New Opportunities to Enhance the Clinical Outcomes of Patients With Follicular Lymphoma
Bruce D. Cheson, MD
Head of Hematology
Deputy Chief, Hematology/Oncology
Georgetown University Hospital
Lombardi Comprehensive Cancer Center
Jointly Provided by
Disclosure of Conflicts of Interest
Bruce D. Cheson, MD discloses the following commercial relationships:
– Advisor/consultant: Astellas, AstraZeneca, Celgene, Gilead, Merck, Pharmacyclics, Pfizer, Roche/Genentech, Seattle Genetics, and Spectrum Pharmaceuticals
– Research support: AbbVie, Acerta, Celgene, Gilead, Medimmune, Pharmacyclics, Roche/Genentech, Seattle Genetics, and Teva
Learning Objectives
Outline patient- and disease-related characteristics that influence selection of appropriate treatment for follicular lymphoma
Differentiate efficacy and safety data on novel therapies for previously untreated and relapsed/refractory follicular lymphoma
Evaluate methods to assess response to follicular lymphoma treatment
NHL = non-Hodgkin lymphoma.Armitage & Weissenburger, 1998; ACS, 2015.
Relative Incidence of NHL Subtypes
MZL6%
LPL1%
LL2%
ALCL2%
PMLBCL2%
Burkitt’s-like2%
PTCL6%
MCL6%
SLL
Composite13%
DLBCL32%
FL22%
>71,000 new cases in US in 2015
6%
Follicular Lymphoma Pathogenesis
t(14;18) gives rise to BCL2-IGH fusion in BM 50-75% of normals harbor low levels of
circulating t(14;18)+ cells Most never develop FL, indicating that BCL2
ectopic expression is necessary but not sufficient
Expanding population of atypical B cells from GC, share genotypic and phenotypic features of FL
Roulland et al, 2014.
GC = germinal center; SHM/CSR = somatic hypermutation/class switch recombination; FLIS = follicular lymphoma in situ.Swaminathan & Müschen, 2014.
Pathogenesis of FL
t(14;18) as a Predictive Biomarker for FL
520,000 healthy participants on EPIC study 100 developed FL 2-161 months after enrollment Clonal analysis - FL developed from pre-existing
t(14;18)+ committed precursors 23-fold increased risk of FL in samples with a
frequency >1/10,000 blood cells Those who developed FL had a higher prevalence of
t(14;18) versus controls (P<0.001) Genes involved in transforming process under study
Roulland et al, 2014.
Su
rviv
al p
rob
abil
ity
Low risk
Intermediate risk
High risk
0
0.2
0.4
0.6
0.8
1.0
Years0 1 2 3 4 5 6 7
No Nodal regions 4
L Elevated LDH
A Age ≥60
S Stage III/IV
H Hemoglobin <120 g/L
Risk Group No. of Factors % of Patients 5-Yr OS (%) 10-Yr OS (%)
Low 0-1 36 90.6 70.7
Intermediate 2 37 77.8 50.9
High 3-5 27 52.5 35.5
P<10-4
FLIPI = Follicular Lymphoma International Prognostic Index; LDH = lactate dehydrogenase; OS = overall survival.Solal-Céligny et al, 2004.
Overall Survival According to FLIPI: Clinical Prognostic Factors
Initial Treatment of Advanced FL: Current Challenges
When to treat Optimal induction regimen Role of postinduction strategies Integration of new agents Need for surrogate end points
Criteria for High Tumor Burden FL
Maximum diameter >7 cm >3 sites with a diameter of >3 cm Systemic symptoms “Substantial” spleen involvement Serious effusions Risk of local compression symptoms Circulating lymphoma cells Peripheral blood cytopenias
Brice et al, 1997.
Impact of Rituximab on OS in Frontline Follicular NHL
Hiddemann et al, 2005.
Herold et al, 2007.
Marcus et al, 2008.
Federico et al, 2013.
FOLLO5: Time to Treatment Failure and Progression-Free Survival
100
80
60
40
20
0 6 12 18 24 30 36 42 48 54 60
100
80
60
40
20
0 6 12 18 24 30 36 42 48 54 60
Trea
tmen
t F
ailu
re (
%)
Time (months)
Pro
gre
ssio
n-F
ree
Su
rviv
al (
%)
Time (months)
A B
R-CVPR-CHOPR-FM
R-CVPR-CHOPR-FM
No. at riskR-CVPR-CHOPR-FM
168165171
136147150
119137139
95120120
748395
516668
364750
233232
131920
51212
154
No. at riskR-CVPR-CHOPR-FM
168165171
154157163
136147151
108128130
8589
101
607073
415155
273636
142223
61414
165
Federico et al, 2013.
FOLL05: Grade 3/4 Toxicities by Arm
0.63.1 4.2
28.0
49.7
63.7
0.03.1
7.72.5 3.1 4.8
0
20
40
60
Pe
rce
nta
ge
Anemia Neutropenia Thrombocytopenia Infections
R-CVP R-CHOP R-FM
Anemia P=0.089Neutropenia P<0.001Thrombocytopenia P<0.001Infections P=0.527
2.4 4.7
aR-CHOP, n=22.IRC = independent review committee; iNHL = indolent NHL; CR = complete response; PR = partial response.Finn et al, 2014.
BRIGHT: Response Rates
IRC Assessment of Response by Histology, n/N (%)
CR CR + PR
BR R-CHOP/R-CVP BR R-CHOP/R-CVP
iNHL 49/178 (28) 43/174 (25) 173/178 (97) 160/174 (92)
FL 45/148 (30) 37/149 (25) 147/148 (>99) 140/149 (94)
MZL 5/25 (20) 4/17 (24) 23/25 (92) 12/17 (71)
LPL 0/5 1/6 (17) 3/5 (60) 6/6 (100)
MCL 17/34 (50) 9/33 (27)a 32/34 (94) 28/33 (85)a
aP<0.0001. AEs = adverse events.Finn et al, 2014.
BRIGHT: Grade ≥3 Adverse Events
Grade ≥3 AEs (occurring in ≥3% of patients), n (%)
Preselected for R-CHOPPreselected for R-CVP
(n=116 )BR (n=103) R-CHOP (n=98) BR (n=118 )
Hematologic
White blood cell count 33 (32) 71 (72) a 51 (43) 44 (38)
Absolute neutrophil count 40 (39) 85 (87) a 58 (49) 65 (56)
Lymphocyte count 63 (61) 32 (33) a 74 (63) 32 (28)a
Hemoglobin 0 3 (3) 6 (5) 6 (5)
Platelet count 10 (1) 12 (12) 6 (5) 2 (2)
Non-hematologic
Nausea 3 (3) 0 1 (<1) 0
Vomiting 5 (5) 0 2 (2) 0
Abdominal pain 2 (2) 3 (3) 0 3 (3)
Drug hypersensitivity 3 (3) 0 2 (2) 0
Fatigue 4 (4) 2 (2) 4 (3) 1 (<1)
Pneumonia 2 (2) 0 5 (4) 1 (<1)
Infusion-related reaction 6 (6) 4 (4) 7 (6) 4 (3)
Infection 12 (12) 5 (5) 8 (7) 8 (7)
Hyperglycemia 0 2 (2) 1 (<1) 5 (4)
Back pain 0 1 (1) 0 4 (3)
Syncope 1 (<1) 0 0 3 (3)
Dyspnea 2 (2) 2 (2) 3 (3) 1 (<1)
PRIMA Study Design
CRu = Complete response unconfirmed; PD = progressive disease; SD = stable disease.Salles et al, 2013.
PD/SDoff study
Rituximab maintenance375 mg/m2
every 8 weeks for 2 years
Observation
CR/CRuPR
Random 1:1
Immunochemotherapy8 x rituximab
+8 x CVP or
6 x CHOP or6 x FCM
High tumor burden
untreated follicular lymphoma
INDUCTION MAINTENANCE
5 YEARS FOLLOW-UP
Registration
Overall Survival by Maintenance
Martinelli et al, 2010.Hochster et al, 2009.
Ardeshna et al, 2010. Salles et al, 2011.
RESORT Study Design
Rituximabretreatment atprogressiona
375 mg/m2 qw 4
RANDOMIZE
Rituximab375 mg/m2 qw
4CR or PR
RituximabMaintenancea
375 mg/m2 q 3 months
aContinue until treatment failure• No response to retreatment or PD within 6 months of R• Initiation of cytotoxic therapy or inability to complete rx
Kahl et al, 2014.
SAKK 35/10 Study Design
Phase II study of frontline R vs. R2 in FL grades 1, 2, and 3a and requiring systemic therapy
Primary end point: CR/CRu at week 23a
– Study goal: 20% increase for R2 over R with 90% power and type I error (α) of 0.10
Secondary end points: ORR, DOR, PFS, OS, and safety
Response per NCI Cheson 1999
criteria
Previously untreated FL (N=154)• Histologically
confirmed FL grades 1, 2, and 3A
R2 (n=77): rituximab (see below) +lenalidomide
15 mg/d PO for 19 weeks total(2 weeks prior, 15 weeks during,
and 2 weeks after rituximab)
Rituximab (n=77)375 mg/m2, Day 1 of Weeks 1, 2, 3,
4, 12, 13, 14, and 15
aTreatment discontinued Week 10 if <25% reduction in sum of product of tumor diameters.ORR = overall response rate; DOR = duration of response; NCI = National Cancer Institute.Kimby et al, 2014.
Frontline R2 vs. R in FL (SAKK 35/10): Overall Response Rate
Rituxim
ab_x000d_(n =
77)
R2_x000d_(n =
77)
Rituxim
ab_x000d_(n =
77)
R2_x000d_(n =
77)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
10% 13%25%
36%35%
62% 36%
45%
PRCR/CRu
Pa
tie
nts
( %
)
Week 10P<0.0001
Week 23P=0.002
45%
75%
61%
81%
Kimby et al, 2014.
SAKK 35/10: Safety
Adverse Events (>1 patient), n (%)
Rituximab (n=76) R2 (n=77)
Grade 3 Grade 4 Grade 3 Grade 4
Neutropenia − 1 (1) 11 (14) 4 (5)
Thrombocytopenia − − 2 (3) 1 (1)
Suicide attempt − 1 (1) − −
Hypertension 3 (4) − 7 (9) −
Fatigue 1 (1) − 2 (3) −
Maculopapular rash − − 4 (5) −
Allergic reaction − − 2 (3) −
UTI − − 2 (3) −
Depression − − − 1 (1)
Psychosis − − − 1 (1)
Treatment was discontinued by 21 patients (28%) in arm R, in 16 due to lack of response at Week 10 and in 1 due to toxicity, and by 19 patients (25%) in arm R2, in 3 due to lack of response at Week 10 and in 13 due to toxicity.
UTI = urinary tract infection.Kimby et al, 2014.
PET = positron emission tomography.Martin et al, 2014.
CALGB 50803: R2 in Previously Untreated FL
OverallN=55
FLIPI 0-1n=16
FLIPI 2n=35
FLIPI 3n=2
FLIPI Unknown
n=2
ORR 53 (96%) 16 (100%) 33 (94%) 2 (100%)
2 (100%)
CR 39 (71%) 12 (75%) 24 (69%) 2 (100%)
1 (50%)
PR 14 (25%) 4 (25%) 9 (26%) - 1 (50%)
SD 2 (4%) 0 (0%) 2 (6%) - -
Four additional patients in PET CR but not confirmed by bone marrow biopsy.There was no significant association between CR rate and FLIPI score, presence of bulky disease, or grade.
CALGB 50803: Response Characteristics
Median follow-up = 2.3 years Median time to first response = 10 weeks Median time to complete response = 10 weeks 92% of PET negative CRs occurred by 24 weeks 8/65 evaluable patients have progressed so far
– 2 stopped after 1-2 cycles due to toxicity– 2 had achieved a best response of CR– No patients have died
Martin et al, 2014.
Martin et al, 2014.
CALGB 50803: Progression-Free Survival
Years from Study Entry
Pro
ba
bili
ty
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0.0
0.2
0.4
0.6
0.8CALGB 50803
Progression-Free Survival
Unmet Needs in Frontline FL
PET positive after induction Early relapses How to integrate novel agents Surrogate end points
Casulo et al, 2013.
20% of Patients With FL Experience Disease Progression Within 24 Months of Chemoimmunotherapy
Press et al (2013). SWOG S0016. J Clin Oncol.
60
R-CHOP
100
80
60
40
20
024 30 36 42 48 540 6 12 18Time (months)
Pro
gre
ssio
n-F
ree
Su
rviv
al (
%)
1.0
Eve
nt-
Fre
e R
ate
Salles et al (2011). PRIMA Lancet.
Rituximab maintenance0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60
Time (months)
Pro
ba
bili
ty
1.0
0.8
0.6
0.4
0.2
0.0
Rummel el al (2013). Lancet.
B-R
R-CHOP
Time (months)
0 6 12 18 24 30 36 42 48 54 60
This suggests a high-risk group of patients who will relapse
early despite different treatment approaches including
maintenance.
aX2.ECOG PS = Eastern Cooperative Oncology Group performance status.Casulo et al, 2013.
Distribution of Characteristics by Group
Characteristic Early
ProgressorReference
Group Significancea
Grade 3 histology 34% 40% P=0.50
High-risk FLIPI 57% 40% P=0.01
Elevated LDH 43% 28% P=0.01
Low Hgb 35% 22% P=0.01
≥2 nodal sites 40% 25% P=0.01
Poor ECOG PS 16% 4% P<0.01
CI = confidence interval.Casulo et al, 2013.
OS of Patients With FL Who Relapsed Within 2 Years of R-CHOP (“Early POD”)
122 patients were classified as early progressors (n=110 POD and n=12 non-POD deaths within 2 years)
2-year OS (95% CI) was 71% (61.5-78.0)
5-year OS (95% CI) was 50% (40.3-58.8)
1.0
0 1 2 3 4 5 6 7 8 9 100.0
0.2
0.4
0.6
0.8
Patients at risk:101 78 69 58 49 45 33 14 6 0
Time (years)
Sur
viva
l pro
bab
ility
122
Early Progressor
420 420 407 387 363 344 252 144 33 0420Reference
Early
Reference Group
Postinduction Response Assessment With PET/CT: Limitations to These Studies…
PRIMA: 122 Patients 2004-2010 Trotman et al (2011). J Clin Oncol.
Hypothesis generating
Retrospective analysis of local PET interpretation within a prospective study with independent CT
assessment Results confirmed by independent scan review of 61 patients
Tychyj-Pinel et al (2014). EJNMMI.
FOLL05: 202 Patients 2005-2010 Luminari et al (2013). Ann Oncol.
Retrospective analysis of local PET reports within a prospective study with local CT assessment
Prospective standardized PET acquisition/assessment in accordance to the 5-Point Scale, with
local CT assessment Shorter follow-up
PET Folliculaire: 106 Patients 2007-2009 Dupuis et al (2012). J Clin Oncol.
Prospective standardized PET acquisition/assessment in accordance to the 5-Point Scale, with
local CT assessment Shorter follow-up
CT = computed tomography.Trotman et al, 2014.
PFS According to CT Response
SD/PD vs. • PR, HR 4.2• CRu, HR 5.6 • CR, HR 7.8, P<0.0001
PR vs. • CR/CRu, HR 1.7 (1.1-2.5),
P=0.02
CRu/PR vs. • CR, HR 1.6 (1.1-2.4),
P=0.02
Both PET Cut-Offs Predictive of PFS
Score ≥3 Score ≥4
HR 3.9 (95% CI 2.5-5.9, P<0.0001)Median PFS: 16.9 (10.8-31.4) vs. 74.0 months (54.7-NR)
63%
23%
Trotman et al, 2014.
Postinduction PET Status (Cut-Off ≥4) and Overall Survival
87%
97%
HR 6.7, 95% CI 2.4-18.5, P=0.0002Median OS: 79 months vs. NR
Trotman et al, 2014.
MRD Predicts Progression-Free Survival in FL
DNA from BM from 415 pts from FOLLO-5Assessed for BCL2/IGH at diagnosis,
posttreatment, and at 12 and 24 monthsMarker detected in 53% pretreatmentThose without or with low levels had
higher CR rates and longer PFS
MRD = minimal residual disease.Galimberti et al, 2014.
PFS From Randomization Longer in Pts Without BCL2/IGH Rearrangement During Follow-Up
Independent of Quality of Responsea
aP=0.001.Galimberti et al, 2014.
PFS From Randomization Significantly Longer in Pts Without BCL2/IGH Detectable After 12 Months
of Follow-Upa
aP=0.015.Galimberti et al, 2014.
Relapsed vs. Refractory FL
Relapsed – Initial response (CR or PR)
– Progress >6 months following completion of standard induction therapy
Poor risk relapse– PET/CT scan positive postinduction
– <12 months following treatment
Refractory– <PR to standard induction
– CR or PR that lasts <6 monthsPET/CT = positron emission tomography/computed tomography.NCCN, 2015.
US Bendamustine Trials
Two phase II, multicenter, single-agent studies Relapsed, follicular, and low-grade Refractory to rituximab: progression <6 months
– First dose of rituximab
– Completion of rituximab maintenance
– Completion of chemotherapy + rituximab
Dosage: bendamustine 120 mg/m2 IV over 30-60 minutes, Days 1 and 2 every 21 days x 6 cycles
Cheson et al, 2009.
US Bendamustine Trials
N=176 Median age 61 years (range, 31-84) Histologies: FL ( 68%), SLL (20%), MZL
(11%), and LPL (1%) Stage III-IV in 81% Median three prior chemotherapy regimens 34% refractory to last chemotherapy
Cheson et al, 2009.
US Bendamustine Trials: Response in Rituximab-Refractory Patients
Patient Group (N=161)
OverallFLIPI - Low
Int High
Alkylating agentSensitive
RefractoryPurine analog
SensitiveRefractory
CR/CRu (%)
23 17 28 27
28 12
25 20
ORR (%)
76 77 75 79
88 59
81 60
Cheson et al, 2010.
Bendamustine-R in Relapsed iNHL: % Response Rate by Histology
ResponseCategory
All Patients Indolent Lymphoma
Mantle Cell Lymphoma
ORR 92 93 92
CR 41 41 42
CRu 14 13 17
PR 38 39 33
SD 8 7 8
PD 0 0 0Robinson et al, 2008.
New Targeted Agents
Agent Target
Daratumumab CD38
Polatuzumab vedotin CD79b
Ibrutinib Btk
ACP-196 Btk
GS-9973 Syk
Idelalisib PI3-K
GS9901 PI3-K
IPI-145 PI3-K
Nivolumab PD-1
Pembrolizumab PD-1
Pidilizumab PD-1
ABT-199 Bcl-2
Selinexor XP01 (Nuclear transport)
Ibrutinib Monotherapy In Relapsed/Refractory FL (n=40)
Bartlett et al, 2014.
Responses: 2 CRs and 9 PRs by CT criteria Three patients with PR and 1 with
SD were PET/CT negative at C3D1 72% of patients had reduction in
tumor volume
Median time to response: 2.8 months (range, 1.8-7.4)
1-year PFS 50.1% (95% CI 35.3-71.1) Median follow-up 10.2 months
C1D8 SUVmax correlates with response (P=0.04) and PFS (P=0.003)
61
101-09: Overall Response Rates by Disease Subgroups
*LPL/WM = lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patient.Gopal et al, 2014.
June 2013
Complete Response Stable Disease Progressive Disease Not evaluablePartial Response Minor Response
June 2014
n=2
47%n=59
33%n=41
57%
OverallResponsen=71/125
(95% CI:47.6–65.6)
50%n=63
34%n=42
10%n=12
6%n=7
1%n=1*
2%n=22%
8%n=10
1%n=1*
58%
OverallResponsen=72/125
(95% CI:48.4–66.4)
0% 20% 40% 60% 80% 100%
FLn=72 56% (43–67)
ORR, % (95% CI)
14%n=10
42%n=30
32%n=23
8%n=11
SLLn=28
MZLn=15
LPL/WMn=10
61% (41–79)
47% (21–73)
80% (44–98)
57%n=16
40%n=6
70%n=7
10%n=1
36%n=10
47%n=7
10%n=1
10%n=1
4%n=1
1%n=1
4%n=1
7%n=1
7%n=1
CompleteResponse
StableDisease
ProgressiveDisease
Notevaluable
PartialResponse
M
Overall Response Rate By Disease Subgroups: 2014
Gopal et al, 2014.
101-09: Progression-Free Survival
PFS 2014 (All Patients)* PFS 2014 (By Disease Group)
72 35 18 11 5 128 12 7 4 4 115 6 3 210 7 5 5 3 2
Patients
at risk, n
2014 Median PFS: 11.0 months
*Includes patients who achieved a CR or PR (or MR for LPL/WM) according to IRC assessments
Key Takeaways
Follicular lymphoma is a heterogeneous disease
Need biomarkers to distinguish among subtypes
Treatment goals– Move towards noncytotoxic approaches
– Individualized strategies
– Cure
Case Study 1: Initial Treatment of FL
70-year-old woman with a history of a herniated disc was having a
routine follow-up CT scan, which revealed: – Left-sided hydronephrosis caused by a nodal mass 11.1 x 10.5 cm– Inguinal, paraaortic, and portacaval adenopathy adenopathy– Spleen enlarged at 15 cm
Laboratory studies showed a mild anemia and creatinine of 2.4 mg/dL Fine needle aspiration of her enlarged right inguinal node was
nondiagnostic. Subsequent excisional lymph node revealed grade 1/2 FL When questioned carefully, patient reported 5 pounds of unintentional
weight loss, a sense of abdominal fullness, but no fevers or night sweats Bone marrow biopsy revealed 10% involvement by FL Now patient’s performance status is 2. CBC reveals a hematocrit of 32%,
absolute neutrophil count of 750/mm3, and platelets of 80,000/mm3. Bone
marrow biopsy reveals 30% infiltration by FL
Case Study 1: Initial Treatment of FL
Which initial treatment approach would you recommend for this patient?
a. Watch and wait
b. Rituximab monotherapy
c. R-CHOP
d. R-bendamustine
Case Study 2: Relapsed FL
Previously healthy 68-year-old man presented with complaints of fatigue, drenching night sweats, a 10-pound weight loss, and a mass in his neck
CT scan revealed diffuse lymphadenopathy and PET scan confirmed FDG-avidity with standard uptake values in the range of 6-12. One of the brightest nodes was biopsied and the pathology was interpreted as grade 2 FL
Received six cycles of R-CHOP to a complete remission that lasted for 4 years. Subsequently experienced increasing adenopathy and splenomegaly, with a return of symptoms. Bendamustine/rituximab was administered for six cycles
Achieved a good partial response but experienced prolonged neutropenia and thrombocytopenia. At approximately 12 months, at age 73, his disease recurs
Case Study 2: Relapsed FL
Which treatment approach would you recommend for this patient?
a. Repeat R-CHOP
b. R-ICE with autologous stem cell transplant
c. Idelalisib
d. Radioimmunotherapy with Y-90 ibritumomab tiuxetan
Case Study 3: Refractory FL
A 56-year-old woman noticed new lumps around her neck, making it difficult to button her blouse. She visited her primary care physician who, despite any other symptoms, administered a series of antibiotics, with no resolution
Fine needle aspiration was non-diagnostic. Excisional biopsy revealed a diagnosis of grade 3a FL
Patient was referred to an oncologist who completed staging:– Normal CBC and liver chemistries, with elevated LDH
– PET/CT scan revealed diffuse adenopathy, with several nodal masses of 4-5 cm in the axillae, abdomen, and retroperitoneum
– Bone marrow biopsy showed 40% peritrabecular infiltration with small cleaved cells, consistent with FL
Patient received bendamustine/rituximab for six cycles, which was well tolerated Posttreatment PET/CT scan showed a moderate amount of persistent disease, with
only a 35% reduction in tumor volume. She declined stem cell transplant As the patient was asymptomatic, the decision was made to watch and wait to
determine the pace of her disease. However, in 11 months, substantial progression was noted
Case Study 3: Refractory FL
Which treatment approach would you recommend for this patient?
a. Clinical trial of a novel targeted therapy
b. R-CHOP
c. Rituximab/lenalidomide
d. High-dose therapy with autologous stem cell transplant
References
American Cancer Society (2015). Cancer facts & figures 2015. Available at: http://www.cancer.org
Ardeshna KM, Smith P, Norton A, et al (2003). Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet, 362(9383):516-522.
Ardeshna KM, Qian W, Smith P. (2014). Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncology, 15:424-435.
Ardeshna KM, et al (2010). Rituximab versus a watch and wait strategy in patients with stage II–IV asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a): a preliminary analysis. 52nd ASH Meeting and Exposition. Abstract 6.
Armitage JO & Weisenburger DD (1998). New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998;1698):2780-2795.
Bartlett NL, LaPlant BR, Qi J, et al (2014). Ibrutinib monotherapy in relapsed/refractory follicular lymphoma (FL): preliminary results of a phase 2 consortium (P2C) trial. 56th ASH Meeting and Exposition. Abstract 800.
Brice P, Bastion Y, Lepage E, et al (1997). Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol, 15:1110-1117.
Casulo C, Byrtek M, Dawson KL, et al (2013). Early relapse of follicular lymphoma after R-CHOP uniquely defines patients at high risk for death: an analysis from the National Lymphocare Study. 55th ASH Meeting and Exposition. Abstract 510.
Cheson BD, Friedberg JW, Kahl BS, et al (2009). Bendamustine produces durable responses with an acceptable long-term safety profile in patients with rituximab-refractory non-Hodgkin’s lymphoma: a pooled analysis. 51st ASH Meeting and Exposition. Abstract 2681.
Cheson BD, Friedberg JW, Kahl BS, et al (2010). Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Clin Lymph Leuk Myeloma, 10(6):452-457. DOI:10.3816/CLML.2010.n.079
Cheson BD, Fisher RI, Barrington SF, et al (2014). Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol, 32(27):3059-3068.
Dave SS, Wright G, Tan B, et al (2004). Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. New Engl J Med, 351(21):2159-2169.
Federico M, Luminari S, Dondi A, et al (2013). R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol, 31(12):1506-1513. DOI:10.1200/JCO.2012.45.0866
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