Cost-Effectiveness of Interim PET Response Adapted Therapy In ABVD-Treated, Advanced-Stage Hodgkin Lymphoma

ABVD chemotherapy (AT) is the standard treatment for patients with advanced-stage Hodgkin lymphoma (HL). However, BEACOPP achieves a higher disease control at a cost of a definitely higher toxicity. Positron emission tomography (PET) after two chemotherapy cycles (PET2) is the most reliable predictor of treatment outcome in ABVD-treated patients. A PET-2 response-adapted strategy with a therapy shift from ABVD to BEACOPP in PET2 positive patients (A/B-T) was shown to increase the 2-y Failure Free Survival (FFS) in the latter from 12% to 62% by indirect retrospective comparison, and to improve the disease control in the overall patient population (Gallamini Br. J. Haematol 2011). However, PET is an expensive test which deserves a careful economic assessment before widespread adoption and reimbursement.

We built a Markov decision model comparing A/B-T with AT strategies for advanced HL. The model was calibrated on the reported retrospective cohort of 154 ABVD-treated HL patients in which treatment intensification with BEACOPP was given in PET-2 positive patients. Briefly, patients were treated with standard ABVD × 2 courses and an interim-PET performed afterwards: PET-2 negative patients continued with ABVD × 4 and consolidation RxT in presence of bulky disease; PET-2 positive patients shifted to BEACOPP escalated × 4 + BEACOPP baseline × 4. Patients failing either AT or A/B-T underwent rescue treatment with IGEV × 4, followed by Autologous Stem Cell Transplantation (ASCT). In patients failing ASCT, DHAP reinduction therapy was given and allogeneic SCT (alloSCT) was performed whenever possible. The model included 12 health-states: ABVD cycles 1–2, ABVD cycles 3–6, BEACOPP escalated (4 cycles), BEACOPP baseline (4 cycles), IGEV (4 cycles), ASCT, DHAP + allogeneic SCT, follow-up (FFS patients PET2 negative), follow-up (FFS patients PET2 positive), follow-up (FFS after ASCT/CST), relapse, death. Each health state last 1 month and the overall time horizon at baseline was 5 years. We considered severe toxicity needing inpatient care and transplant-related mortality. Quality of life was reduced by 20% for chemotherapy-treated patients, 30% for transplanted ones and 40% in relapsed ones. The model assessed the following endpoints: survival, quality of life – adjusted survival (QALY) and costs (in the perspective of the health-care system) as the principal end-points. TreeAge SW (2008) was run. National charges were used as estimators of unitary costs. First and second-order sensitivity analysis was performed.

A/B-T reduced the overall percentage of patients failing treatment (refractory and relapsing) from 27% to 14%. This clinical advantage induced a prolongation of quality-adjusted survival from 53.20 to 55.63 quality-adjusted months, that is a gain of 0.18 QALYs (90% CI: −0.1;+1.4). The number of interim PET needed to avoid one ASCT was 8.3. The cost of universal interim PET (€1,546) was offset by the reduced number of ASCT procedures (€36,575). Consequently, health-care costs were €27,861 for A/BT versus €29,050 for AT strategy which is a €1189 (90%CI: −41,208; +13,240) saving. At sensitivity analysis we verified that the results were mildly sensitive to the costs of PET and ASCT: A/B-T was not cost saving if PET would cost more than €3,031 and ASCT less than €20,200. A/B-T would cost more than €40,000/QALY only at a PET cost higher than €16,300. The results were also sensitive to the portion of PET2 positive patients: A/B-T wouldn't turn out cost saving if the portion was higher than 22%. The results were not sensitive to the rate of severe adverse events during chemotherapy. The results were overall robust, since A/B-T cost less than €30,000/QALY in more than 80% out of 100,000 simulations (MonteCarlo analysis).

A/B-T is more efficacious and less expensive than standard AT treatment for advanced-stage HL patients, therefore the routine use of interim-PET is warranted in treatment planning and chemosensitivity adapting in these patients.

Off Label Use: The study includes use of Rituximab as maintenance in responding patients after first line chemoimmunotherapy.