proving noninferiority with 80% power and 1-sided α = 0.05 (planned sample size: N = 592, assuming 10% loss yields final N = 532)
Other endpoints: response, EFS, OS, safety
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; IPI, International Prognostic Index; R, rituximab.
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781.

5. FLYER: Baseline Characteristics
R-CHOP x 4 → R x 2 (n = 293)
R-CHOP x 6 (n = 295)
Female, n (%)
118 (40)
116 (39)
Median age, yrs (range)
49 (18-60)
47 (19-60)
Stage, n (%) I II
III/IV
174 (59)
117 (40)
2 (1)
172 (58)
119 (40) 4 (1)
Age-adjusted IPI, n (%) 1
291 (99)
4 (1)
Extralymph. involvement, n (%)
95 (32)
96 (32)
Bulky disease, n (%)
1 (0.3)
B symptoms, n (%)
27 (9)
9 (3)
Pathology
R-CHOP x 4 → R x 2 (n = 257)
R-CHOP x 6
(n = 251)
DLBCL, %
Centroblastic
Immunoblastic
Plasmoplastic
Anaplastic large cell
T-cell–rich B-cell lymphoma
NOS
Prim. mediast. B-cell lymphoma 78 40 2
0.4 1 32 80 44 34
Follicular lymphoma IIIB/III + DLBCL, %
5/9
3/10
Burkitt lymphoma, %
MCL (blastoid), %
Aggressive MZL, %
NOS, %
Unclassified (insufficient material), %
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NOS, not otherwise specified; PS, performance status; R, rituximab.
No patients had LDH > UNV or ECOG PS > 1
Significantly higher frequency of B symptoms at baseline in R-CHOP x 4 → R x 2 arm (P = .002)
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781.

6. FLYER: PFS (Primary Endpoint)
1.0
0.8
0.6
Proportion With PFS
Patients, n
293
295
36-Mo PFS,
% (95% CI)
96 (94-99)
94 (91-97)
0.4
R-CHOP x 4 → R x 2
R-CHOP x 6
0.1
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; f/u, follow-up; R, rituximab. 10 20 30 40 50 60 70 80 90
100
110
120
130
140
150
Mos
After median f/u of 66 mos, PFS noninferior with R-CHOP x 4 → R x 2 vs R-CHOP x 6
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781. Reproduced with permission.

7. FLYER: Response, EFS, OS (Secondary Endpoints)
Outcome
R-CHOP x 4 → R x 2 (n = 293)
R-CHOP x 6
(n = 295)
Response, %
CR/CRu PR
No change
Progression
Unknown
CR/CRu and additional tx 91 1 5 2 92
0.3
36-mo EFS rate, % (95% CI)*
89 (86-93)
89 (85-92)
36-mo OS rate, % (95% CI)†
99 (98-100)
98 (96-99)
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CRu unconfirmed CR; EFS, event-free survival; f/u, follow-up; R, rituximab; tx, therapy.
*Median f/u: 65 mos. †Median f/u: 67 mos.
Comparable rates of efficacy with R-CHOP x 4 → R x 2 vs R-CHOP x 6
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781.

8. FLYER: Cumulative Incidence of Relapse
0.20
Patients, n
267
271
538
Relapse,
n (%)
11 (4)
13 (5)
24 (4)
1.18
0.16
R-CHOP x 4 → R x 2
R-CHOP x 6
Total
0.14
0.12
Proportion
0.10
0.08
0.06
0.04
P = .679
0.02
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; f/u, follow-up; R, rituximab. 20 40 60 80
100
120
140
Mos
Relapse rates similar with R-CHOP x 4 → R x 2 vs R-CHOP x 6 with longer f/u
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781. Reproduced with permission.

9. FLYER: Safety
AE, n
R-CHOP x 4 → R x 2 (n = 293)
R-CHOP x 6 (n = 295)
Any Grade
Grade 3/4
Hematologic AEs
Leukocytopenia*
171 80
237
110
Anemia*
107 2
172 8
Thrombocytopenia* 16 5 17 7
Nonhematologic AEs
835 46
1295 70
Paresthesia
227 12
370 14
Nausea
195 6
319
Infection 98 20
156 23
Vomiting 56 1
117
Mucositis 68
105 3
AE, adverse event; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CT, chemotherapy; R, rituximab.
*Blood counts between CT cycles available in 73% of cycles for R-CHOP x 4 → R x 2 vs 69% of cycles for R-CHOP x 6.
Nonhematologic AEs with R-CHOP x 6 reduced by approximately one third with R-CHOP x 4 → R x 2
Therapy-associated mortality rate was 0% with R-CHOP x 4 → R x 2 vs 1% with R-CHOP x 6
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781.

10. FLYER: Conclusions
In younger patients with aggressive B-cell lymphoma and favorable prognosis, first-line treatment with R-CHOP x 4 → R x 2 showed noninferior PFS, EFS, and OS vs standard R-CHOP x 6
36-mo PFS rate: 96% with R-CHOP x 4 → R x 2 vs 94% with R-CHOP x 6
Nonhematologic AEs were decreased by approximately one third with R-CHOP x 4 → R x 2 vs R-CHOP x 6
Number of any-grade nonhematologic AEs (grade 3-4): R-CHOP x 4 → R x 2, n = 835 (46); R-CHOP x 6, n = 1295 (70)
Both arms exhibited comparable relapse patterns and rates
Relapse rate was 4% with R-CHOP x 4 → R x 2 vs 5% with R-CHOP x 6
AE, adverse event; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; EFS, event-free survival; R, rituximab.
Slide credit: clinicaloptions.com
Poeschel. ASH Abstr 781.

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