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 amp Myeloma 2014 An International Congress on Hematologic Malignancies ID: 287067
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Slide1
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 25
th
, 2014Slide2
No DisclosuresSlide3
Case Presentation63 year old woman with grade 2-3 FL, stage IVNo other significant PMHTreated with R-CHOP 18 months later developed enlarged 3 cm neck massPET scan showed widespread disease Otherwise feels wellWhat is her prognosis?How aggressive should you be?Slide4
IntroductionFollicular lymphoma (FL) represents the most common indolent non-Hodgkin lymphoma (NHL) in the worldGains in overall (OS) and progression-free survival (PFS) have been made in FL with aggressive treatment strategies and maintenance rituximabMost 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
, 2005Slide5
Recurrent FL and Risk of DeathContributors to relapse:Biologic risk factors:BCL6 rearrangement, MYC abnormalities, modification of histonesChanges in microenvironment; gene expression profilingClinical risk factorsFLIPI score – predicts PFSTime to progression?
Smith,
Hematology
, 2013Slide6
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
2
4
30
36
42
4
8
54
0
6
12
18
Time (months)
Progression-free survival (%)
1.0
Event-free rate
Salles
et
al.
Lancet.
2011. (PRIMA)
Rituximab maintenance
0.8
0.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
54
60
Time (months)
Probability
1.0
0.8
0.6
0.4
0.2
0.0
Rummel el al.
Lancet.
2013.
B-R
R-CHOP
Time (months)
0
6
12
18
24
30
36
42
48
54
60Slide7
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 510Slide8
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/
transformed
FL
Stage II-IV
Treatment with
1
st
line R-CHOPSlide9
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=122Slide10
Distribution of Characteristics by Group
Characteristic
Early Progressor
Reference 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
*
X
2Slide11
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
10
0.0
0.2
0.4
0.6
0.8
Patients at risk:
101
78
69
58
49
45
33
14
6
0
Time (years)
Survival probability
122
Early
Progressor
420
420
407
387
363
344
252
144
33
0
420
Reference=
Early =
Reference Group
5 year
OS
95%Slide12
NLCS: Outcomes for Early ProgressorsSimilar to other studies:21% of patients relapsed early after treatmentEarly 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) Slide13
Replication/Validation StudyNLCS outcomes replicated at the University of Iowa/Mayo ClinicCohort: 103 patients with FL treated with R-CHOP in first line settingCharacteristics 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
NLCSSlide14
UI/Mayo Validation Set: Poor Outcomes in Early Relapsed FLAfter 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
Survival probability
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)Slide15
NLCS ConclusionsRelapsed FL is a heterogeneous entityVariable outcomesPD 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 trialsSlide16
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 therapiesRole of stem cell transplantIs there hope for long term disease control?No consensus on risk stratification, prognostic tools at relapse Slide17
Conventional Treatment Options in Relapsed FLTreatment
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. Slide18
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 2007Myelodysplasia following ASCT (up to 20% at 10 years, especially with TBI regimens)Slide19
The CUP Trial: ASCT in Relapsed FLCHOP 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
,
2003Slide20
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
2003Slide21
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 Slide22
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 years
5
yr
OS 71%
10 yr OS 54%
Median
fu 8 years10 yr
OS 66, 75%Slide23
ASCT vs. allo for Relapsed FL in the Rituximab Era: NCCN analysis 184 patients with relapsed/refractory FL following rituximab containing treatmentASCT, N=136alloSCT, N= 48Median 3 prior treatmentsMost 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
alloSlide24
NCCN Risk Factors: ASCT for Relapsed FLMultivariate Analysis Older age, more treatment: adverse predictorsAt 3 years OS0 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 TherapiesSlide25
Non myeloablative alloSCT for Relapsed FL: MD Anderson Experience 47 patients9 year follow up
Khouri
et al.
Blood
2012Slide26
Conclusions: NCCN Study on ASCT vs. allo in Relapsed FLASCT 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 Slide27
What about Novel Agents?IdelalisibPhase II, 72 FLCombinations+ lenalidomide + bendamustine + rituximab IbrutinibPhase 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 Slide28
Back to our patient….63 year old woman with FL, stage IV, relapsed 18 months from R-CHOPWhat 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 strategiesSlide29
Conclusions FL with short first remission has a poor prognosisConsider intensive second line treatmentsASCT associated with durable long term remissions, possible cure?Combinatorial, novel targeted agents may pave the way for improved outcomesSlide30
AcknowledgmentsMentorJonathan FriedbergFunding Sources -ASH Clinical Research Training Institute -University of Rochester SPORE Career Development Award in Lymphoma Research