PET-Guided Strategy Improves the Safety of Beacopp-Based Treatment in Advanced Hodgkin Lymphoma: Prolonged Follow-up of the Lysa Ahl 2011 Phase 3 Study
Authors: Casasnovas Olivier , Racape Judith , Dechene Julie , Bouabdallah Reda , Brice Pauline , Lazarovici Julien , Ghesquieres Hervé , Stamatoulas Bastard Aspasia , Dupuis Jehan , Gac Anne-Claire , Gastinne Thomas , Joly Bertrand , Bouabdallah Krimo , Nicolas-Virelizier Emmanuelle , Feugier Pierre , Morschhauser Franck , André Marc , Berriolo-Riedinger Alina , Edeline Veronique , Joubert Clémentine , Meignan Michel , Demeestere Isabelle 
Published: February 2021

Background
AHL2011 study (NCT01358747) demonstrated that PET negativity after 2 cycles of upfront BEACOPPescalated (BEA) allows to switch to 4 cycles of ABVD 84% of patients (pts) with advanced Hodgkin lymphoma (HL) leading to reduce immediate treatment toxicity without loss of tumor control (Casasnovas RO, Lancet Oncol 2019). We report an updated follow-up of the study with a focus on the late treatment-related adverse events including secondary primary malignancies (SPM) and unfertility.
Methods
In AHL2011 823 patients aged 18-60 with a newly diagnosed advanced HL defined by an Ann Arbor stage III, IV or IIB with M/T&gt;0.33 or extranodal involvement were prospectively randomized between a standard arm (n=413) delivering 6 x BEA and a PET-driven arm (n=410) after 2 x BEA delivering 4 x ABVD in PET2- pts and 4 x BEA in PET2+ pts. In both arms PET performed after 4 cycles of chemotherapy had to be negative to complete the planned treatment. We aimed at excluding inferiority of the PET-driven arm of at least 10% compared to the standard arm which was achieved with the analysis on 10/2017. The data cutoff for the present analysis was 29 April 2019.
A prospective fertility substudy for patients &lt;45y at time of randomization was performed analyzing: - In females, ovarian function using serum levels of FSH, estradiol and centralized anti-mullerian hormone (AMH) measurements. Acute premature ovarian insufficiency (POI) was defined as FSH &gt; 24 IU/L twice during 5y follow-up when available, with estradiol &lt; 50pg/ml, and low ovarian reserve (OR) by AMH &lt; 0.16ng/ml. - In males, FSH serum levels and sperm analysis.
Results
With a 5.6 year median follow-up, 5y PFS and OS were similar in both randomization arms (PFS: 87.5% vs 86.7% ; HR 1.07, 95%CI 0.74-1.57; p=0.67; OS: 97.7% in both arms; HR=1.012, 95%CI 0.50-2.10; p=0.53). In the whole cohort full interim PET assessment predicted patients PFS (5y PFS = 92.3% in PET2-/PET4-, 75.4% [HR= 3.26 ; 95%CI 18.3-5.77] in PET2+/PET4- and 46.5% [HR= 12.4 ; 95%CI : 7.31-19.51] in PET4+ pts respectively; p &lt;0.0001; figure 1) independently of IPS. OS was also impacted by interim PET results and PET2+/PET4- patients (5y OS : 93.5% ; HR=3.3, 95%CI : 1.07-10.1; p=0.036) and PET4+ patients (5y OS 91.9%; HR=3.756, 95%CI 1.07-13.18, p=0.038) had a significant lower OS than PET2-/PET4- patients (98.2%).
22 patients (2.7%) developped a secondary primary (SPM), 13 (3.2%) and 9 (2.2%) in the standard and experimental arms respectively.
424 males and 145 females with a median age 27y (16 - 45) entered the fertility sub-study. Baseline ovarian functions based on FSH and AMH levels were similar in the 70 and 75 female of the standard and PET-driven arms. During follow-up, 32 pts experienced POI (46.1% versus 14.5% in the standard and PET-driven arms, respectively). The risk of POI was significantly associated with both age, total dose of alkylating agents, and was reduced in the PET-driven arm (HR=0.20, 95%CI 0.08-0.5; p&lt;0.001). The risk of low OR was related to cumulative dose of etoposide &gt;5g (HR=0.36, 95%CI 0.14-0.96; p=0.04) but not to arms. In males, median baseline FSH levels were similar in both arms but 19 and 23% experienced severe oligospermia at baseline in standard (n=214) and PET-driven arms (n=210), respectively. Chemotherapy dramatically reduced sperm numeration in both arms but recovery occured more frequently in the PET-driven arm (severe oligospermia at 4-5 year: 50% vs 93%). A total of 84 patients (14.7%) reported pregnancies including 49 (17.2%) in the PET driven arm vs 35 (12.3%) in the standard arm (p=0.12) and required assisted reproductive technology treatment more frequently in the standard arm (23% vs 14%).
Conclusions
The prolonged follow-up confirms that the PET-driven strategy delivering 4 cycles of ABVD in PET negative patients after 2 cycles of BEA is non inferior compared to standard 6 cycles of BEA. PET4 provides additionnal prognostic information to PET2 and identifies patients with particularly poor prognosis. The PET-driven treatment allows to reduce significantly the risk of infertility in both men (recovery of oligospermia) and women (decreasing by 5 the risk of POI) and improves the chances of spontaneous pregnancy after completion of HL treatment. With the current follow-up the risk of SPM was low (2.7%) and similar in both arms.

Disclosures
Casasnovas: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; abbvie: Consultancy, Honoraria. Brice:Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Honoraria; MSD: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Ghesquieres:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Stamatoulas Bastard:Takeda: Consultancy; Celgene: Honoraria; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Gac:Roche: Consultancy; Takeda: Consultancy. Bouabdallah:Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Morschhauser:Genentech, Inc.: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. André:Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Abbvie: Consultancy; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Demeestere:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; THERAMEX FERRING: Other: TRAVEL, ACCOMMODATIONS, EXPENSES.