How Do I Manage the Advanced Stage Hodgkin Lymphoma Patient and What Do I Do at First

Relapse?

Kami Maddocks, MDThe Ohio State University James Cancer Center Columbus, Ohio

• Research Funding§ Pharmacyclis, Novartis, Merck, BMS

• Advisory/Honorarium§ Pharmacyclics, AstraZeneca, Celgene, Morphosys, Teva, Bayer

Disclosures

Background• ~ 8,500 new cases diagnosed

• ~ 1,050 deaths each year

• Bimodal age distribution

• Risk factors of Immunodeficiency

• Advanced Stage – III/IV– Inclusion of high risk stage II: Bulky, B

symptoms

Hasenclever D et al. N Engl J Med. 1998;339(21):1506-1514

Prognostic Factors• Advanced stage (III-IV, OS 60-

90%)

• Hasenclever score§ Age > 45§ Male§ Albumin < 4.0§ Hgb < 10.5§ Stage IV§ WBC > 15§ Lymphopenia < 0.6

5 yr FFP 5 yr OS

0 84% 89%

1 77% 90%

2 67% 81%

3 60% 78%

4 51% 61%

5 42% 56%

0-3 70% 90%

4-7 47% 60%

Canellos et al. NEJM 1992;327:1478-1484

ABVD for Advanced Stage HD

CR rateMOPP: 67% versusABVD: 82% and MOPP/ABVD: 83%(p=0.006)

OSMOPP: 66%ABVD: 73% and MOPP/ABVD: 75%(p=0.28)

ABVD vs BEACOPP/escBEACOPP

Improve PFS but not OS at expense of toxicity and fertility

Cure ~70% with ABVD

Interim PET scan Predictive of Outcomes

Stroobants S, Hematology 2004:188-190.

Baseline PET/CTABVD x 2 cycles,

then PET/CTN=1203

BEACOPP-14 (4 cycles) or BEACOPPesc (3 cycles), N=172 (94, 78); PET/CT

2 cycles BEACOPP-14 or BEACOPPesc (1 cycle); no

RT

PET positiveN=41

PET negativeN=119

RT or salvage regimen

Randomize

Follow-up (no RT)

PET POSITIVEN=182

ABVD (4 cycles)

N=470

Johnson. NEJM. 2016;374:2419.

RATHL STUDY Advance Stage Disease

PET/CTN=1119

PET NegativeN=937

AVD (4 cycles)

N=465

Follow Up(No XRT)

De-escalation based on iPET§ AVD is noninferior to ABVD in all subgroups; no loss of disease control, FFP 85 %

§ Interim PET negative rate ~ 80%

ABVDAVD

n470465

3-Yr OS,%

97.297.6

n470465

ABVDAVD

3-Yr PFS,%

85.784.4

Johnson. NEJM. 2016;374:2419.

Toxicity Concerns

Johnson. NEJM. 2016;374:2419.

Escalation based on iPETStudies in stage III-IV HL ABVD for 2 cycles followed by PET/CT, with pts receiving 4 additional cycles of A(B)VD (PET negative) or BEACOPPesc (PET positive)

Gallamini, 2011 165(≤65) 28/165 17 65% (3Y)

Johnson RATHL, 2016 1214(18-79) 182/1119 16 68% (3Y)

Press, SWOG 0816, 2016 336(18-60) 60/331 18 64% (2Y)

Ganesan, 2015 50(12-60) 8/49 16 50% (2Y)

Interim PET positive rate: ~ 20%Interim PET positive impact of switch to intensive treatment: FFP ~60%

Pts (age) iPET+ % PFS

RATHL Escalation

Johnson. NEJM. 2016;374:2419.

3-year PFS 67.5%

No significant difference higher thrombocytopenia and neutropenia with escBEACOPP

Baseline PET/CTABVD x 2 cycles,

then PET/CTN=358

6 cycles BEACOPPesc

N=55

Randomize

Follow-up (no RT)

PET POSITIVEN=60 (18%)

ABVD (4 cycles)

N=470

US Intergroup Study S0816

PET/CTN=331

PET NegativeN=271v(82%)

Follow Up(No XRT)

Press. J Clin Oncol. 2016;34:2020.

US Intergroup Study S0816 • Prospective study assessing efficacy of response-adapted therapy (ABVD for 2 cycles followed by PET/CT assessment and

subsequent BEACOPPesc or ABVD) for patients with stage III-IV HL (N = 358)

Press. J Clin Oncol. 2016;34:2020.

Brentuximab Vedotin

• Brentuximab vedotin targets CD30• ORR 72% in R/R HD• Peripheral Neuropathy

Younes A, et al. Lancet Oncol 2013;14:1348–56; Connors JM, et al. Blood 2017;130:1375–7.

cHL, classic Hodgkin lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EOT, end-of-treatment; PFS, progression-free survival

ECHELON-1: Randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced cHL

• Inclusion criteria– cHL stageIII or IV– ECOG PS 0, 1 or 2– Age≥18 years – Measurable disease– Adequate liver and renal

function

218 study sites in 21 countries worldwide

Scre

enin

gC

T/PE

T sc

an

1:1

rand

omiz

atio

n(N

=133

4)

ABVD x 6 cycles (n=670)

A+AVD x 6 cycles (n=664)Brentuximab vedotin: 1.2 mg/kg IV infusion

Days 1 & 15

EOT

CT/

PET

scan

Follow-up

Every 3 months for 36 months, then every

6 months until study closure

End-of-Cycle-2 PET scan• Deauville 5; could receive alternate

therapy per physician’s choice (not a modified PFS event)

Modified PFS per independent review

TimeA+AVD (95% CI)

ABVD(95% CI)

2-year

82.1 (78.7–85.0)

77.2 (73.7–80.4)

Median follow-up (range): 24.9 months (0.0–49.3)

CategoryA+AVDN=117

ABVDN=146

Progression 90 102Death 18 22Modified progression

ChemotherapyRadiotherapy

972

22157

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

664670

640644

623626

606613

544522

530496

516476

496459

474439

447415

350328

334308

311294

200179

187168

174153

9978

8568

7762

2716

2413

2112

61

41

41

00

00

Time from randomization (months)

Prob

abili

ty o

f mod

ified

PFS

No. of patients at risk:A+AVDABVD

HR 0.77 (95% CI: 0.60–0.98)Log-rank test p-value: 0.0348

A+AVDABVD

CensoredCensored

0.9

0.7

0.5

0.3

0.1

Modified PFS estimates

Number of events

Connors JM et al. N Engl J Med. 2018;378:331-344.

Forest plot of modified PFS per IRF: subgroup analysis

0.1 0.5 1

Favors ABVD

Hazard ratio

Favors A+AVD

Overall 117/664 (17.6) 146/670 (21.8) 0.77 (0.60–0.98)Age <60 years 93/580 (16.0) 117/568 (20.6) 0.73 (0.56–0.96)Age ³60 years 24/84 (28.6) 29/102 (28.4) 1.01 (0.59–1.73)Age <45 years 70/451 (15.5) 83/423 (19.6) 0.73 (0.53–1.01)Age ³45 years 47/213 (22.1) 63/247 (25.5) 0.86 (0.59–1.26)Region: Americas 41/261 (15.7) 58/262 (22.1) 0.65 (0.44–0.97)Region: North America 38/250 (15.2) 57/247 (23.1) 0.60 (0.39–0.90)Region: Europe 62/333 (18.6) 74/336 (22.0) 0.83 (0.59–1.17)Region: Asia 14/70 (20.0) 14/72 (19.4) 0.91 (0.43–1.93)IPS: 0–1 22/141 (15.6) 25/141 (17.7) 0.83 (0.47–1.48)IPS: 2–3 57/354 (16.1) 68/351 (19.4) 0.79 (0.56–1.13)IPS: 4–7 38/169 (22.5) 53/178 (29.8) 0.70 (0.46–1.07)Stage III 40/237 (16.9) 43/246 (17.5) 0.92 (0.60–1.42)Stage IV 77/425 (18.1) 102/421 (24.2) 0.71 (0.53–0.96)B symptoms: Present 77/399 (19.3) 94/381 (24.7) 0.74 (0.55–1.01)B symptoms: Absent 40/265 (15.1) 52/289 (18.0) 0.79 (0.52–1.20)Extranodal sites: 0 40/217 (18.4) 39/228 (17.1) 1.04 (0.67–1.62)Extranodal sites: 1 36/217 (16.6) 45/223 (20.2) 0.75 (0.48–1.16)Extranodal sites: >1 39/194 (20.1) 57/193 (29.5) 0.67 (0.44–1.00)Gender: Male 64/378 (16.9) 90/398 (22.6) 0.71 (0.51–0.97)Gender: Female 53/286 (18.5) 56/272 (20.6) 0.86 (0.59–1.26)

Subgroup A+AVD ABVDEvent / N (%) Hazard ratio (95%

CI)

Connors JM et al. N Engl J Med. 2018;378:331-344.

Forest Plot pre-specified subgroups per investigator

PET2+ Disease with AVD + BV

ECHELON-1(Stage III or IV, < 60 years)

A+AVD ABVD

3-year PFSAll patients

84.9% 77.8%

3-year PFSPET2(-) patients

87.2% 81.0%

3-year PFSPET2(+) patients

69.2% 54.7%

Treatment-Emergent Febrile Neutropenia and AEs by Primary Prophylaxis With G-CSF

Connors JM et al. N Engl J Med. 2018;378:331-344.

• G-CSF primary prophylaxis for BV+AVD resulted in an overall safety profile comparable to ABVD• G-CSF primary prophylaxis is recommended for all BV+AVD patients

Peripheral Neuropathy and Pulmonary Events

Connors JM et al. N Engl J Med. 2018;378:331-344.

• 67% of patients with PN in the BV+AVD arm had resolution or improvement by ≥1 grade at last follow-up

• Of those with ongoing PN at last follow-up:– Grade 1: 67%– Grade 2: 29%– Grade 3: 7%

Drug discontinuations due to PN• BV+AVD: 7%• ABVD: 2%

§ Nivolumab and Pembrolizumabapproved in HD

§ Nivolumab 87% ORR and 17% CR in relapsed/refractory HD

PD-1 Antibodies

Ramchandren et al JCO 2019

Checkmate 205: AVD + Nivolumab

Ramchandren et al JCO 2019

Checkmate 205: AVD + Nivolumab

Ansell et al ICML 98 2019

Checkmate 205: AVD + Nivolumab

Linch et al Lancet 1993; Schmitz et al Lancet 2002

Relapsed/Refractory Disease

Relapsed/Refractory DiseaseRegimen Overall Response Rate Complete Response Rate

Brentuximab Vedotin 68 35

Brentuximab Vedotin + Bendamustine 78, 93 43, 74

Brentuximab vedotin + Nviolumab 82 61

DHAP (dexamethasone, cisplatin, high-dose cytarabine) 70 24

ESHAP (etoposide, methylpred, cytarabine, cisplatin) 67 50

Gemcitabine, bendamustine, vinorelbine 83 73

GVD (gemcitabine, vinorelbine, liposomal doxorubicin) 70 20

ICE (ifosphamide, carboplatin, etoposide) 68 27

IGEV (ifosphamide, gemcitabine, vinorelbine) 81 54

• PET-directed therapy and AVD+BV for advanced stage Hodgkin

• Future therapy investigating further role of immunotherapies in initial treatment

• Several options at first relapse

• Consolidation with HSCT

Summary