Management of Hodgkin Lymphoma

Dr Pam McKayBeatson Cancer Centre

Lymphoma Action Meeting Glasgow, September 2018

How common is HL?

•<1% of all cancers

•~ 2000 cases in UK per year

•males > females

•peak incidence in 20 – 24 year olds

•50% of cases diagnosed in >45 year olds

•second peak in elderly people (70-79 years)

What are the symptoms?

• Usually present with painless, enlarged lymph node

– Neck lump most common

• May have cough, shortness of breath

• Spreads from one nodal group to immediately adjacent nodes

• Later, may spread to liver, lungs, bone marrow

• May have B symptoms

– weight loss

– night sweats

– fever

How is the diagnosis made?

Biopsy of tissue, usually LN; core or excision

Reed Sternberg cell

What tests may be required?

• Blood tests – Full blood count - ? anaemia; white cell count– ESR– Kidney & liver function (including albumin)

• Imaging– CT scan of neck, chest, abdomen, pelvis– PET/CT scan

• Bone marrow (rarely done)• Pulmonary function tests• Echocardiogram• Assisted conception unit referral

Imaging Tests

CT scan

PET/CT scan

PET/CT scan

Fused image

PET

PET scan

How do we stage the disease? Ann-Arbor Classification system

Stage I: single lymph node group

Stage II: more than one lymph node group SAME side of the diaphragm

Stage III: lymph node groups BOTH sides of the diaphragm (includes spleen)

Stage IV: Extranodal involvement e.g. liver, bone marrow

Itch (pruritis) is not a B symptom. Can occur in NHL and HLAlcohol induced pain is a rare feature of HL

A or B added after to signify absence or presence of B symptoms

How do we determine the prognosis?

• staging results– extent of disease

– presence or absence of B symptoms

• prognostic scores– early stage

• EORTC score

• GHSG score

• advanced stage– Hasenclever score

Prognostic scores – early stage

EORTC

• >/= 4 nodal areas

• age >/= 50 yrs

• mediastinal mass > 1/3 max transverse thoracic diameter

• ESR >/= 30 + B symptoms

• ESR >/= 50; no B symptoms

GHSG

• >/= 3 nodal areas

• extra nodal disease

• mediastinal mass > 1/3 max transverse thoracic diameter

• ESR >/= 30 + B symptoms

• ESR >/= 50; no B symptoms

Prognostic score – advanced stageHasenclever score

Risk factors

• albumin < 40

• Hb < 105

• male

• stage IV

• age >/= 45

• WCC >/= 15

• Lymphocyte count < 0.6

Risk factors and 5yr OS

• 0 89%

• 1 90%

• 2 81%

• 3 78%

• 4 61%

• >/=5 56%

How do we treat HL?

• Very effective

• High cure rates (>90% in early stage;

75- 85% in advanced stages)

• Early stage combined modality Rx -chemotherapy followed by radiotherapy

• Advanced stage chemotherapy

• Late effects important eg malignancy, cardiac, pulmonary, fertility, endocrine

ABVD

• A=adriamycin(doxorubicin)

• B=bleomycin

• V=vinblastine

• D=dacarbazine

• Given on days 1 and 15 of 28 day cycle

• most common regimen

• well tolerated

• neutropenia but infection uncommon

• bleomycin pneumonitis

• cardiac toxicity

• alopecia variable

• fertility usually spared

What are the treatment options?

Early stage

EORTC or GHSG score

• low risk – no adverse features ABVD x 2 + RT

• high risk – ABVD x3-4 + RT or ABVD x6

• RAPID study approach

Advanced stage

• ABVD x 6

• ABVD x 6 (RATHL approach)

• A+AVD

• Escalated BEACOPP

• Escalated BEACOPDAC

Trials for early stage patients

RAPID study

• patients who were PET negative after 3 cycles of ABVD

were randomized between no further treatment and

radiotherapy

• 3-year progression-free survival rate was 97.1% in the radiotherapy group and 90.8% in the group with no further therapy

• Modest improvement in the 3-year PFS rate (6.3%) can be obtained with the addition of radiotherapy

• Avoidance of RT may reduce incidence of second cancers and cardiac disease

RAPID study

OS

PFS

Current treatment of early stage patients at the Beatson

• 2-4 cycles of ABVD depending on risk factors

followed by radiotherapy

• Discuss RAPID trial on an individual basis, especially young females

Trials for advanced stage patients

RATHL study

• Using PET scan after 2 cycles to determine treatment

• Is it safe to omit bleomycin in those that are PET negative?

• Does escalation of therapy to BEACOPP improve outcome in those who are PET +ve?

NEJM, 2016, Johnson P et al

2 cycles ABVD

PET positivePET 2

PET 1

4 cycles BEACOPP-14

or 3 cycles escBEACOPP

RATHL1200 advanced HL

PET 3

RT or salvage 2 cycles BEACOPP-14

or 1 cycle escBEACOPP

No RT

PET positive PET negative

Endpoint : PFS

4 cycles ABVD

PET negative

Randomize

No further treatment

No RT

4 cycles AVD

no bleomycin

RATHL study

• 1203 patients; UK, Europe, Australia, NZ• 83.7% of patients had a negative PET2• 3 yr PFS 85.7% (ABVD) vs 84.4% (AVD)• 3 yr OS 97.2% vs 97.6%Conclusion:• bleomycin can be omitted from C3-6 with no loss

of efficacy• respiratory events reduced• escalation to BEACOPP improves outcomes in PET

+patients compared with historical controls

• Inclusion criteria

– cHL stage III or IV

– ECOG PS 0, 1 or 2

– Age ≥18 years

– Measurable disease

– Adequate liver and renal function

ECHELON-1 STUDY

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

218 study sites in 21 countries worldwide

Scre

enin

gC

T/P

ET s

can

1:1

ran

do

miz

atio

n(N

=13

34

)

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

sca

n Follow-upEvery 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 90 102

Death 18 22

Modified progressionChemotherapyRadiotherapy

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)

Pro

bab

ility

of

mo

dif

ied

PFS

No. of patients at risk:A+AVDABVD

HR 0.77 (95% CI: 0.60–0.98)Log-rank test p-value: 0.035

A+AVDABVD

0.9

0.7

0.5

0.3

0.1

Number of events

Overall survival

Echelon 1 study summary

• phase III study, untreated HL, stage III-IV

• ABVD v A(brentuximab)+AVD x 6

• 2 yr modified PFS: 77.2% vs 82.1%

• A+AVD – superior efficacy (4.9% improvement in modified PFS)

• Peripheral neuropathy more common with A+AVD (67% vs43%)

• Serious pulmonary toxicity more common with ABVD (3% vs1%)

• OS data yet to mature

• Is it really good enough to be the new “standard of care”?

NEJM, 2018, Connors. J et al

German HD18 study - Early interim PET

Borchmann P. et al:Abstract no 0737

Advanced stage

Hodgkin lymphoma

PET2 +ve(DS3-5)

PET2 –ve(DS1-2)

eBEACOPP x2

eBEACOPP x4/6

R-eBEACOPP x4/6

eBEACOPP x4/6

Lancet. 2017 Dec23;390(10114):2790-2802

HD15 Lancet. 2012 May 12;379(9828):1791-9

eBEACOPP x2

R

R

HD18 study

• 4 cycles of eBEACOPP is as effective as 6 or 8 if PET negative after 2 cycles

• 3 yr PFS 95% vs 91%

• 3yr OS 98.8% vs 95.7%

Should we use eBEACOPP for higher risk patients?

BEACOPDac may have less side effects

Current treatment of advanced stage patients at Beatson

• majority managed by RATHL approach ieABVD x 6 with omission of bleomycin if PET scan negative after 2 cycles

• Consider escBEACOPDac if high prognostic score, especially in males

How do we treat older or frail patients?

• ABVD - difficult to deliver

• VEPEM-B

• ChlVPP

• newer agents?

– Brentuximab – BREVITY study

Andrew M. Evens et al. Blood 2012;119:692-695

©2012 by American Society of Hematology

Elderly HL - PFS with multi-agent

chemotherapy

Age >70Cannot perform ADLs

BREVITY study

• untreated HL

• not for standard treatment due to age, frailty, co-morbities

• single agent brentuximab, 3 weekly

• total of 12-16 cycles, depending on PET response

BREVITY study

• ORR 84% (CMR or PMR at PET 4)

• CMR rate at PET4 was 26%

Median PFS 7.4 months PFS for 8 patients in CMR 11.9 months

31 patients

BREVITY study

• Tolerable therapy but high incidence of low-grade toxicity and dose reductions – Peripheral neuropathy an issue

• High overall response rates but mainly partial response– CMR and PFS unsatisfactory

• Need to combine with other agents

Management of relapsed HL

• Usually salvage therapy + ASCT

• Aim is to achieve PET negativity prior to transplant – outlook same whether require 1 or 2 salvage therapies

• If PET negativity not achieved, consider allo

• For minority of patients whose disease remains localised at relapse, chemotherapy + RT may be an option

Younes 2016

Novel Agents

Brentuximab vedotin

SMC approval: treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

1.following autologous stem cell transplant (ASCT)

2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option

Current uses:

Above indications

Bridge to allograft

Check Point Inhibitors

• Harness power of immune system to combat cancer

• Hodgkin’s RS cells express high levels of PD-L1 selective blockade of anti tumor immune response

• monoclonal antibodies directed against the receptors or ligands can be used to augment the immune response

Targeting PD1/PDL1 pathway in HL

T cell

PD1TCR

PD-L1

PD L2MHC I/II

PD-L2

HRSAdapted from Stathis & Younes: Ann Oncology 2015

R lt f PD1 bl ki tib di i l d HLResults of PD1 blocking antibodies in relapsed HL

Drug Dose/

schedule

N %

ORR

% CR ORR in BV

treated HL

1st Author

Pembrolizumab

(humanized

IgG4)

10 mg/kg IV

Q 2wks

29 66% 21% 66% (n=19) Moskowitz C

gG )

Nivolumab

(Fully human

IgG4)

3 mg/kg IV

Q 2wks

23 87% 17% 70% (n=16) Ansell S

ASH 2014

NEJM 2014

Check point inhibitors

• Responses seen in ASCT and BV failures• Nivolumab: SMC approval as monotherapy in adults with

relapsed/refractory HL after ASCT and Brentuximab• Pembrolizumab: as above + unsuitable for ASCT• Side effects mainly immune related

– Pneumonitis – usually early– Colitis – often late

• Trials– Relapsed setting– ? In combination with BV – ?Front line

Late effects to avoid as cures increase

• Secondary MDS/AML from alkylating agents

• Solid tumours from extended field radiation

• Pulmonary fibrosis from bleomycin

• Ischaemic heart disease from mediastinal

irradiation and doxorubicin

• Infertility from alkylating agents and pelvic RT

Ovarian function sub-study of RATHL

• Premenopausal women entering RATHL

• Recording of:

– Menstrual function, fertility

– Serum markers of ovarian function (LH, FSH, estradiol) in local labs.

– AMH pre-treatment, during and following treatment

– Comparison between treatment arms

Anti-Mullerian Hormone is produced by small growing follicles

Oestradiol / FSHAMH

Anderson RA 2012 Clin Endocrinol 77, 652

This reflects the number of primordial follicles, the ‘Ovarian Reserve’, which determines reproductive lifespan

Sequential changes in AMH

BEACOPP

ABVD/AVD

0

0.5

1

1.5

2

2.5

Baseline EOT at 1 year

AB(V)D

BEACOPP

Risk of premature ovarian insufficiency (POI)(defined as FSH > 25 iu/l)

ABVD/AVD BEACOPP p

Women 35 or over, N (%)End of treatment2 years

37 (66)4 (10)

11 (100)7 (70)

0.022*<0.001**

Women under 35, N (%)End of treatment2 years

21 (14)0

16 (89)2 (20)

<0.001*0.007**

Median time to recovery (days)35 or overUnder 35

516209

824664

0.008***<0.001***

% Recovery at 2 yearsK-M estimate (95% CI)

35 or overUnder 35

78% (68 -86)93% (89-96)

37% (19 -65)56% (36 -77)

* Chi squared test, ** Fisher’s exact test, *** Log rank test.

Time to recovery of FSH below 25 iu/l

Risk of premature ovarian insuffiency – defined as FSH > 25

Conclusions

• BEACOPP regimens are significantly more toxic to ovarian

function than ABVD, an effect which worsens with age

• There is no detectable evidence of lasting ovarian damage by

ABVD in patients under 35

• Reduction in AMH levels appears to be permanent following

BEACOPP, although a minority of women will recover normal

gonadotrophin levels

Thank you for listening

Any questions?