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