Treatment of Early Stage Hodgkin Lymphoma

Massimo FedericoUniversity of Modena and Reggio Emilia

Città di Lecce Hospital - GVM Care & Research

Massimo Federico

I hereby declare the following potential conflicts of interest concerning my presentation:

• Consultancy:

– Seattle Genetics, Takeda Oncology,

• Research Funding:

– Takeda Oncology,

• Honoraria:

– Takeda Oncology,

Conflict of Interest Disclosure

Background

The outcome for patients with cHL hasimproved dramatically over the last 60 years,so that the disease is now considered one ofthe most curable forms of cancer through theuse of highly effective chemotherapy, withradiotherapy in a proportion of cases.

These high cure rates however come at a costof substantial long-term treatment-relatedmorbidity and mortality.

Cumulative incidence of 2nd cancer in 3

different periods

Schaapveld M,N Engl J Med 2015;373:2499-511.

Solid line: study populationDashed line: normal age-matched population

1965 - 1976 1977 - 1988 1989 - 2000

2nd cancer SIR

Any 4.2

G.I. 4.6

Esophagus 9.5

Lung 6.4

Mesothelioma 15.1

Sarcoma S.T. 12.0

Breast (F) 4.7

Thyroid 14.0

Hemolympho 10.4

Hodgkin Lymphoma Management Considerations for Individual Treatment

Highest Cure Rate

with Primary

Therapy

Fewest Complications

Optimal Survivorship

Fertility

Second cancers

Cardiac toxicity

Pulmonary toxicity

Quality of life

Survivorship starts with initial treatment selection

Assess the risk

Prognostic factors that identifypatients at low or high risk forrecurrence help in optimizingtherapy for patients with limited oradvanced stage disease.

The approach

Patient Allocation

(According to EORTC and GHSG)

* Risk Factors: B-symptoms; High ESR; Bulky tumour; >3 lymph node areas;

Extranodal disease; # B-symptoms & Extranodal disease or bulky tumour

Early Favourable (20%)

• Stage I-II without Risk- Factors*

Early Unfavourable

(25%)

• Stage I-II with Risk Factors*

Advanced(55%)

• Stage II B#

• Stage III-IV, IIB LMM

Anatomical staging and clinical/biological risk factors still

determine treatment decision!

Eich H et al. J Clin Oncol. 2010;28:4199-206;

Eichenauer, DA et al, on behalf of the ESMO Guidelines Working Group

Assess the risk

Check for available therapies

The approach

EF HL: 30 or 20 Gy IF-RT?

57530 Gy RT 559 531 504 476 429 332 238 140 62 858820 Gy RT 564 544 514 490 420 321 220 127 51 7

Pts. at RiskTime [months]

HD10, RT-comparison

30 Gy RT 20 Gy RT

Pro

gre

ss

ion

Fre

e S

urv

iva

l

0.0

0.1

0.2

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0.5

0.6

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0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Median observation time = 79 months

Arm difference in 5y-PFS = -0,6%

95% CI [-3,6%; 2,5%]

p= 0,93

9

EF HL: 4 or 2 cycles ABVD?

5964xABVD 569 546 519 492 442 339 233 135 59 65942xABVD 566 541 509 484 416 321 230 135 54 9

Pts. at RiskTime [months]

HD10, CT-comparison

4xABVD 2xABVD

Pro

gre

ssio

n F

ree

Su

rviv

al

0.0

0.1

0.2

0.3

0.4

0.5

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0.8

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1.0

0 12 24 36 48 60 72 84 96 108 120

arm difference in 5y-PFS = -2,3%

95% CI [-5,3%; 1,2%]

p=0,24

10

OS, all arms (HD10)

Median observation time = 79 months

298A 293 289 286 283 271 240 182 116 63 12298B 290 286 283 279 270 231 166 111 67 12295C 291 285 283 282 276 241 179 117 62 20299D 298 293 289 285 273 241 182 122 64 16

Pts. at RiskTime [months]

HD10, all ev aluable patients

A B C D

Ov

era

ll S

urv

iva

l

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Engert et al., N Engl J Med 2010;363:640-52

5y-OS difference arm A vs arm D: -0,4%

95% CI [-3,4%; 2,7%]

11

GHSG - HD13: enrollments and primary endpoint

646 Pts

(09/2009)

198 Pts

(02/2006)

648 Pts

(09/2009)

167Pts

(09/2005)

Behringer et al., Lancet 2015

Conclusion:

Dacarbazine cannot

be omitted from

ABVD!

ABVD vs. AVD: “Impact of bleomycin within the ABVD regimen?

“Efficacy: non-inferiority test with margin of 1.72 for Hazard

Ratio (corresponding to 6% difference in 5y-FFTF)”

GHSG - HD13: final analysisABVD vs. AVD: “Impact of bleomycin within the ABVD regimen?”

Behringer et al., Lancet 2015

GHSG - HD13: overall survival

Behringer et al., Lancet 2015

GHSG - HD13: conclusions

• Dacarbazine cannot be omitted without considerable loss of

efficacy

• Bleomycin cannot be omitted with the predefined non-inferiority

margin of 6%

• Reduction in FFTF does not translate into poorer OS

• Moderate reduction in acute toxicity when omitting Bleomycin

(leucopenia) and Dacarbazine (nausea or vomiting)

• 2xABVD+20Gy IFRT remains the standard for early favorable HL!

Behringer et al., Lancet 2015

Early unfavorable HL: HD14 trial

von Tresckow B et al. JCO 2012

ESMO Guidelines For The Treatment Of Early UnfavorableHL: 4xABVD or 2 cycles of Beacoppesc + 2 cycles of ABVD(<60 Years)

(Eichenauer Et Al. Annals Of Oncology Advance Access Published July 25, 2014)

“2+2„ demonstrated superiority in terms of PFS but not OScompared to 4xABVD in the combined modality setting

SummaryEarly Unfavorable Hodgkin Lymphoma

Initial treatment: 3xABVD

Re-assessment: NR/PD: off

study

CR/PR: PET

Stage IA/IIA; no bulk

4th cycle ABVD + IFRT

IFRT Follow-up

PET+ (DS 3-5) PET- (DS 1&2)

Randomisation

420 pts

25% 75%

602 pts registered

Early favorable HL: UK RAPID trial

RAPID study: outcome of iPET negative patients

3-Y OS3-Y PFS 94.6% (95% CI 91.5-97.7)

3-Y PFS 90.8 (95% CI 86.9-94.8)

P= 0.27

Radford J N Eng J Med 2015; 372: 1598-607

3 year PFS for IFRT: 94.6%; (95% C.I.: 91.5-97.7%),

Non inferiority margin: 87.6%

3 year PFS for NFT: 90.8%; (95% C.I. 86.9-94.8%).

PET

NEGATIVE

H10 F

H10 F

H10 U

H10 U

M. Andre et al., J Clin

Oncol 2017:

35(16):1786-1794

H10 PET negative: sites of relapse

Site of

progression/relapse

Favourable Unfavourable

Std.

ABVD+INRT

N=2/238

Exp.

ABVD, no RT

N=30/227

Std.

ABVD+INRT

N=16/292

Exp.

ABVD, no RT

N=30/302

N N N N

Initially involved 0 22 5 20

Initially uninvolved 1 5 4 4

Both 1 3 6 6

Median time to relapse

N(%) relapses <= 24 months

36 months

7/16 (44%)

12 months

27/30 (90%)

Marc Andre et al., J Clin Oncol 2017: 35(16):1786-1794

Response adapted therapy in early HL.The H10 trial by

EORTC/LYSA/FIL PET+ group: escBEACOPP versus ABVD

BEACOPPesc+INRT 90.6%

ABVD+INRT 77.4%

96.0%

89.3%

ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, prednisone; HL, Hodgkin lymphoma; Involved-nodal radiotherapy;PET, positron emission tomography

Marc Andre et al., J Clin Oncol 2017: 35(16):1786-1794

Prognostic value of early PET patients randomized for

standard CMT

HR (95% CI) = 5.7 (3.6, 9.1), p<0.001

5 yr PFS: 77% vs. 95%

HR (95% CI) = 6.7 (3.2, 14.1), p<0.001

5 yr OS: 89% vs. 98%

N= 954PET positive N=192 (20,1%)

HR Hazard Ratio PET Positive vs. PET Negative

Raemaekers et al13th ICML, Lugano, June 17-20, 2015

Conclusions Intergroup H10 Trial

✓ Patients with early PET positive scan (after two cycles ofABVD) significantly benefit from intensification of ABVD toBEACOPPesc followed by IN-RT

• 5 yr PFS increase from 77% to 91%

✓ In patients with early PET negative scan, the non-inferiority objective of omitting IN-RT could not be met(interim analysis sustained)

•Though overall outcome was excellent

Early favorable stages: GHSG HD16-study

CS I/II without RF

2 x ABVDPET-

20 Gy IF

2 x ABVDPET+

2 x ABVDPET (+/-)

Follow up 20 Gy IF

Experimental arm

„Early unfavorable“ stages: GHSG HD17-trial

Follow up 30 Gy IN

30 Gy IF

2x BEACOPPesc

2 x ABVD

PET (+/-)

Experimental arm

Follow up

PET -

2x BEACOPPesc

2 x ABVD

PET

PET +

Randomization

Assess the risk

Check for available therapies

Make the right choice

The approach

Early HL: new standard of care ?

• INRT effectively prevents local relapse.

• Early PET (after 2 cycles of ABVD) is prognostic and facilitatesearly PET adapted treatment

• Early PET positive: significant benefit from intensification ofchemotherapy in combined modality setting: consider as newstandard of care.

• Early PET negative: omitting INRT after ABVD is defensible, albeitat the cost of higher “early” relapse rate.

• Early PET adapted treatment should become the newstandard of care in early HL.

What is next?

Prognostic value of baseline total metabolic tumor

volume (TMTV) for patients with early stage

Hodgkin’s lymphoma (HL) enrolled in the standard

arm of the H10 (EORTC/LYSA/FIL) trial (N=258).

AS Cottereau et al, 2017, submitted

Anticipating interim PET after the 1st ABVD cycle

Hutchings M: J Clin Oncol. 2014; 32(25):2705-11

Stage I 10

Stage IIA 34

Stage IIB 24

Stage III 24

Stage IV 34

_________________

_

Total

126

• Interpretation key: 5-PS

• 14 PET1-positive patients converted to a negative PET2

• All PET1-negative patients(N=88) were also PET2-negative.

54%

PET-1 neg. (71%) 2-Y PFS 94.1%

PET-1 pos. (29%) 2-Y PFS 40.8%

RAdiotherapy Free Treatment IN Good prognosis nonbulky early stage Hodgkin Lymphoma

(RAFTING study)

Writing committee

A Gallamini (F)JM Zaucha (PL)B MalkowskiI Kryachok (UA)M Federico (I)A Biggi (I)S. Chauvie (I)S. VivianiA. Versari (I)

RAFTING Study: Trial Design

PET-0 ABVD X 1 PET-1

PET-0 ABVD X 1 PET-1

-

-

+

Early favorable: I-IIA nonbulky HL

Early unfavorable: I-IIA nonbulky HL

INRT 30 Gy

ABVD X 3

INRT 30 GY

(15%)

(20%)

Stringent follow

up for 3 years

Stringent follow

up for 3 years

- = DS 1-2-3 = DS 4-5

+

+

MTV

MTV MTV

MTV

ABVD X 2

ABVD X 2

ABVD X 3

CMR

CMR

No CMR

No CMR

INRT

INRT

Brentuximab vedotin: testing in first line

Study Flow Chart

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BV

X 2 Cycles

Stage IIIA

ABVD

x 6 cycles +/- RT*

Stage I-IIA

ABVD

x 3 cycles +/- RT*

*On initial bulky sites or on responding sites with residual PET positivity

Presented by: Massimo Federico

BV Followed By ABVD +/− Radiotherapy In Patients

With Previously Untreated Early Stage HL

• 12 patients were enrolled

• After the 2 cycles of BV, 10 patients (83%) achieved a CMR, and oneachieved a partial metabolic response (ORR of 92%).

• Following BV, patients received 3-4 cycles of ABVD

• Additional RT was delivered to 5 patients.

• After the full treatment program, the ORR reached 100%.

• At a median follow up of 12 months, all patients were alive, with 11 still in

complete remission, and one relapse.

• Median 1-year PFS (range 7–16 months) was 92% (95%CI: 55–99).

Federico M., et al: Haematologica April 2016 101: e139-e141.

Case 009

• 28-year-old male;

• Treatment:– 2 x Brentuximab vedotin

1.8 mg/kg, Q3wk CR

(DS2 pictured)

– 3 x ABVD CR

• Remission duration = 3+ mo

Baseline PET 2

Presented by: Massimo Federico

Case 002

• 19-year-old female;

• Early unfavorable HL

• Treatment:– 2 x Brentuximab vedotin

1.8 mg/kg, Q3wk PR

(DS4 pictured)

– 4 x ABVD CR

– RT IF 30 Gy CR

• Remission duration = 4+ mo

Baseline PET 2

Presented by: Massimo Federico

BREACH

Brentuximab vedotin (SGN-35) associated with chemotherapy in untreated patients with

stage I/II Unfavourable Hodgkin’s lymphoma A RANDOMIZED PHASE II LySA-FIL-EORTC INTERGROUP STUDY

BREACH

Study chairman : Marc André (Lysa)

Coordinators : Massimo Federico (FIL)

Igor Aurer (EORTC)

BREACH

Study designRND ratio St/Exp 1:2

PET-based Response After 2 Cycles of Brentuximab Vedotin in Combination with AVD for First-Line Treatment of Unfavorable Early-Stage Hodgkin Lymphoma: First Analysis of the Primary Endpoint of BREACH, a Randomized Phase II Trial of LYSA-

FIL-EORTC Intergroup.

L. Fornecker, J. Lazarovici, I. Aurer, O. Casasnovas, AC. Gac, C. Bonnet, K. Bouabdallah, A. Perrot, L. Specht, M. Touati, JC Eisenmann, L. Obéric, A. Stamatoulas, Emmanuelle Nicolas-Virelizier, L. Pascal, P. Lugtenburg, M. Bellei, A. Traverse-Glehen, C. Copie-Bergman, M. Hutchings, A. Versari, M. Meignan, M.

Federico, M. André

Conclusions

Novel targeted therapies may represent an additionalopportunity to improve disease control while reducingthe risk of long-term consequences.

Today, a risk-adapted and response-orientedtherapeutic approaches represent the landmarkfor planning initial therapy in Early Stage HL

THE END