E-Learning Treatment of Newly Diagnosed Classical Hodgkin ...

TREATMENT OF NEWLY DIAGNOSED CLASSICAL HODGKIN LYMPHOMADiscussion of different approaches

Peter Borchmann

German Hodgkin Study Group

University Hospital Cologne, Germany

LEARNING OBJECTIVES

To describe the use of risk classifications systems for treatment allocation

To understand endpoints and designs used in clinical trials of HL from a scientific and a patient’s perspective

To know potential risks and benefits of different treatment approaches

To describe the potential and pitfalls of metabolic response adapted therapy

To get an insight into evolving therapies

TREATMENT OF NEWLY DIAGNOSED CLASSICAL

HODGKIN LYMPHOMA

1. Staging and upfront risk allocation

2. Early stages: standard of care and open questions

3. Advanced stages: standard of care and open questions

4. Evolving therapies

THE MANAGEMENT OF HODGKIN LYMPHOMA

PET/CT for disease assessment

Voltin CA, et al. Ann Oncol 2018;29(9):1926–31.

Images: data on file courtesy of German Hodgkin Study Group (GHSG).


PET/CT for initial staging?

Voltin CA, et al. Ann Oncol 2018;29(9):1926–31.

BM biopsy negative (n=812) BM biopsy positive (n=20)

BM PET negative (n=703) 702 1

HD16 219 0

HD17 181 0

HD18 302 1

BM PET positive (n=129) 110 19

HD16 0 0

HD17 3 0

HD18 107 19

Very high negative

predictive value

Bone marrow biopsy is not

necessary anymore

Correlation between the results of baseline PET and BM biopsy


Staging procedures/organ function assessment

Biopsy (preferably whole LN) and histology

ceCT (neck, thorax, abdomen) + PET

Laboratory diagnostics including chemistry, blood counts, virology (HIV, Hep B/C, EBV)

Organ function: ECG, echocardiography, lung function test, TSH, sexual hormones (if relevant)

Upon patient’s decision: fertility protection, oocyte/spermatocyte cryo-conservation


Staging procedures

The German Hodgkin Study Group (GHSG). Available at: https://en.ghsg.org/disease-stages; accessed May 2020. Images courtesy of Prof Borchmann.

AreasRegions

https://en.ghsg.org/disease-stages


GHSG staging system

The German Hodgkin Study Group (GHSG). Available at: https://en.ghsg.org/disease-stages; accessed May 2020

Ann Arbor Stage

IA, IB, IIA IIB IIIA, IIIB IVA, IVB

No risk factors Early stages

Ris

k fa

ctor

s ≥3 LN-areas

ESR > UNL Early unfavourable stages Advanced stages

Large Mediastinal Mass (LMM)

Extranodal disease



Risk allocation

(A) w/o B-symptoms, (B) w/ B-symptoms. LP, lymphocyte depletion; MC, mixed cellularity; GHSG, German Hodgkin Study Group; EORTC, European Organisation for Research and

Treatment of Cancer; NCIC, Institute of Canada; ECOG, Eastern Cooperative Oncology Group; NCCN, National Comprehensive Cancer Network National Cancer.

CSIIB with resprective RF extranodal disease or large mediastinal mass are considered advanced stage by the GHSG.

Risk factor GHSG EORTC NCIC/ECOG NCCN

Large mediastinal mass (≥1/3 of

thoracic diameter)Yes Yes Yes Yes

Extranodal disease Yes No No No

Nodal involvement Yes, ≥3 nodal areas Yes, ≥4 nodal areas Yes, ≥4 nodal areas Yes, ≥4 nodal areas

Erythrocyte Sedimentation Rate

(ESR)

Yes, ≥50 mm/h (A) or

≥30 mm/h (B)

Yes, ≥50 mm/h (A) or

≥30 mm/h (B)Yes, ≥50 mm/h Yes, ≥50 mm/h

B-symptoms No No Yes Yes

Bulky disease No No Yes, >10 cm Yes, >10 cm

Age No Yes, ≥50 years Yes, ≥40 years No

Histological subtype No No MC or LD subtype No


Early stages – comparing different risk classification systems

Reprinted from Ann Oncol, 24(12), Klimm R, et al. Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions, 3070–6,

Copyright 2013, with permission from Elsevier.

All patients received 4x ABVD + 20 or 30 Gy IFRT

Risk classification systems are all reasonable, reliable, and relevant!

TREATMENT OF NEWLY-DIAGNOSED CLASSICAL

HODGKIN LYMPHOMA






Early stage favourable

The German Hodgkin Study Group (GHSG). Available at: https://en.ghsg.org/disease-stages; accessed May 2020

Ann Arbor Stage


No risk factors Early stages

Ris

k fa

ctor

s ≥3 LN-areas



Extranodal disease



Early stage favourable – GHSG HD7: End of RF-RT alone

Sasse S, et al. J Clin Oncol 35(18), 2017:1999–2007. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

CMT with 2x ABVD + 30 Gy EF-RT is

superior to 30 Gy EF-RT alone after 15 years

in terms of PFS

However, no OS difference in this study


Early stage favourable – GHSG HD10: Reducing chemo- and radiotherapy within the CMT

Sasse S, et al. J Clin Oncol 35(18), 2017:1999–2007. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

2x ABVD + 20 Gy IF-RT after 10 years

non-inferior to 4x ABVD + 30 Gy

1977–1988

1965–1976

1989–2000

} Expected incidence

in the general population


Long-term sequelae in HL survivors

From N Engl J Med, Schaapveld M, et al. Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma, 373(26), 2499–511. Copyright © 2015 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

Can late effects be reduced

by PET-guided omission of

radiotherapy?

Solid lines represent the observed incidence, and dashed

lines the expected incidence in the general population.

The inset show the same data on enlarged y axes

SIR for breast cancer in women:

4.7 (95% CI: 4.0, 5.4)


Early stages: RAPID Trial – Design

Radford J, et al. N Engl J Med 2015;372(17):1598–607.

Primary Endpoint:

Non-inferiority (lower margin 7%) of

PET-guided poly-CTX vs. CMT

regarding progression-free survival3 ABVD

PET

PET

–

+

R

No further treatment

30 Gy IFRT

+1 ABVD + 30 Gy IFRT


RAPID Trial – Results in the per protocol analysis

From N Engl J Med, Radford J, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma, 372(17), 1598–607. Copyright © 2015 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

3-year PFS 97% (94.5%, 99.6%) vs.

90.7% (86.7%, 94.7%)

HR 2.39 in favour of IF-RT: p=0.02

Non-inferiority cannot be concluded.

Radiotherapy prevents patients from relapse,

even in case of PET negativity

Per-protocol analysis


EORTC H10 Trial – Design

Andre MPE, et al. J Clin Oncol 2017;35(16):1786–94.

Primary Endpoint:

Omission of RT without loss of

efficacy (PFS) in PET-negative

patients after two cycles of

ABVD possible?

Lower margin 10%H10U

N=1196

PET-

+ 2 eBEACOPP + IN-RT 30 Gy (+6)

R

2 ABVD

2 ABVD

PET

N=126 (21%)

4 ABVD

2 ABVD + IN-RT 30 Gy (+6)

H10F

N=754

PET-

+ 2 eBEACOPP + IN-RT 30 Gy (+6)

R

2 ABVD

2 ABVD

PET

N=43 (11%)

2 ABVD

1 ABVD + IN-RT 30 Gy (+6)


EORTC H10 Trial – Results

Progression-free survival (PFS) of 1,059 early positron emission tomography-negative patients who were treated per the initial protocol. Shown are the rates of PFS of the

Favourable (F) groups of patients randomly assigned to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + involved-node radiotherapy (INRT; n=227) or ABVD only

(n=238) and of the Unfavourable (U) groups randomly assigned to ABVD + INRT (n=292) or ABVD only (n=302). O, observed.

Andre MPE, et al. J Clin Oncol 35(16), 2017: 1786–94. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

F: 5-year PFS rates were 99% vs.

87.1%, HR 15.8 (95% CI: 3.8, 66.1) in

favour of ABVD + INRT

U: 5-year PFS rates were 93% vs. 89.6%,

HR 1.45 (95% CI: 0.8, 2.5) in favour of

ABVD + INRT

Favourable (F) Unfavourable (U)


Early stage favourable: GHSG HD16 Trial – Design

Fuchs M, et al. J Clin Oncol 2019;37(31):2835–45.

Early favourable HL

2 x ABVDPET–

20 Gy IF

2 x ABVDPET+

2 x ABVDPET (+/–)

Follow-up 20 Gy IF

Experimental arm

Can RT be omitted from standard CMT

without relevant loss of tumour control in

PET2-negative HL patients (lower margin set

to 10% PFS at 5 years)?


GHSG HD16 Trial – Results

Kaplan-Meier estimates for the PET2 (positron emission tomography after two cycles of chemotherapy) –negative per-protocol population.

ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; IFRT, involved-field radiotherapy.

Fuchs M, et al. J Clin Oncol, 37(31), 2019: 2835–45. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.

Non-inferiority margin of 3.01 (represents a difference of 10% after 5 years) cannot be excluded.

Almost identical results to RAPID and EORTC H10 (!)

Progression-free survival Overall survival


CMT or chemo alone in early cHL?

We use CMT in early stage favourable HL because we

know that omitting RT from our treatment results in loss

of efficacy in terms of PFS (HD16, H10, RATHL)

However, there is no OS difference! Shouldn’t we then

save patients from radiotherapy?

CAVE: our Phase 3 studies are not powered to draw any

conclusions on OS!

Olszewski AJ, et al. J Clin Oncol, 33(6), 2015: 625–33. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.P

ropo

rtio

n su

rviv

ing

THE MANAGEMENT OF EARLY STAGE

FAVOURABLE HODGKIN LYMPHOMA

Conclusions

1. PET-guided omission of RT in early stage favourable HL results in inferior PFS in all trials: we recommend CMT

with 2x ABVD + 20 Gy IS-RT

2. We cannot de-escalate treatment in PET-negative patients without loss of tumour-control; however, should we

escalate therapy in PET-positive patients?

◆ Is a PET/CT a valid prognostic tool to assess the risk for treatment failure?

THE MANAGEMENT OF EARLY HODGKIN LYMPHOMA

PET/CT as a prognostic marker during treatment? (HD16)

Fuchs M, et al. J Clin Oncol, 37(31), 2019: 2835–45. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.

353 327 285 223 157 102

218 197 179 137 89 48

122 107 98 76 52 28

number at risk

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╵╵╵╵ ╵╵╵╵╵╵

╵

╵ ╵╵╵╵╵╵╵╵╵ ╵ ╵ ╵

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╵ ╵╵ ╵╵╵╵

╵╵ ╵╵╵ ╵╵ ╵╵╵

╵ ╵ ╵╵ ╵ ╵ ╵ ╵

╵ ╵

╵

╵╵╵ ╵ ╵ ╵╵╵ ╵╵

╵ ╵ ╵ ╵ ╵╵ ╵╵╵ ╵╵╵╵ ╵╵

╵╵ ╵ ╵╵╵╵╵╵╵╵╵╵ ╵╵ ╵╵ ╵╵╵ ╵╵╵╵╵╵ ╵ ╵╵╵╵╵╵

╵╵╵╵╵ ╵╵╵╵ ╵ ╵

╵ ╵ ╵ ╵ ╵ ╵╵╵╵ ╵╵╵ ╵╵╵╵╵ ╵╵╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵

0 12 24 36 48 60

Time [months]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PF

S r

ate

uptake > liver

uptake > mediastinum but <= liveno uptake or uptake <= mediastin

5-year estimate [95% CI] Hazard ratio [95% CI]*

DS 1-2: 93.2% [90.2%, 96.2%]

DS 3: 92.8% [88.8%, 96.9%] 1.17 [0.60, 2.27]; p=0.64

DS 4: 80.9% [72.2%, 89.7%] 3.14 [1.62, 6.08]; p=0.0007

Median observation time: 46 months

A positive PET2 DS4 is

associated with an inferior PFS

compared with DS1-3 (negative)


Early stage unfavourable

The German Hodgkin Study Group (GHSG). Available at: https://en.ghsg.org/disease-stages; accessed May 2020.

Ann Arbor Stage


No RF Early stages

Ris

k fa

ctor

s ≥3 LN-areas



Extranodal disease



UNFAVOURABLE HODGKIN LYMPHOMA

Is there a standard treatment?

1. 4x ABVD followed by cons. RTx

1. Ferme C, et al. N Engl J Med 2007

2. Noordijk EM, et al. J Clin Oncol 2006

3. Eich HT, et al. J Clin Oncol 2010

2. PET-guided systemic CTx starting with 2x ABVD followed by cons. RTx

1. André M, et al. J Clin Oncol 2017

3. 2x eBEACOPP + 2x ABVD followed by cons. RTx

1. Von Tresckow, et al. J Clin Oncol 2012

4. 2x eBEACOPP + 2x ABVD + PET-guided RTx

1. GHSG HD17, Borchmann P, et al. submitted 2020

THE MANAGEMENT OF EARLY UNFAVOURABLE

HODGKIN LYMPHOMA

4x ABVD + RTX

Pro:

◆ Established

◆ Optimised for outpatient setting

◆ Low and manageable acute toxicity

◆ Feasible in resources-restricted settings

Contra:

◆ PFS could be better

How can we improve this SOC?


HODGKIN LYMPHOMA

PET-guided escalation from 4x ABVD to 2x ABVD +2x eBEACOPP

(+ RTX, EORTC H10)

Andre MPE, et al. J Clin Oncol 35(16), 2017: 1786–94. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

5-year PFS: 91% vs. 77%

HR (95% CI) = 0.42 (0.23, 0.74)

p = 0.002*Note: early favourable and unfavourable

analysed together

5-year OS: 91% vs. 77%

HR (95% CI) = 0.45 (0.19, 1.07)

p = 0.062*Note: early favourable and unfavourable

analysed together


HODGKIN LYMPHOMA

Conventional CTx intensification: GHSG HD14

Republished with permission of American Society of Hematology, from Blood, Gillessen S, et al. 134(Suppl_1), copyright 2019, permission conveyed through Copyright Clearance

Center, Inc. Preseneted at SHS 2019.

Early unfavourable HL

2 x eBEACOPP +2 x ABVD

4 x ABVD

Experimental arm

30 Gy IF30 Gy IF

Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term

Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial


HODGKIN LYMPHOMA

GHSG HD17 trial – Can we omit RTx after intensive CTx induction?

Borchmann P, et al. EHA25 Virtual, 11-21 June 2020, Abstract S101

Early unfavourable HL

2x eBEACOPP + 2x ABVD

2x eBEACOPP + 2x ABVD

Experimental arm

30 Gy IN RT30 Gy IS RT

Standard arm

Follow-up

+–

PETPET


HODGKIN LYMPHOMA

GHSG HD17 trial – Primary endpoint: PFS

Borchmann P, et al. Positron emission tomography guided omission of radiotherapy in early-stage unfavorable Hodgkin lymphoma: final results of the international, randomized phase III

HD17 trial by the GHSG. EHA25 Virtual, 11-21 June 2020, Abstract S101. With permission from Prof P Borchmann.

274 259 234 191 125 72

323 308 278 227 156 86

number at risk

0 12 24 36 48 60Time [months]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PF

S r

ate

Log-rank p = 0.20 PET-stratified treatment

Standard treatment

5-year PFS (95% CI)

Arm A: 97.7% (93.6, 99.2)

Arm B: 95.9% (92.4, 97.9)

Diff. in 5-year PFS (95% CI)

1.7% (–5.3, 1.8)


UNFAVOURABLE HODGKIN LYMPHOMA

Conclusions

PET-guided omission of RT in early stage unfavourable HL is non-inferior to standard CMT, if intensive systemic

treatment is applied (“2+2”):

◆ We recommend 2x eBEACOPP + 2x ABVD + PET-guided IS-RT for patients <60 years

CMT starting with 2x ABVD and PET-guided escalation to eBEACOPP (EORTC H10) for some patients shows

comparable efficacy; however, cons. RTx then remains part of the treatment strategy and might result in late effects

IF PET is not available, also CMT with either “2+2” or 4x ABVD might be used with moderate loss in primary tumour

control, but probably no impact on OS


HODGKIN LYMPHOMA






Advanced stages

The German Hodgkin Study Group (GHSG). Available at: https://en.ghsg.org/disease-stages; accessed May 2020.

Note: EORTC and GHSG use a similar classification; NCCN guidelines consider only Ann Arbor-stages III and IV as advanced stage

Ann Arbor Stage


No RF Early stages

Ris

k fa

ctor

s ≥3 LN-areas



Extranodal disease


THE MANAGEMENT OF ADVANCED STAGE

HODGKIN LYMPHOMA

Current scientific debate

eBEACOPP still not unanimously considered first-line SOC in advanced HL, though it has shown a significant PFS

advantage over ABVD in all trials and a 5-year OS advantage over ABVD of 10% (95% CI: 5%, 13%) in a large

metanalysis

This is mainly due to the fact that approximately 70% of the patients treated with eBEACOPP could possibly be cured

with ABVD only and thus a less toxic approach

Unfortunately, known baseline risk factors cannot reliably predict the individual risk and can therefore not guide the

treatment strategy

Can we guide treatment intensity by early interim metabolic response assessment, i.e. by PET/CT?

Skoetz N,. et al. Lancet Oncol 2013;14(10):943–52;

Skoetz N, et al. Cochrane Database Syst Rev 2017;5(5):CD007941.


HODGKIN LYMPHOMA

PET overcomes the International Prognostic Score (IPS)

Gallamini A, et al. J Clin Oncol 25(24), 2007: 3746–52. Reprinted with permission. © 2007 American Society of Clinical Oncology. All rights reserved;

Hasenclever D, et al. N Engl J Med 1998;339(21):1506–14.

Pro

gres

sion

-fre

e su

rviv

al

Time (years)


HODGKIN LYMPHOMA

PET2-guided treatment-optimisation trials

1. Gordon L, et al. J Clin Oncol 2013;31(6):684–91;

2 Engert A, et al. Lancet 2012;379(9828):1791–9.

Escalation (increasing PFS)

RATHLSWOG S0816

PET guided

6–8 ABVD1

(27% failure rate at 5 years)

De-escalation (decreasing tox)

AHL2011HD18

PET guided

6x eBEACOPP2


Caveat:

◆ This is a non-inferiority

study for PET-negative

patients!

◆ 42% stage II patients

(14% in HD18)!

PET2-GUIDED ABVD: RATHL STUDY DESIGN

Johnson P, et al. N Engl J Med 2016; 374:2419–29.

+ PET2–

+ PET3–

4 cycles BEACOPP-14or 3 eBEACOPP

2 cycles ABVD, full dose,

on schedule

Randomise

4 cycles ABVD 4 cycles AVD

RT or salvage regimen2 cycles BEACOPP-14

or 1 eBEACOPP (no RT)Follow-up (no RT)


HODGKIN LYMPHOMA

RATHL: PFS for PET-negative patients

From N Engl J Med, Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma, 374(25), 2419–29. Copyright © 2016 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

3-year PFS, ABVD: 85.3%

95% CI: 81.6, 88.4

3-year PFS, AVD: 84.6%

95% CI: 80.8, 87.7

Assumed 3-year PFS: 95%

Observed 3-year PFS: 85%

3-year PFS [%]

BEACOPP-14: 66.0 (55.0, 74.9)

eBEACOPP 71.1 (59.0, 80.2)

PET2-neg

3-year PFS

PET-pos

3-year PFS

All patients

3-year PFS

82.1% 63.9% 79%


HODGKIN LYMPHOMA

RATHL: PFS for PET-positive patients and overall outcome

From N Engl J Med, Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma, 374(25), 2419–29. Copyright © 2016 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

PFS for advanced stages Ann Arbor III and IV


HODGKIN LYMPHOMA

SWOG S0816: PET2-guided ABVD in the USA

Stephens DM, et al. Blood 2018;132(Suppl 1):929.

ABVD x 2

(n=331 central review PET2)

PET2 negative

(n=270, 82%)

HIV negative

(n=358; 336 eligible/evaluable)

PET2 positive

(n=61, 18%)

Enrolment from:

July 2009 – Dec 2012

ABVD x 4

(n=270)

eBEACOPP x 6

(n=49)

◆ 6 did not enrol in step 2

◆ 3 refused treatment

◆ 3 received ABVD


HODGKIN LYMPHOMA

SWOG S0816: PET2-guided ABVD in the USA

Republished with permission of American Society of Hematology (ASH), from Blood, Stephens DM, et al, 134(15), copyright 2019, permission conveyed through Copyright Clearance

Center, Inc.

PET2+

(n=61)

PET2–

(n=270)

Events, n (%) 20 (33) 64 (25)

5-year PFS (%) 66 76

95% CI (%) 52, 76 70, 81

PFS PET2 Positive PFS PET2 Negative

Authors’ conclusion: PFS in PET2-negative patients is too low. PET2 is NOT suited to guide treatment


HODGKIN LYMPHOMA

PET2-guided treatment-optimisation trials

1. Gordon L, et al. J Clin Oncol 2013;31(6):684–91;



RATHLSWOG S0816

PET guided

6-8 ABVD1



AHL2011HD18

PET guided

6x eBEACOPP2


1x

eBEACOPP

5x Rituximab/

eBEACOPP

Arm A

2x eBEACOPP

FDG-PET2-positive:

End of therapy AND residual disease ≥ 2.5 cm AND positive PET: RT

1x

eBEACOPP 6x

eBEACOPP

2x

eBEACOPP

FDG-PET2-negative:

Centrally reviewed FDG-PET/CT

5x

eBEACOPP

Arm B Arm C Arm D

2x eBEACOPP

Centrally reviewed PET/CT

THE GHSG HD18 STUDY

PET-guided therapy of advanced-stage HL

Final analysis of the GHSG HD18 trial

Does metabolic response determined by PET after two cycles (PET2) allow reduction of treatment intensity?


HODGKIN LYMPHOMA

GHSG HD18 – Primary endpoint PFS

Reprinted from The Lancet 390(10114), Borchmann P, et al. PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label,

international, randomised phase 3 trial by the German Hodgkin Study Group, 2790–802. Copyright 2018, with permission from Elsevier.

Non-inferior 5-year PFS for

PET2-negative patients after 4

cycles of eBEACOPP compared

with 8/6 cycles (primary endpoint)

at a very high level (95% at 3 years,

92% at 5 years)

HD18 FOR PET2-NEGATIVE PATIENTS

Overall survival

Reprinted from The Lancet 390(10114), Borchmann P, et al. PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label,

international, randomised phase 3 trial by the German Hodgkin Study Group, 2790–802. Copyright 2018, with permission from Elsevier.


HODGKIN LYMPHOMA

GHSG HD18 – Overall survival outcome

Significant reduction of severe acute haematological and non-haematological toxicities

Relevant reduction of mortality for other reasons than HL <1%

Elimination of HL as relevant cause of death (7/1005; i.e. 0.7%)

Significantly superior OS with 4 cycles of eBEACOPP (99% at 3 years, 98% at 5 years) over 6/8 cycles

READING PET IN HD18 (PFS)

Cut-off score 3 vs. cut-off score 4

Republished with permission of American Society of Hematology (ASH), from Blood, Kobe C, et al. 132(21), copyright 2018, permission conveyed through Copyright Clearance Center, Inc.

216 196 169 113 60

506 443 386 240 147

Pts. at risk

╵╵ ╵╵╵ ╵╵╵╵╵ ╵╵ ╵╵ ╵ ╵ ╵╵╵╵╵

╵╵ ╵ ╵╵╵ ╵ ╵╵╵╵╵╵╵╵ ╵ ╵╵ ╵ ╵╵ ╵╵╵╵ ╵╵╵╵╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵╵╵╵╵╵

╵╵╵╵╵ ╵╵╵╵ ╵╵ ╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵ ╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵ ╵

╵ ╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵ ╵╵╵╵ ╵╵╵ ╵╵╵ ╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵ ╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵

╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵

╵╵╵╵╵╵╵ ╵╵╵╵ ╵ ╵╵╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵╵

0 12 24 36 48

Time [months]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PF

S r

ate

Deauville 3-4Deauville 1-2

3-year estimate [95% CI]

Deauville 1-2 92.2% [88.5%, 96.0%]

Deauville 3-4 92.0% [89.3%, 94.6%]

Difference –0.3% [–4.9%, 4.4%]

Hazard ratio 1.09 [0.61, 1.95]; p=0.8Median observation time 37 months

Cut-off score 3 = positive

486 436 375 246 144

236 203 180 107 63

Pts. at risk

╵╵ ╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵ ╵╵╵╵╵ ╵╵╵╵╵ ╵ ╵╵╵ ╵╵╵╵ ╵╵╵╵╵╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵ ╵╵ ╵╵╵╵╵ ╵ ╵╵╵

╵ ╵╵╵╵╵╵╵╵╵╵╵

╵╵╵ ╵╵╵╵╵╵ ╵ ╵

╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵╵╵ ╵╵╵╵╵╵╵ ╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵ ╵╵╵ ╵╵╵╵╵ ╵╵╵ ╵ ╵╵╵╵╵╵ ╵╵ ╵╵╵ ╵╵╵

╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵ ╵

╵╵╵ ╵ ╵╵ ╵ ╵╵╵ ╵╵ ╵

0 12 24 36 48

Time [months]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PF

S r

ate

Deauville 4Deauville 1-3

3-year estimate [95% CI]

Deauville 1-3 94.2% [92.0%, 96.5%]

Deauville 4 87.6% [83.0%, 92.3%]

Difference –6.6% [–11.8%, –1.4%]

Hazard ratio 2.27 [1.35, 3.84]; p=0.002Median observation time 37 months

Cut-off score 4 = positive

PET2-guided therapy of advanced HL

THE PROGNOSTIC IMPACT OF PET2

What did we learn from HD18?

PET2 DS 4 allows identification of those patients who

really need intensive therapy with 6 cycles of eBEACOPP

However, survival in this high-risk group regarding both

PFS and OS is very good and certainly does not require

any further escalation!

PET2 DS 1-3 has a very good negative predictive value

and allows to treat 75% of all patients with only 4 cycles.

This is a fast, safe and super-effective strategy!1,2

1. Borchmann P, et al. Lancet 2017; 2. Borchmann P, et al. Lancet Oncol 2015. Data on file used with permission from GHSG.

Total, N=1945

Total

0%

25%

50%

75%

100%

Deauville 4Deauville 1ne

gativ

e 52

%po

sitiv

e 48

%

DS 3

N=471 (24%)

DS 4

N=469 (24%)

DS 2

N=325 (17%)

DS 1

N=680 (35%)

Neg

ativ

e

76 %

Pos

itive

24 %

WE RECOMMEND PET2-GUIDED eBEACOPP AS SOC

Because PFS is also the most relevant endpoint from our patients’ perspective

Turner S, et al. Br J Cancer 1996;73(2):222–7.

165 patients treated for HL between 1970 and 1991 completed questionnaires to determine the relative importance of various

side effects of disease and treatment

Late morbidity ranking by all patients (whether or not complication experienced) and number actually experiencing complication

Potential late complication No. experiencing No. ranking Median rank Percentage ranking 1, 2, or 3

Development of second cancer 0 97 1 88

Relapse of HD 38 104 2 80

Cardiovascular disease 8 93 2.5 71

Chronic energy loss 48 104 5 18

Infertility 53 106 5 25

Divorce/relationship problem 21 92 5 21

Anxiety/depression 41 102 6 28

Impaired sex life 22 96 6 11

Occupation/life insurance problem 30 95 6 16

Any kind of cancer, including relapse of HL (!), after having been treated for HL is by far the worst case:

PFS (death or relapse of HL) is the most relevant endpoint from the patients’ perspective!

The “second shot” is never the patients’ first choice!


HODGKIN LYMPHOMA

Implementing brentuximab vedotin into first-line therapy

1. Gordon et al. J Clin Oncol 2013;31(6):684–91;



RATHLSWOG S0816

PET guided

6-8 ABVD1



AHL2011HD18

PET guided

6x eBEACOPP2


ECHELON-1

BV

HD21

BV


HODGKIN LYMPHOMA

ECHELON-1

Connors JM, et al. N Engl J Med 2018;378(4):331–44.

Scr

eeni

ng

CT

/PE

T s

can

1:1

rand

omis

atio

n

(N=

1334

)

ABVD x6 cycles (n=670)

A+AVD x6 cycles (n=664)

Brentuximab vedotin: 1.2 mg/kg IV infusion

Days 1 and 15

EO

T

CT

/PE

T s

can

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)

Primary endpoint: mPFS per independent review facility (IRF)


HODGKIN LYMPHOMA

ECHELON-1: modified PFS at 2 years

From The New England Journal of Medicine, Connors JM, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma, 378(4), 331–44. Copyright © 2018

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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

HR 0.77 (95% CI: 0.60, 0.98)

Log-rank test p-value: 0.04

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

664

670

640

644

623

626

606

613

544

522

530

496

516

476

496

459

474

439

447

415

350

328

334

308

311

294

200

179

187

168

174

153

99

78

85

68

77

62

27

16

24

13

21

12

6

1

4

1

4

1

0

0

0

0

Time from randomisation (months)

Pro

bab

ility

of

mo

dif

ied

PF

S

No. of patients at risk:

A+AVD

ABVD

A+AVD

ABVD

Censored

Censored

0.9

0.7

0.5

0.3

0.1

A+AVD: 2-year 82.1 (78.7, 85.0)

ABVD: 2-year 77.2 (73.7, 80.4)

◆ Only modest mPFS advantage over ABVD

◆ Rather toxic: 25% persisting neuropathy as of

2020, G-CSF mandatory due to high incidence of

febrile neutropenia

◆ Also no superiority for PFS at 3 years for patients

>60 years; however, more toxicity!

◆ Expensive

2x BEACOPP esc

PET2/CT Staging

2x BrECADD

4x

BEACOPP esc

Randomisation

2x

BEACOPP esc

4x

BrECADD

2x

BrECADD

PET2 neg. PET2 pos. PET2 neg. PET2 pos.

End of therapy AND residual nodes >2.5 cm: PET positive: Rx

PET negative: Follow-up

Co-primary endpoint:

◆ Non-inferiority for efficacy

AND

◆ Superiority for treatment-

related morbidity

THE GHSG HD21 STUDY

Remodelling eBEACOPP


HODGKIN LYMPHOMA

Summary

Different options are available; however, with rather large differences regarding the primary cure rate (reflected

by PFS) favouring a more intensive upfront treatment strategy (GHSG HD18, LYSA AHL2011)

Healthcare infrastructure and individual preferences should be regarded for shared decision making on

primary treatment

Age is an important factor for resilience and needs to be taken into account. Different treatment strategies for

different age groups should be applied! 60 years is a reasonable cut-off for eBEACOPP


HODGKIN LYMPHOMA

Summary for stage III/IV patients <60 years

Strategy PFS (%) OS (%) Pros Cons

PET-guided

eBEACOPP

(HD18)

91 @ 5 years 96 @ 5 years Outstanding primary cure rate (PFS),

very short treatment (3 months) for

most patients

Advanced medical infrastructure needed,

not recommended in older patients

PET-guided

eBEACOPP

(AHL2011)

86 @ 5 years 96 @ 5 years Good lymphoma control, better

tolerability as reflected by fewer

infections and serious adverse events

Advanced medical infrastructure needed,

longer treatment duration, higher cumulative

anthracycline and bleomycin dose, not

recommended in older patients

PET-guided

ABVD

(RATHL)

79 @ 3 years 97 @ 3 years Omission of bleomycin in PET-neg

patients

PET-negative patients have a poorer outcome

than assumed. Overall outcome only slightly

better than non-PET-guided ABVD

BV-AVD

(ECHELON-1)

mPFS:

81 @ 2 years

96 @ 2 years Slightly improved PFS over ABVD Non-individualised strategy, relevantly more

toxicity (neutropenia and neuropathy), much

more expensive


HODGKIN LYMPHOMA

Summary of recommendations for patients >60 years

Strategy PFS (%)/FFS (%) OS (%) Pro Cons

6x A(B)VD

(Evens, Br J Haematol 2013)

FFS: 48 @ 5 years 58 @ 5 years Safe Low efficacy

6x BV-AVD

(ECHELON-1)

PFS: 81 @ 2 years 96.6 @ 2 years No better survival outcome

than with ABVD

More neurotoxicity and

neutropenia than ABVD

2xBV+ 6xAVD+ 4xBV

(Evens, J Clin Oncol 2018)

PFS: 84 @ 2 years 93 @ 2 years Better PFS than 6x

A(B)VD

Low evidence

CHOP-21

(Kolstad, Leuk Lymphoma 2007)

PFS: 76 @ 3 years 79 @ 3 years Safe and feasible also in

elderly patients

Low evidence


HODGKIN LYMPHOMA





ORR IN HL VS. OTHER CANCERS WITH PD-1

ANTIBODY TREATMENT

HL: Nivolumab for r/r HL (Ansell, et al. NEJM 2015), NSCLC (from left to right): Nivolumab in previously treated nsNSCLC (Borghaei, et al. NEJM 2015), Nivolumab in previously

treated sNSCLC (Brahmer, et al. NEJM 2015), Pembrolizumab in untreated NSCLC (Garon, et al. NEJM 2015), Melanoma (from left to right): Pembrolizumab in previously treated

melanoma (Robert, et al. NEJM 2015), Nivolumab in untreated melanoma (Postow, et al. NEJM 2015), Nivolumab for previously treated melanoma (Weber, et al. Lancet Oncology

2015), RCC: Nivolumab for previously treated mRCC (Motzer, et al. NEJM 2015).

0

10

20

30

40

50

60

70

80

90

100

HL NSCLC NSCLC NSCLC Melanoma Melanoma Melanoma RCC

OR

R (

%)

Malignancy

CR

PR

Approval for nivolumab and pembrolizumab for r/r HL after failure

of two prior lines including BV due to high response rates


HODGKIN LYMPHOMA

Phase 2 study of nivolumab + AVD

Ramchandren R, et al. J Clin Oncol 2019;37(23):1997–2007.

4x nivolumab + AVD

FDG-PET/CT

FU

The primary endpoint was safety and tolerability, assessed

by the incidence of grade 3 to 5 treatment-related adverse

events (TRAEs) between the first dose and 30 days after

the last dose

FDG-PET/CT

2x nivolumab + AVD

FDG-PET/CT

4x nivolumab


HODGKIN LYMPHOMA

PFS of nivolumab + AVD

Modified progression-free survival (mPFS) per independent radiology review committee. mPFS was defined as time to progression, death, or next sub-sequent therapy,

regardless of response.

Ramchandren R, et al. J Clin Oncol 37(23), 2019:1997–2007. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved

CAVEAT: extremely short follow-up!

Leaving the personalised

PET-guided approach by

testing an add-on design for

all patients

THE “AMERICAN” WAY: S1826 STUDY FOR ADVANCED

STAGE CHL PATIENTS

Brentuximab or nivolumab + AVD?

Randomise

1:1

Newly diagnosed

Stage III-IV

Hodgkin

lymphoma

Nivolumab + AVD

6 cycles

Nivolumab 240 mg Days 1, 15

Doxorubicin 25 mg/m2 Days 1, 15

Vinblastine 6 mg/m2 Days 1, 15

Dacarbazine 375 mg/m2 Days 1, 15

Brentuximab vedotin + AVD

6 cycles

BV 1.2 mg/kg Days 1, 15

Doxorubicin 25 mg/m2 Days 1, 15

Vinblastine 6 mg/m2 Days 1, 15

Dacarbazine 375 mg/m2 Days 1, 15

470 patients

470 patients

THE MANAGEMENT HODGKIN LYMPHOMA IN 2020

Summary and conclusions: Early stages

PFS does nor necessarily translate into OS in early stage HL: failing low-intensity treatment leaves a chance for the

“second shot”

Early stage favourable disease: PET-guided omission of radiotherapy missed the proof of non-inferiority in 3/3 large

trials: CMT remains SOC

Early stage unfavourable disease: PET-guided therapy can improve the treatment

◆ After starting with 2x ABVD: PET allows identification of poor-responders AND improvement of their outcome

by intensification from ABVD to eBEACOPP (EORTC H10)

◆ After starting with eBEACOPP (“2+2”): PET-guided omission of consolidation radiotherapy is feasible without

loss of tumour control (GHSG HD17)


Summary and conclusions: Advanced stages

In advanced-stage HL, PFS differences translate into OS differences. PFS and thus primary cure reflects the primary

treatment goal of our patients!

Interim PET after 2x ABVD cannot reliably identify low-risk patients (poor negative predictive value) and treatment

escalation for high-risk patients to eBEACOPP achieves much poorer results than upfront treatment with eBEACOPP

Adding BV to AVD has a modest effect on mPFS, but intensification of chemotherapy and combination of two tubulin

inhibitors (MMAE and vinblastine) has clear effects on the toxicity profile

Interim PET after 2x eBEACOPP can guide de-escalation (AHL2011: 2x eBEACOPP + 4x ABVD; HD18:

4x eBEACOPP) shows excellent outcomes in terms of efficacy and safety. GHSG HD18: extremely good outcome

and short treatment for most patients

BrECADD (GHSG HD21) might further improve eBEACOPP-based strategies in terms of tolerability


Summary and conclusions: Perspectives

The role of PD1-inhibition in combination with chemotherapy needs to be defined still, but the proof of principle is

extremely positive in cHL

Besides lymphoma control, which is overall very good with all the different therapies, future developments should

include patient-reported outcomes and should focus on supporting our patients to get back into normal life

THANK YOU!

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