Andrew M. Evens, DO, MSc October 26th, 2019

Professor of Medicine, Rutgers RWJ Medical SchoolAssociate Director (Clinical Services), Rutgers CINJ

Director, Lymphoma ProgramMedical Director, Oncology Service Line, RWJBH

New Brunswick, New Jersey, USA

How Best to Approach Hodgkin Lymphoma in Older Patients

• Research advisory board or educational event (with honorarium): Seattle Genetics, Epizyme, Novartis and Pharmacyclics; Physician Education Resource Research to Practice

• Research support: Takeda, Seattle Genetics, and Tessaro

• Off label: checkpoint inhibitor therapy in frontline

Disclosures

US Age-Specific SEER Incidence Rates

SEER 21 (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta, San Jose-Monterey, Los Angeles, Alaska Native Registry, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, Georgia excluding ATL/RG, Idaho, New York and Massachusetts).

Age-Related Racial Incidence: US SEER Data

Evens AM, et al. Ann Oncol 2012

White Black

A/PI Hispanic

• Defined: age ≥ 60 years• Under-represented in clinical trials: <5-10%

(vs 15-25% population)

Elderly Hodgkin Disease/Lymphoma

• Outcomes disproportionately inferior to younger patients: EFS and OS ~ 40-50%

• Standard treatment approach been absent• Why?

– Co-morbidities precluding appropriate Rx– Inadequate treatment delivery/intensity– Treatment-related toxicities (esp. BLT)– Advanced stage (60-80%)– ? Different biology/disease (e.g., mix cell, EBV)

Overall survival (by age)

OS by age

OS of pts ≥ 60 years compared with an age-and sex-matched (ASM) population

Outcomes of Elderly HL

Stark et al. BJH, 2002; 19:432

Treatment of Elderly HL(1970 to 2000)

• Decreased intensity of chemotherapy and individualized dosing– e.g., CVP/CEB, ChlVPP +/- OEPA, VEPEMB

• Non-anthracycline options– e.g., VBM, ChlVPP, BCVPP

• Dose intensity important?– 5-year CSS 51%, OS 39% (MOPP/ABV)– RDI > 65% improved OS (P=0.001)

• BEACOPP baseline: 21% TRMLevis A et al. Haematologica 1996; Enblad G et al. Acta Oncol 2002; Bakemeier RF et al. Ann Intern Med 1984; Zinzani PL et al. Haematologica 2000; McElwain TJ et al. Br J Cancer. 1977; Levis et al Ann Oncol. 2004; Weekes, et al. JCO. 2002; Landren et al. Haematologica. 2003;

Anthracyclines important?• From 1982 to 1998: 56 pts ≥60 years old

ChlVPP or ChlVPP/ABV– 5-year EFS and OS for pts <60: 75% and 87%

vs pts ≥60 years EFS and OS: 31% and 39%– 5-year OS pts >60: 30% with ChlVPP (n=31) vs

67% with ChlVPP/ABV (n=25), P 0.0086 Weekes, et al. JCO. 2002.

Chicago Elderly HD (2000-2009)• Retrospective analysis (1/00-1/10), n=95 HD

pts ≥ age 60 years (median 67 yrs; 60-89; 33% ≥ age 70)– U Chicago, Rush, Northwestern, LGH, Loyola

• Characteristics– NOS 42%, NS 34%, MC 18%, and LP 6%– Prior malignancy 27%, Hx CAD 20%, B sx 52%,

Wt loss 35%, PS >1 29%, and stage III/IV 65%, and IPS 4-7 in 64%

• Functional status– 61% with any grade 3-4 co-morbidity (CIRS-G),

29% “not fit”, 13% loss ADLs, and 18% w/ geriatric syndrome

Evens AM et al. Blood 2012; 119:692-5

Chicago Elderly HD: EFS + OS: A Prognostic Model?

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1) ADL loss2) >70 years

Evens AM et al. Blood 2012; 119:692-5

• MVA: age >70 & loss ADLs• BLT 33% (mortality: 31%)

Evens AM and Hong F. JCO 2013

Survival: Older vs Younger HL

< 60 years =/> 60 years PFFS 3-year 76% 56% 0.002

5-year 74% 48%OS 3-year 93% 70% <0.0001

5-year 90% 58%

Failure-free survival Overall survival

<60 yr ≥ 60 yr <60 yr ≥ 60 yr

Evens AM et al. BJH 2013

E2496 Older Patients: Toxicity

• Overall treatment-related mortality: 9.3% (vs 0.3% <60 years, p<0.001)– Grade 5: 2 ABVD (bleomycin lung toxicity n=2)

and 2 Stanford V (GI bleed/RF+ colitis/sepsis) • Bleomycin lung toxicity

– CTCAE coding: grade 3 or 4 hypoxia, DLCO, pneumonitis, pulmonary other, etc

– Overall incidence: 26% (fatality rate: 18%)– Age 69 yrs (61-78) and 50% (5/10) non-smokers– 91% (10/11) received ABVD– Timing: Cycle 3 (n=2), cycle 4 (n=2), cycle 5 (n=2),

cycle 6 (n=3), month 3 (n=1)2 Fatalities Evens AM et al.

Brit J Haem 2013

Targeted Therapeutic Platforms (Contemporary Clinical Trials)

Geriatric Assessment (GA) 101• Co-Morbidity: Cumulative Illness Rating

Scale-Geriatrics (CIRS-G)– 14 organs (cardiac, vascular, heme, respiratory,

ENT, upper/lower GI, hepatobil, renal, GU, bone-skin, neuro, endocrine, psych)

• Instrumental vs self care ADLs– Instrumental: Housework, Meal Prep, Manage

money, Take meds, Shopping, Laundry, Use phone, Use transportation

– Self care: bathing, dressing, transferring, toileting, feeding, continence

• Fit: no ADL loss; < 3 grade 3 CIRS-G (or <5 grade 2); & and no geriatric syndrome

Mohile SG et al. J Clin Oncol 2018

Clinical Judgment vs GA• CGA performed in 84 DLBCL pts aged >65 years• Treatment w/ curative vs palliative intent chosen

according to clinical judgment• 50% deemed fit by GA (ORR 93% vs 48% for unfit)• 50% unfit by GA: half treated with curative and half

palliative Rx — outcomes not different

Tucci A et al. Cancer 2007

Brentuximab Vedotin in Unfit Elderly HL

• Single agent brentuximab vedotin:– 1.8 mg/kg q 3 wks in 27 elderly HD pts – Median age 78 yrs, 63% stage III/IV

• ORR 92% (73% CR)• 30% pts grade 3 neuropathy

PFS (all pts) PFS (CR pts)

Forero-Torres et al. Blood, 2015

BV + DTIC or Bendamustine in Elderly HL

• 1.8 mg/kg BV + 90/70 mg/m2 bendamustine– 65% SAE (including 2 toxic deaths)

• 1.8 mg/kg BV + 375 mg/m2 DTIC (12 cycles)– BV + DTIC: ORR 100% (62% CR)– 27% pts grade 3 neuropathy

PFS (all pts) PFS (CR pts)

Friedberg J et al. Blood, 20173 yr PFS & OS: 52% & 90%; 1 G3 PN (ASCO 2018)

Incorporation of Brentuximab Vedotin into Frontline Therapy

PET1 and CT1 (Staging)

BV x 2 cycles(1.8 mg/kg q 3 wks)

AVD x 6 cycles

BV consolidation(1.8 mg/kg q 3 wks x4)

PET2 (first 22pts)

CT + PET (all pts)

METHODS• Simon 2-stage with 48 total pts (8/2012 to 8/2016)•Primary endpoint: complete remission (CR) rate after AVD• Co-morbidity (CIRS-G) & ADL assessments• If ≥14 CRs among 23 evaluable pts, accrual continued to 2nd stage (evaluable = 2 cycles of AVD therapy)• Lugano criteria utilizing FDG-PET/CT

Benchmark for CR Rate?

GHSG• PVAG: ORR 81%, CR 78%

SHIELD• ABVD: ORR 64%, CR 46%• VEPEMB (ITT): CR 61%

E2496• ABVD/Stanford V – ORR 78%/70%,

CR 70%/65%Proctor S et al. Blood 2012

Boll B et al. Blood 2011

Evens AM et al. BJH 2013

Patient CharacteristicsCharacteristic N=48 (median) Percent (range)Age Median 69 years 60-88 yrsGender Male

Female63%37%

Histology NSMCcHDLR

46%25%25%4%

EBV EBER 14 30%ECOG PS Median 1 21% PS=2Bone marrow (+) 11 23%Stage III / IV 39 82% IPS Median 4 3-7 in 58%Functional status Median CIRS 7 (1-20)

Loss of IADLsGeriatric syndrome

52% Grade 3-413%8%

Results: Efficacy

Bv x 2 AVD x 3AVD x 3 Bv x 4

ORR 82%CR 36%

(PET)

ORR 98%CR 76%

ORR 95%CR 90%

ORR 95%CR 93%

(N=48) (N=41)

ITT (n=48) after 6 AVD: ORR 88% and CR 81%

Evens A et al. J Clin Oncol 2018

Adverse Events

• SAE in 42% of pts• Initial 2 AVD: Six

grade 3 (14%) and one (2%) grade 4 non-hematologic AEs

• Grade 2 PN in 33% pts (27% sensory)• 69% reversible

Grade 3/4 SAE PercentInfection 15%Febrile Neutropenia 6%Elevated transaminases 6%Renal insufficiency 6%UTI 6%Pneumonia 6%Hyponatremia 6%Fatigue 6%Diarrhea 4%Pancreatitis 4%Peripheral neuropathy 4%Pruritis 2%

Older cHL pts Sequential A-AVD: Survival

2-year EFS 80%

2-Year PFS 84%

2-year OS 93%

Evens AM et al. J Clin Oncol 2018

Outcomes based on function

ECHELON-1 Forest plot of modified PFS per IRF by age

Connors J et al. NEJM 2018

N=186 pts ages ≥ 60 years

- Detailed analysis ECHELON-1 older pts ASH 2018

ECHELON-1 Older HL Patients

Evens AM et al. ASH 2018

• 2-year modified PFS: ABVD 70.3% vsA+AVD 71.4%– Stage 4 median PFS: 60 vs 74 months

(P=0.20)• Toxicity (ABVD vs A+AVD)

– Fatal AEs: 5% vs 4%, respectively– Febrile neutropenia: 17% vs 37%,

respectively– Pulmonary: 13% vs 2%, respectively– Neurotoxicity: 10% vs 29%, respectively

(grade 3 PN: 3% vs 18%, respectively)

Overall Summary• Outcomes historically suboptimal; recent

data suggesting survival improvement• Geriatric measures important (minimum: co-

morbidities & ADLs)• Fit: Bv-AVD effective & tolerable (sequential)

– B-CAP, PVAG, CHOP, AVD– Caution bleomycin lung toxicity

• Frail: Bv +/- DTIC, ChlVPP, etc• Need continued prospective studies

– Tailor therapy on geriatric measures– Integrate newer targeted therapeutics

Acknowledgements

• Stephen Proctor (UK) and Sandra Horning

• Co-I’s (P.Hamlin & L.Gordon) • NCI R01 GM127714, NIH R33

CA223908, NCI U01CA187947, NIH R01 EB012521, LLS TRP and ORIEN

• Patients and families

THANK YOU!

BACK UP SLIDES

Competing risk analysis

Evens AM and Hong F, JCO 2013; 31:1502-1505

Bleomycin lung toxicity (BLT): potentially life threatening

• Risk factors– renal insuff, pulm. RT, underlying lung disease,

tobacco hx, supplemental O2 and older age– G-CSF causes infiltration alveolar neutrophils with

pro-inflammatory cytokines + free radicals (bleomycin) à pulmonary edema and fibrosis

• Incidence– 5% to 31% w/ assoc. mortality rate of 9% to 23%– Mayo Series, BLT: 26% +G-CSF vs. no G-CSF 9%

(24% mortality rate)

Adachi. Tox Path 2003; Azouly A. Crit Care Med 2002; Evens A. Blood 2009. Stamatoullas A. BJH 2015

Early-stage Elderly HD: GHSG

• HD10 and HD11: 68 and 49 elderly HD pts (median ages 65 and 64 years)

• HD10: 2-4 ABVD + 20-30 Gy• HD11: ABVD vs BEACOPP(base) +

20/30Gy• WHO grade 3/4 toxicities: 68% (grade 4)

18%• TRM of 5% (vs 0.4% in age <60 years) • CR rate 89% (vs 95% younger pts,

p=0.001)Boll B et al. JCO 2013; 31:1522-29

CHOP in elderly HD• CHOP-21: 29 pts (11 stage I/II; 18 stage III/IV)

with median age 71 years (60–91 yrs) treated with 2-4 cycles + XRT or 6-8 cycles of CHOP– CR rate 93% – Median f/u 41 months:

3-year PFS 76%, OS 79%– Early stage pts (n=11):

3-yr PFS 82% and OS 91%– Advanced stage (n=18):

3-yr PFS 72% and OS 67% – Febrile neutropenia 31%,

10% grade 3 polyneuropathy

Kolstad et al. Leuk Lymphoma. 2007; 48:570

SHIELD Programme• VEPMB: median age 72 years• CR rate: 75% for ES and 61% for AS • 3-year OS and PFS of 66% and 58%,

respectively• TRM 7%

Proctor S et al. Blood 2012CR: Hgb, ADL, IDL, Comorbid, PS, albumin

Brentuximab vedotin in older R/R HD pts

• Clinical trials SG035-0001 to SGN35-008 • N=16 pts (median age 66, range 60-82)• Versus young pts: worse PS, creatinine, co-

morbidities, con meds, and prior cancer Rx• More anemia (30% vs 10%), sensory PN (60%

vs 46%), fatigue (58% vs 43%), and any grade 3/4 (70% vs 56%)

• ORR 56%, median OS 12.4 months (2-yr 48%)• No factors predicted response or toxicity

(besides prior hx of AEs)Gopal A. Leuk and Lymph 2014

Fanale, et al. J Targ Ther Cancer 2015

Evaluable patients (for ORR/CR)

- 42 / 48 patients evaluable (<2 cycles AVD)- 6 inevaluable

- 1 TRM d/t pancreatitis (BV)*- 4 toxicity (pneumonia/diarrhea/UTI [BV]

diarrhea [BV], hepatic [BV], wound infection/syncope [C1 AVD])

- 1 withdrew consent (diarrhea [BV])- CIRS score of inevaluable pts (median):

12 (range, 10-19) vs. 6 (range, 0-20) for evaluable pts, P=0.001

*Ghandi MD et al. Blood 2014

Sequential Bv-AVD: Therapy Received

- 88% completed at least three cycles of AVD

- 77% pts completed 6 cycles of AVD- 73% received at least 1 Bv

consolidation (including pts who received <6 AVD)

- 52% pts completed all 12 cycles of therapy

Evens A et al. J Clin Oncol 2018

Pancreatitis in patients treated with brentuximab vedotin

Ghandi MD, et al. Blood. 2014; 123:2895-7

Characteristics DataMedian age (years) 45 (range: 23-65)

Indication cHL (n=7); ALCL (n=1)Median number of BV doses 2 (range, 1-3)

Median BV dose 150 mg (range: 85-180 mg)Median onset from most recent

dose 12 days (range: 9-16 days)

Median lipase (u/L) 599 (range: 169-1143)

Severity of pancreatitis AE Grade 5 (n=2); Grade 4 (n=1); Grade 3 (n=6)

- Overall incidence acute pancreatitis: 0.16 to 0.25%

Reasons for Discontinuation of Treatment

• 52% completed all intended Tx• 65% at least 1 Bv consolidation

• 9% withdrew consent• 6% No response or PD • 33% due to toxicity (TRM 2%)

• 12% discontinued for PN (all grade 2 status-post cycles 6, 8, 9 and 11)

Evens AM et al. J Clin Oncol 2018

Prognostication

Univariate (inferior PFS)• Increasing age (continuous) HR 1.16

(P=0.005); female sex HR 4.97 (P=0.05); loss IADLs HR 14.88 (P=0.005); and increased CIRS (>10) HR 1.20 (P=0.005)

Multivariate (inferior PFS)• Loss IADLs HR 13.02 (P=0.05)

Evens A et al. J Clin Oncol 2018

Sequential A-AVD in older HL pts: Conclusions

• Bv incorporated sequentially before & after AVD associated with high CR rate and well tolerated in majority of pts

• Excellent survival rates – longer follow-up warranted

• Geriatric measures are prognostic• Future directions

– Need identify novel/less toxic therapy for less fit/frail (co-morbid) patients

– Fit pts: maintain outcomes w/ less therapyEvens AM et al. J Clin Oncol 2018

B-CAP trial designHL patients ≥ 60 years

Interim staging

30 Gy RT on PET+ lesions ≥2.5cm

2x B-CAP

Advanced stage and eligible for poly-chemotherapy

4x B-CAP

Restaging

Interim staging

+ ≤10x BV + RT at investigator’s discretion

2x BV

Any stage and not eligible for poly-chemotherapy

4x BV

Restaging

Main inclusion criteria:• Histologically proven

classical HL• 60 years or older• Advanced stages (II B

with large mediastinal mass and/or EN HL, III and IV)

• CIRS-G score ≤6 and ≤3 per organ system

Response after ≤6 cyclesITT population

#LCL, Lower confidence limit * Response after B-CAP missing in 1/49 patients (death before restaging).

ITTN=48*

N % 95%LCL#

CT-basedresponseCR/CRu 21 44%

PR 26 54%

PD 1 2%

Objectiveresponse 47 98% 90.5%

CR/CRuN=21

PRN=26

PDN=1

TotalN=48*

PET-basedremissionstatus

DS1 13 2 15(31%)

DS2 7 6 13(27%)

DS3 1 2 3(6%)

DS4 10 10(21%)

DS5 6 1 7(15%)

Metabolic CR rate: 31/48=65%

Progression-free survivalITT population

49 45 23 12number at risk

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One-yearestimate: 73.9%[61.1%to86.6%]Medianobservationtime15months