recurrent follicular lymphoma with a short first remission: how aggressive should we be? carla...
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Recurrent Follicular Lymphoma With a Short First Remission:
How Aggressive Should We Be?
Carla Casulo, MD
Wilmot Cancer Institute
University of Rochester Medical Center
Rochester, New York
Lymphoma & Myeloma 2014: An International Congress on Hematologic Malignancies
October 25th, 2014
No Disclosures
Case Presentation 63 year old woman with grade 2-3 FL, stage IV No other significant PMH Treated with R-CHOP 18 months later developed enlarged 3 cm neck mass PET scan showed widespread disease Otherwise feels well
– What is her prognosis?– How aggressive should you be?
Introduction Follicular lymphoma (FL) represents the most common
indolent non-Hodgkin lymphoma (NHL) in the world
Gains in overall (OS) and progression-free survival (PFS) have been made in FL with aggressive treatment strategies and maintenance rituximab
Most patients live many years with minimal impact of disease, but a subset will have aggressive course and short survival
Zelenetz et al. J Natl Compr Canc Netw. 2011 Swenson et al. J Clin Oncol, 2005
Recurrent FL and Risk of Death
Contributors to relapse:– Biologic risk factors:
• BCL6 rearrangement, MYC abnormalities, modification of histones
• Changes in microenvironment; gene expression profiling
– Clinical risk factors• FLIPI score – predicts PFS
– Time to progression?
Smith, Hematology, 2013
20% of Patients With FL Experience Disease Progression Within 24 Months of First Line
Chemoimmunotherapy
This suggests a high-risk group of patients who will relapse
early despite different treatment approaches; maintenance
Press et al. J Clin Oncol. 2013. (SWOG S0016)
60
R-CHOP
100
80
60
40
20
0
24 30 36 42 48 540 6 12 18
Time (months)
Pro
gre
ssio
n-fr
ee s
urvi
val (
%)
1.0
Eve
nt-
fre
e r
ate
Salles et al. Lancet. 2011. (PRIMA)
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
0.0Rummel el al. Lancet. 2013.
B-R
R-CHOP
Time (months)
0 6 12 18 24 30 36 42 48 54 60
Does Short 1st Remission Predict for Poor Overall Survival in FL?
Given that 20% of FL patients have early relapse, The National LymphoCare Study (NLCS) conducted study to determine whether early PD defines patients at high risk for death
– What is the clinical significance of early progression after treatment in FL?
– Is early progression a marker of short OS in FL?
Casulo et al, Proc ASH 2013, Abstract 510
Friedberg et al. J Clin Oncol. 2009.
National LymphoCare Study Sites and Enrollment
The National LymphoCare Study (NLCS) is a multicenter, prospective observational study of 2,727 newly diagnosed patients with FL from 2004 to 2007 at 265 sites in the US
Evaluable patients
for this subset
analysis:– No mixed/
transformedFL
– Stage II-IV– Treatment with
1st line R-CHOP
WASHINGTON
MONTANA NORTH DAKOTA
SOUTH DAKOTA
WYOMING
COLORADO
NEW MEXICO
OKLAHOMA
KANSAS
NEBRASKA
IOWA
MINNESOTA
WISCONSIN
MICHIGAN
ILLINOIS
INDIANA
KENTUCKY
ALABAMA GEORGIA
FLORIDA
PUERTO RICO
SOUTHCAROLINA
NORTH CAROLINA
VIRGINIA
MARYLAND
DELAWARE
WASHINGTON D.C.
NEW JERSEYPENNSYLVANIA
NEWYORK
CONNECTICUT
RHODE ISLAND
MASSACHUSETTS
NEW HAMPSHIRE
MAINE
VERMONT
WESTVIRGINIA
TENNESSEE
OHIO
MISSOURI
ARKANSAS
TEXAS
LOUISIANA
MISSISSIPPI
ARIZONA
IDAHO
NEVADA
UTAH
CALIFORNIA
OREGON
HAWAII
ALASKA
NLCS Participant Selection and Classification
Evaluable patients in the NLCS with newly diagnosed FL (N=2,655)
Stage I or unknown(n=487)
Watchful waiting or other treatment
(n=1,579)
Stage II, III, lV(n=2,168)
First-line R-CHOP(n=588)
Reference group:NO relapse or death
within 2 years of R-CHOP
n=420
Early progressor:Relapse or death within
2 years of R-CHOP
n=122
Distribution of Characteristics by Group
Characteristic Early
ProgressorReference
Group Significance*
Grade 3 histology 34% 40% P=.50
High risk FLIPI 57% 40% P=.01
Elevated LDH 43% 28% P=.01
Low Hgb 35% 22% P=.01
≥ 2 nodal sites 40% 25% P=.01
Poor ECOG PS 16% 4% P<.01
*X2
Poor Survival in FL Relapsing Within 2 Years of 1st line R-CHOP (“Early PD”)
122 patients with early progression – (n=110 PD and n=12 non-PD death within 2 years)
Two-year OS (95% CI) was 71% (61.5–78.0)
Five-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
5 year OS 95%
NLCS: Outcomes for Early Progressors Similar to other studies:
– 21% of patients relapsed early after treatment
Early PD associated with significantly poor OS:
– Hazard ratio (HR)=13.3 (95% CI: 7.94–22.4)
After adjusting for FLIPI score, early PD associated with an increased risk of death:
– HR=15.4 (95% CI: 9.6–24.7)
Replication/Validation Study NLCS outcomes replicated at the University of
Iowa/Mayo Clinic
– Cohort: 103 patients with FL treated with R-CHOP in first line setting
Characteristics well matched, except more grade 3 FL in UI/Mayo cohort than NLCS (62% vs 38%; p<0.01)
20% (N=21) had early progression/death, similar to NLCS
UI/Mayo Validation Set: Poor Outcomes in Early Relapsed FL
After 1st Line R-CHOP (“Early PD”)
0
Years from diagnosis
0.0
0.2
0.4
0.6
0.8
1.0
1 2 3 4 5 6 7 8 9 10
Sur
viva
l pro
babi
lity
Two-year OS (95% CI) was 57% (40–83) Five-year OS (95% CI) was 32% (17–60)
Median follow up: 6 years
Unadjusted HR=24.2 (95% CI: 8.6–67.8)
FLIPI adjusted HR=23 (95% CI: 7.9–64.3)
NLCS Conclusions Relapsed FL is a heterogeneous entity
– Variable outcomes
PD within 2 years of R-CHOP uniquely defines a group of patients at a substantially greater risk of death
Patients with short remission following chemo-immunotherapy are a high-risk group warranting further exploration in clinical trials
How Aggressive Should We Be With Early Relapse after Treatment in FL?
Can we reverse the poor outcomes associated with early relapse in FL?
What are outcomes with second line treatments?– Standard chemotherapies vs. targeted therapies– Role of stem cell transplant
Is there hope for long term disease control?– No consensus on risk stratification, prognostic tools at
relapse
Conventional Treatment Options in Relapsed FL
Treatment Overall Response
Rate
Remission Duration/
PFS
Rituximab 40% 18 months
Bendamustine + Rituximab
90-94%24 months
R-CHOP 85% 33 months
Davis et al. J Clin Oncol 2000; Rummel et al. J Clin Oncol 2005; Robinson et al. J Clin Oncol 2008; vanOers et al.
Intensification of Treatment in Relapsed FL: Role for ASCT
SHOULD you refer and WHEN ?– no OS benefit in first remission– high response rates, ? plateau in survival
Toxicity considerations; secondary risks
Laport. Hematology 2013; Khabori et al. JNCI 2011; Rohatiner J Clin Oncol 2007
Myelodysplasia following ASCT (up to 20% at 10 years, especially with TBI regimens)
The CUP Trial: ASCT in Relapsed FL
CHOP x 3 if response, randomization:– ASCT with/without purged marrow OR– 3 more cycles CHOP
89 patients randomized:– Trial closed prematurely due to poor accrual– Median follow-up 69 months
No rituximab in induction or maintenance
Schouten et al, J Clin Oncol, 2003
CUP Trial Outcomes: ASCT vs. Chemo in Relapsed FL
PFS: Superior for ASCT
4 yr OS: 46%; 71%; 77%(p=0.071):
ASCT arms
Standard chemo
Schouten et al, J Clin Oncol 2003
Timing of ASCT in Relapsed FL?
Survival impacted by number prior regimens
Vose et al. Biol Bld Mar Trans, 2008; Rohatiner J Clin Oncol 2007
Remission Duration following ASCT in Relapsed FL Can be Durable:
Rohatiner et al J Clin Oncol 2007
Pettengel et al. J Clin Oncol. 2013
Median fu 13 years5 yr OS 71%10 yr OS 54%
Median fu 8 years10 yr OS 66, 75%
ASCT vs. allo for Relapsed FL in the Rituximab Era: NCCN analysis
184 patients with relapsed/refractory FL following rituximab containing treatment– ASCT, N=136– alloSCT, N= 48– Median 3 prior
treatments– Most chemo-sensitive at
transplant
Evens et al, Cancer 2013
ASCT 3 yr OS 87%
alloSCT 3 yr OS 63%
No difference FFS
Higher toxicity, NRM allo
NCCN Risk Factors: ASCT for Relapsed FL
Multivariate Analysis – Older age, more
treatment: adverse predictors
– At 3 years OS• 0 factors: 96% • 1 factor: 82%• 2 factors 62%
Evens et al, Cancer 2013
No Factors
1 Factor
2 Factors
Prognostic Score: Age > 60; > 3 Prior
Therapies
Non myeloablative alloSCT for Relapsed FL: MD Anderson Experience
47 patients– 9 year follow up
Khouri et al. Blood 2012
Conclusions: NCCN Study on ASCT vs. allo in Relapsed FL
ASCT has excellent outcome in the rituximab era – 5 yr OS > 80%
ASCT, alloSCT have equivalent FFS in relapsed FL
Late deaths in allo group (several > 5 yrs after transplant) limit OS– mainly from complications
ASCT should be considered the transplant option for relapsed follicular lymphoma
What about Novel Agents? Idelalisib
– Phase II, 72 FL– Combinations
• + lenalidomide • + bendamustine +
rituximab
Ibrutinib
– Phase I, 16 FL– Combinations
– + lenalidomide
Lenalidomide– Phase II, 16 FL– Combinations
• + rituximab
GDC-0199– Phase I, 11 FL– Combinations
• + bendamustine + rituximab
Gopal et al. NEJM 2014; Fowler et al. Proc ASH 2012, abstract 156; Advani et al J Clin Oncol 2012; Witzig et al. J Clin Oncol 2009; Wang et al. Leukemia 2013; Davids Proc ASCO 2014
Back to our patient…. 63 year old woman with FL, stage IV, relapsed 18
months from R-CHOP– What is her prognosis? 5 yr OS 30-50%– How aggressive should you be?
Standard treatments: median PFS ~18-24 months Investigational treatments: median PFS ~ 12 months ASCT: 3 year OS ~ 85%
– Earlier may be better, non TBI regimen
For an otherwise healthy patient, good PS, may consider aggressive strategies
Conclusions FL with short first remission has a poor prognosis
– Consider intensive second line treatments
ASCT associated with durable long term remissions, possible cure?
Combinatorial, novel targeted agents may pave the way for improved outcomes
Acknowledgments
Mentor
Jonathan Friedberg
Funding Sources
-ASH Clinical Research Training Institute
-University of Rochester SPORE Career Development Award in Lymphoma Research