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LYMPHOMA LAB

Start Up Meeting> Roma, 27 Novembre 2018STARHOTELS METROPOLEVia Principe Amedeo, 3

Linfoma di Hodgkin:terapia di consolidamento

post trapianto autologo

A cura di: Francesco Merli, Ematologia AUSL-IRCCS Reggio Emilia

Survival in Pts With HL Relapsing After HDT/ASCT

Arai S, et al. Leuk Lymphoma. 2013;54:2531-3253.

Phase III AETHERA: Brentuximab Vedotin in Pts With HL at Risk of Progression After ASCT

• Primary endpoint: PFS per IRF

• Secondary endpoints: OS and safety/tolerability

N = 329

Brentuximab vedotin1.8 mg/kg IV outpatient Q3W

+ Best Supportive Care

(n = 165)

Placebo IV outpatient Q3W+

Best Supportive Care(n = 164)

Up to 16 cycles

Moskowitz CH, et al. Lancet. 2015;385:1853-1862.

AfterASCT

high-risk cHL patients:• primary refractory

disease, • disease relapse < 12

months after front-line therapy,

• or extranodalinvolvement

AETHERA: Baseline Pt CharacteristicsPt Characteristic BV (n = 165) Placebo (n = 164)

Median age, yrs (range) 33 (18-71) 32 (18-76)

Males, % 46 59

Previous systemic salvage therapies %

1 57 52

≥ 2 (median: 2; range: 2-8) 43 48

HL status after frontline therapy, %

Refractory 60 59

Relapse < 12 mos 32 33

Relapse ≥ 12 mos with extranodal disease 8 8

Response with salvage therapy pre autoHSCT,* %

CR 37 38

PR 35 34

SD 28 28

Moskowitz CH, et al. Lancet. 2015;385:1853-1862. *PET scans not mandatory in protocol.

AETHERA: PFS by Independent Review

OS

Moskowitz CH, et al. Lancet. 2015;385:1853-1862

PFS• HR 0.57 (95% CI 0.40-0.81)• P= 0.0013• 43% reduction in the

hazard rate for PFS

Median FUP: 30mos

Median PFS in BV arm: 42.9 mos (95% CI 30.4-42.9)

Median PFS in placebo arm: 24.1 mos (95% CI 11,5-not estimable)

2-yrs PFS63% vs 51%

AETHERA: Treatment-Emergent Adverse Events in ≥ 20% of Patients

AE, %BV (n = 167) Placebo (n = 160)

Any Grade Grade ≥ 3 Any Grade Grade ≥ 3

Any 98 56 89 32

Peripheral sensory neuropathy 56 10* 16 1

Neutropenia 35 29† 12 10

Upper respiratory tract infection 26 0 23 1

Fatigue 24 2 18 3

Peripheral motor neuropathy 23 6 2 1

Nausea 22 3 8 0

Cough 21 0 16 0

Diarrhea 20 2 10 1

Moskowitz CH, et al. Lancet. 2015;385:1853-1862.

*No grade 4†1 pt with febrile neutropenia.

Moskowitz CH, et al. Lancet. 2015;385:1853-1862.

AETHERA: PFS by Prespecified Pt Subgroups

AETHERA: Investigator-Assessed PFS With Extended Follow-up

Gautam A, et al. Leuk Lymphoma. 2018;59:69-76.

AETHERA: Conclusions

“delivery of brentuximab vedotin as consolidation therapy was generally well

tolerated immediately after ASCT and provided a sustained PFS benefit for

patients with HL with risk factors for relapse or progression after autologous

stem-cell transplantation salvage therapy”

“Consolidation therapy with brentuximab vedotin might increase the possibility

of cure or potentially avoid exposure to subsequent toxic therapies, and seems

to be effective in this young cancer population with high unmet need”

Moskowitz CH, et al. Lancet. 2015;385:1853-1862.

Relapsed disease

• For most patients with R/R HL, the treatment of choice consists of HDCT followed by ASCT [I, A]

• High-risk patients may benefit from tandem ASCT [III, B]

• Consolidating treatment with brentuximab vedotin following HDCT and ASCT is recommended in patients presenting with defined poor-risk factors

[II, B]

• DHAP, IGEV or ICE can be given before HDCT and ASCT [II–III, A]

• In some patients, single-agent brentuximab vedotin may be sufficient as salvage therapy before HDCT and ASCT [III, B]

• Achieving a negative PET should be the goal of salvage therapy irrespective of the applied protocol [III, B]

• RT before HDCT and ASCT may be discussed in patients with single PET-positive lymph nodes after salvage therapy [IV, C]

Eichenauer et al, Ann Oncol 2018

2017

Purpose: to evaluate the addiction of CONSOLIDATIVE RADIATION THERAPY after HD tehrapy and ASCT for R/R HL

80 consecutive patients (2005-2014)

Eligible patients:

• persistent nodal masses >= 2 cm or

• sites suspicious for residual disease involvement on day +28 post ASCT

Wilke C et al, 2017 RT2-yrs PFS: 67%

No RT 2-yrs PFS: 52%

PFS OS

Median follow up: 25 mos

P<.01

Subgroup analysis: consolidative RT improve PFS in patients with• Bulky disease (62% vs 39% p=0.02)• B-symptoms (48% vs 28%, p=0.02)• Primary refractory (47% vs 32%, p=0.02)• Partial response on pretransplant imaging (47% vs 32%, p=0.02)

Lucy Hiu BS et al, Cancer, 2017

AETHERA Trial Results: consolidation treatment with brentuximab vedotin (BV) decreased the risk of HL progression after autologous stem cell transplantation (ASCT).

the impact of BV consolidation on overall survival, quality of life, and health care costs remain unclear

Markov decision-analytic model:

constructed to measure the costs and

clinical outcomes for BV consolidation

therapy compared with active

surveillance in a cohort of patients aged

33 years who were at risk for HL relapse

after ASCT

For each post-ASCT strategy

were calculate:

• Life-time costs, quality-

adjusted life-years (QALYs)

• Incremental cost-

effectiveness ratios (ICERs)

ICER

The incremental cost-effectiveness ratio (ICER) is a statistic used in cost-effectiveness analysis to

summarise the cost-effectiveness of a health care intervention. It is defined by the difference in

cost between two possible interventions, divided by the difference in their effect. It represents

the average incremental cost associated with 1 additional unit of the measure of effect.

QALY

The quality-adjusted life year or quality-adjusted life-year (QALY) is a generic measure of disease

burden, including both the quality and the quantity of life lived. It is used in economic

evaluation to assess the value for money of medical interventions

• BV consolidation led to significantly higher health care costs ($378,832 vs $219,761), with an incremental cost of $159,071

• The average lifeyears gained with BV consolidation compared with active surveillance was 2.1 years (mean [median] overall survival: mean 28.0 [29.6] vs 25.9 [24.1]).

• After applying qualityof-life adjustment and future discounting, BV as consolidation therapy was associated with an improvement of 1.07 QALYs compared with active surveillance.

• Therefore, the ICER for BV consolidation compared with active surveillance was estimated at $148,664 per QALY.

Lucy Hiu BS et al, Cancer, 2017

The incremental clinical benefit of BV consolidation was associated with significant

health care expenditures, producing an ICER of $148,664 per QALY.

• In the setting of HL after ASCT, approximately 50% of individuals will remain free from HL

recurrence without additional therapy

• Even when selecting patients at high risk using clinical parameters, considerable

proportions remain in remission post-ASCT and are unlikely to benefit from upfront

consolidation with BV

• Among patients with confirmed HL relapse post-ASCT, an overwhelming majority will

derive clinical benefit from BV therapy

Lucy Hiu BS et al, Cancer, 2017

• Under indication-specific pricing, BV in the consolidation setting would be priced

lower than BV used for post-ASCT salvage

• ultimately, our model indicated that price reductions for BV in the consolidative

setting from 18% to 38% produced more reasonable ICERs of $100,000 per QALY and

$50,000 per QALY, respectively.

CONCLUSIONS:

BV as consolidation therapy under current US pricing is unlikely to be cost

effective at a willingness-to-pay threshold of $100,000 per QALY.

However, indication-specific price reductions for the consolidative setting

could reduce ICERs to widely acceptable values.

Lucy Hiu BS et al, Cancer, 2017

Linfoma di Hodgkin:terapia di consolidamento post

trapianto autologo

RISULTATI DELLA SURVEY