Frontline treatment of Hodgkin lymphoma 2019

(or: Embracing PET-Guided therapy)

Michael CrumpDivision of Medical Oncology and Hematology

Princess Margaret Cancer CentreUniversity of Toronto

Ø no disclosures

Ø …. Except talking about Hodgkin Lymphoma in any area in 20 slides really a challenge for me….

Disclosures

content

• Data from previous trials of therapy in early stage HL• New data on use of functional imaging to advanced stage HL• What do patients think?• Cost effectiveness• Conclusions (hopefully there will be time for questions)

Deauville Criteria for FDG PET interpretation Stringent criteria for negative: therapy minimization trial(RAPID, H10, HD18)

Liberal criteria for positive: therapy escalation trial(HD18)

Overall : Deauville 1-3 considered complete metabolic response

A quick look at limited stage HL

Why is pre-treatment (baseline) FDG PET scanning important?

• Upstaging (limited to advanced) occurs 15-20% of cases• Downstaging: < 5%• Treatment change: varies, 10-20% of PET staged pts (vs treatment

that would have been based on CT scanning)

• Ontario data: HL patients upstaged from limited to advanced in 25.9%, additional cycles of chemo in 20.6%

• Not clear if results of therapy are improved….

Barrington, et al, J Clin Oncol 2014

Metser, et al, Radiology 2018

21 yo male: presents with dyspnea, large pericardial effusion, tamponade…

BASELINE

HD10: without risk factorsRisk factors: • Large mediastinal

mass• Extranodal

extension• ESR >50 (30 if B’s)• >3 nodal areas

4 ABVD vs 4 BEACOPP20 vs 30 Gy

HD11: with risk factors

For early favourable: 2ABVD + 20Gy is enough

For early unfavourable: 4ABVD + 30Gy is optimal…

A Engert, NEJM 2010HT Eich, J Clin Oncol 2010

2 ABVD vs 420 vs 30 Gy

Early HL without risk factors:Management without functional imaging:

ESMO Practice Guideline, Ann Oncol 2018

Early HL withrisk factors: Management without functional imaging:

ESMO Practice Guideline, Ann Oncol 2018

EORTC H10 trial design

N=754

N=1196

N randomized*

371

376

583

595

M Andre et al. JCO 2017* 505 PET –ve patients treated with ABVD + INRT following safety amendment

early unfavourableat least one of:- age ≥ 50- 3 or more nodal areas- M-T ratio ≥ 0.35- ESR ≥ 50 (B Sx: ≥ 30)

Overall outcomes of H10

2 ABVD FDG PET

Escalate

Ë

¬¬

Discuss omission of IFRT

(18.8%)

Negative PET scan: uptake more than mediastinal blood pool

New data on PET-guided therapy in advanced HL

Comparison of ABVD to GHSG RegimensABVD BEACOPP escBEACOPP

Dose* Days Dose* Days Dose* DaysBleomycin 10 1, 15 10 8 10 8Etoposide - - 100 1-3 200 1-3Doxorubicin 25 1,15 25 1 35 1Cyclophosphamide - - 650 1 1200 1Vincristine - - 1.4 8 1.4 8Procarbazine - - 100 1-14 100 1-7Prednisone - - 40 1-14 40 1-14Vinblastine 6 1,15 - - - -Dacarbazine 375 1,15 - - - -

* Doses per m2

Advanced Stage HL : Management without functional imaging:

ESMO Practice Guideline, Ann Oncol 2018

Response-Adapted Therapy in Hodgkin Lymphoma (RATHL) StudyCan we make chemotherapy for advanced HL safer? Better?

83.7%16.3%FDG uptake more than liver (D4)

• Positive PET after 2 escBEACOPP: FDG uptake > mediastinum (Deauville 3,4)ØCan treatment be augmented to reduce risk of relapse?• Randomized to rituximab vs control x 6 doses (cycle 3)

• Superiority

• Negative PET after 2 escBEACOPP: uptake < mediastinum (Deauville 1,2)ØCan treatment be minimized to reduce toxicity, similar efficacy?• Randomized to 6 more escBEACOPP vs 2 more cycles (amendment after

HD15: 4 more in standard arm)• Non-inferiority study: margin 6% (95% CI for difference must be <6%)

GHSG HD18: PET adapted therapy in advanced HL (IIBE + LMM, III, IV)

Borchmann, Lancet 2018

Negative PET2: outcomes with 4 escB as good as 6 or 8 cyclesPET2 allows therapy reduction without compromising PFS, OS

Borchmann, Lancet 2018

Kobe, Blood 2018

HD18: Outcome for patients according to Deauville score after 6 cycles of escBEACOPP

AHL 2011: study design

October 29 2018

ISHL meeting 2018

Non-inferiority 5y-PFS design: Standard arm: 85%; Experimental arm: >75% (HR=1.77)

AHL 2011

AHL 2011: PET2 results (central review)

October 29 2018ISHL meeting 2018

PET2Evaluable 398 96% 397 97% 795 97%

Negative 349 88% 346 87% 695 87%Positive 49 12% 51 13% 100 13%

Standard arm Experimental arm Alln = 413 n = 410 n = 823

AHL 2011

Casasnovas et al, Lancet Oncol 2018, in press

Deauville 1-3

AHL 2011: PFS according to treatment arm(Primary endpoint – ITT population)

October 29 2018ISHL meeting 2018

p = 0.68 ; HR = 1.084 (95%CI: 0.73 - 1.59)

4y-PFS = 87.4% ; 5y-PFS = 86.2%4y-PFS = 87.1% ; 5y-PFS = 85.7%

Median follow-up = 50.4 months

(HR Bound < 1.77)

AHL 2011

Casasnovas et al, Lancet Oncol 2018, in press

Summary of PET-guided Studies for Advanced HL

PFSABVD 1st PET-2 NEG PET-2 POS

SWOG 5 y 76% 5 y 66%GITIL/FIL0607 3 y 87% 3 y 60%RATHL 3 y 85% 3 y 67%

escBEACOPP 1stGHSG HD 18 5 y 94% 5 y 87%AHL 2011 5 y 89% 5 y 71%

Initiating Treatment with escBEACOPP + De-escalating if PET2 –ve Results in Less Toxicity

AHL2011escBEACOPP x 6 2escBEACOPP

"ABVDany toxicity gr ≥3 98% 98%

anemia 69% 28% p < .001

febrile neutropenia 87% 23% p < .001

thrombocytopenia 66% 40% p < .001

HD18escBEACOPP x 6 escBEACOPP x 4

anemia 51% 39%thrombocytopenia 70% 57%febrile neutropenia 18% 18%transfusion RBC/PLT 60/33% 47/24%

Non-Hematologic Toxicities Reported in Recent De-escalation Trials in Advanced HL

Grade 3-5 toxicityPulmonary Neurologic

RATHL ABVD/AVD 1% 3%ABVD 3% 5%

HD18 escBEACOPP x 6/8 2/6% 13/7%

escBEACOPP x 4 2% 3%

AHL 2011 6 escBEACOPP 4% 4%2escBEACOPP/ABVD 4% 2%

Conclusions—about imaging• PET scan for staging of HL: important to have (not essential, but close)

• No need to do bone marrow (unless to sort out cytopenias)• (not all of the trials reviewed today had baseline PET)• Proportion of patients upstaged and have treatment potentially altered is clinically relevant

• Early (cycle 2) FDG PET scanning required in limited stage HL• To make thoughtful decisions regarding omission of radiation• To identify need for treatment escalation (and inclusion of INRT) for those with positive PET2

• Early PET is needed in advanced HL to• Allow reduction in number of cycles of escBEACOPP if scan is negative

• 2 more escBEACOPP or 4 more ABVD)—most patients at least 80%)• To define patients treated with ABVD who need therapy escalation (15%)

(although more such patients might be best treated with escBEACOPP initially)• Allow omission of bleomycin for those on ABVD (eg older patients)

HD2000, Viviani, EORTC

ABVD x 2 PET-negative AVD x 4RATHLPET-positive eBEACOPP x 4

A-AVD x 6 Echelon-1

ABVD x 6-8 with no interim PET scan

eBEACOPP x 2 PET-negative

ABVD x 2PET-positive eBEACOPP x 2

BEACOPP x 2

AHL2011

PET-negativePET-positive Salvage therapy

PET-negative

ABVD x 2

eBEACOPP x 2 PET-negativePET-positive eBEACOPP x 4-6

eBEACOPP x 2HD18 HD15

eBEACOPP x 6

1

2

3

4

5

Cost-effectiveness analysis* of treatment options for advanced HL

Treatment strategy

20 yr quality-adjusted survival 20 yr survival Direct costs (CAD)

AHL2011 13.2 years 14.6 years $53,129RATHL 12.7 years 14.1 years $64,172BEACOPP 12.4 years 13.7 years $76,777A-AVD 12.3 years 13.4 years $240,856

ABVD 11.7 years 12.2 years $94,801

ICER AHL2011 strategy dominates

Vijenthira, Lancet Hematology, in press* Includes cost of ASCT for relapse, subsequent therapies; patient utility values for fertility, toxicities

Cost-effectiveness acceptability curve

Based on a WTP of $100,000, AHL2011 strategy is the dominant strategy 84% of the time

Vijenthira, Lancet Hematology, in press

What do patients (and their doctors) want from treatment for advanced HL?• On-line survey of patients before, during or within 2 years of

treatment: France, Germany, UK• Physicians who treated HL from same countries

• Discrete choice experiment—12 scenarios, PFS, OS estimates from recent trials (ABVD, escBEACOPP, brentuximab-AVD)

• Patients and physicians asked to choose between 2 hypothetical (unnamed) regimens with regard to efficacy, toxicities

• 289 evaluable patients / 381 enrolled; most (45%) currently on treatment, 25% post-therapy

Brockelmann, Br J Hematol 2019

Patient preferences: higher PFS, OS, less toxicity

Brockelmann, Br J Hematol 2019

PFS valued more than OS in all scenarios

Treatment naïve patients placed less weight on side effects

Changes in OS (8.5%) and risk of relapse (15%) had to be relatively large for patients to accept greater toxicity risk

What is important to patients depends….Preference weights—relative importance of attributes of treatment

Brockelmann, Br J Hematol 2019

med F/U AML NHL Solid TumourGHSG HD9 9y 3% 1% 1.9%

HD12 6.5y 1.3% 0.6% 2.3%HD15 4y 0.3% 0.8% 1.3%

COPP ABVD 9y 0.4% 2.7% 2.7%

ABVD (E2496) 6.4y 0.3% 0.5% 3%

RATHL AVD(B) 3.5y < 1% 2% 1%AHL 2011 de-esc 4.2y 0.2% 0.5% 0.5%HD18 4 cycles 5y <1% 2% 1%

Second Malignancies Reported in Randomized Trials of Treatment for Advanced HL

Patients receiving escBEACOPP need a fair bit of supportive care• Aprepitant days 1-3 in addition to dex, 5HT3 antagonists

• Lots of nausea from day 1 cyclophosphamide• Anti – infection prophylaxis:

• Trimethoprim-sulfamethoxazole (PJP prophylaxis)• Oral antibiotic prophylaxis (recommended in most GHSG protocols)• Acyclovir: HSV

• GCSF day 9-16 (shorter if bone pain)

• Dose reductions can / have been used if significant myelosuppression• Addition of epo previously not been shown to be better

conclusions• Response-adapted therapy based on PET2 results represents new

standard for management of HL• Allows identification of limited stage patients who benefit from therapy

escalation and ISRT• Permits de-escalation of therapy without loss of efficacy

• Initiation of treatment for advanced HL with escBEACOPP results in better outcomes that with ABVD—and response-adapted therapy reduces toxicity vs non-adapted therapy

• Fertility preservation options are available • Intensive support of patients is needed—toxicity is managable

PET Scan Criteria Used

RAPID trial: Deauville score

- positive if score 3,4,5 (> mediastinal blood pool)

EORTC H10: International Harmonization Project

- mass ≥ 2 cm: +ve if > mediastinal blood pool

- mass < 2 cm/normal size node: +ve if > background

PET + PET -

8 BEACOPP 6-8BEACOPP

4BEACOPPNo R R

F/U (mos) 69 66 56 57

Radiation post 33% 38% 3% 3%

Relapse 6% 8% 5% 7%

Death

Toxicity < 1% 1% 1% 0%

2nd cancer 1% 1% 2% 1%

AML/MDS 2% 2% 2% <1%

*5 yr cumulative incidence second cancer 3.3-4.0%

• A decrease of treatment cycles led to a decrease of severe infections (p=0·0005), organ toxicities (p<0·0001), and treatment-related morbidity (p<0·0001).

HD18 Toxicity summary and some pertinent big ticket items:

Probability of resumption of menses is dependent on age and chemotherapy

Likelihood of amenorrhea at 4 y increases with use of escBEACOPP vs ABVD

Behringer, et al, J Clin Oncol 2012

4 cycles?

What about the LMM subgroup?

HD14: ABVD x 4 + IFRT (A) vs escBEACOPP x2 + ABVD x2 + IFRT (B)

• Stage II 95%; stage IIB 27.7%• Large mediastinal mass: 18.7%

• High risk patients (LMM, elevated ESR)appear to benefit from more intensiveupfront therapy (then de-escalate).

∆ PFS 7.5%Von Tresckow, J Clin Oncol 2011