Interim PET-Guided ABVD or ABVD/Escalated BEACOPP for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma (JCOG1305, INNOVATE-HL study)

Introduction Interim positron-emission tomography (PET) can predict clinical outcomes in patients with classic Hodgkin lymphoma (cHL). The objective of this single-arm confirmatory study (JCOG1305, INNOVATE-HL) is to establish interim PET-guided treatment strategy for newly diagnosed advanced-stage cHL.

Methods Patients aged 16-60 years with cHL received 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as an induction chemotherapy, and then underwent an interim PET scan. Images were centrally reviewed with the use of a 5-point scale for PET findings for further response guided treatments.

Patients with negative interim PET findings (defined as score 1 to 3) continued additional 4 cycles of ABVD, whereas those with positive interim PET findings (score 4 or 5) switched to 6 cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone). Involved site radiation therapy (ISRT) was set as a protocol treatment if patients with partial response had a single residual lesion after completion of chemotherapy.

The primary endpoint were 2-year progression-free survival (PFS) among all eligible patients and among interim PET-positive patients (co-primary endpoints). We had the following hypotheses: 2-year PFS of eligible patients and interim-PET positive patients will exceed 75% and 35%, respectively, compared to a historical control with one-sided alpha of 0.1. Secondary endpoints included overall survival (OS), event-free survival (EFS), in which events were defined as death, progression or not achieving complete response at end of protocol treatment, and incidences of adverse events and secondary malignancy. This study was registered at jRCTs031180218.

Results A total of 93 patients were enrolled from 35 institutions between January 2016 and December 2019. One patient was ineligible because of diagnostic error. Baseline characteristics of 92 eligible patients who underwent an interim PET scan were as follows: a median age of 35 years (interquartile range [IQR]: 28-48); 58% were male; most of patients (87 [95%]) had performance status of 0 or 1; Ann Arbor stage III and IV consisted of 40 (43%) and 43 (47%), respectively, the remaining 9 (10%) had stage IIB with bulky (10 cm or more) mediastinal lesion or nodal lesion involving directly to extranodal lesion; 51 (55%) and 15(16%) had B symptoms and bulky lesions, respectively.

An interim PET scan showed 19 patients (21%) with positive findings; those patients received escalated BEACOPP; 18 completed 6 cycles of BEACOPP including one who underwent ISRT, the remaining one discontinued BEACOPP. On the other hand, 73 patients (79%) who had interim PET-negative findings continued ABVD; 70 completed additional 4 cycles of ABVD including two who underwent ISRT, the remaining 3 discontinued ABVD. Average relative dose intensity of induction ABVD, additional ABVD and escalated BEACOPP were 98.6% (±4.0), 96.7% (±5.7) and 82.2% (±9.3%), respectively.

With a median follow-up of 41.1 months (IQR: 29.7-53.1), the 2-year PFS were 84.8% (80% confidence interval [CI]: 79.2-88.9) and 84.2% (80% CI: 69.7-92.1) among all 92 eligible patients and 19 interim PET-positive patients, respectively (Figure 1). The 2-year EFS were 76.1% and 68.4% among all eligible patients and interim-PET positive patients, respectively.

Bleomycin lung toxicity (BLT) occurred in 9 patients, but no patients led to BLT-related death.

Twelve and three patients underwent autologous and allogeneic hematopoietic stem cell transplantation (HSCT) as a salvage treatment, respectively, including one received allogeneic HSCT for relapse after autologous HSCT.

The 2-year OS was 98.9%; two patients died due to interstitial pneumonia after autologous HSCT and brain hemorrhage without relapsing cHL among the interim PET-positive patients, whereas no patients died among interim PET-negative patients.

Diffuse large B-cell lymphoma developed in one patient with interim PET-negative findings as a secondary malignancy 4.6 years after enrollment.

Conclusions This INNOVATE-HL study demonstrated that interim PET-guided treatment strategy was useful for younger patients with newly diagnosed advanced-stage cHL. Of note, 6 cycles of escalated BEACOPP is a feasible and effective regimen for interim PET-positive cHL patients.

Kusumoto:Abbvie: Honoraria, Research Funding; Amgen BioPharma: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; One Pharmaceutical: Honoraria, Patents & Royalties; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Takeda: Honoraria, Research Funding. Munakata:Takeda Pharmaceutical Company Limited: Honoraria, Research Funding. Iida:Amgen BioPharma: Research Funding; AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Otsuka: Research Funding; Caelum: Research Funding. Nosaka:Eisai Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Consultancy, Honoraria, Research Funding; Meiji Seika Parma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Bristol Myers Squibb: Honoraria; Abbvie: Honoraria; Daiichi-Sankyo: Honoraria. Miyazaki:AstraZeneca: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; Celgene: Honoraria; Nippon-Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria; Symbio: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika: Honoraria; AbbVie: Honoraria; Novartis Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Research Funding; Kyowa Kirin: Honoraria, Research Funding. Fukuhara:Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria; Eli Lilly: Consultancy; HUYA: Consultancy; Novartis: Consultancy, Honoraria; Bayer: Research Funding; Chugai pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Genmab: Research Funding; Incyte: Research Funding; Dainippon Sumitomo: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Kyowa kirin: Honoraria; Nippon Shinyaku: Honoraria; Ono pharma: Honoraria; Celgene: Honoraria, Research Funding; Sanofi: Honoraria; Symbio: Honoraria; Takeda: Honoraria. Ohmachi:Kyowa Hakko Kirin: Honoraria; Chugai Roche: Honoraria; Meiji Seika Pharma: Honoraria; SymBio: Honoraria; Bristol-Myers Squibb: Honoraria. Yamamoto:Yakult: Research Funding; Takeda: Honoraria, Research Funding; Astellas: Honoraria; Micron/Daiichi-Sankyo: Honoraria; Solasia Pharma: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; MSD: Honoraria; Mundipharma: Honoraria, Research Funding; Zenyaku: Research Funding; SymBio: Honoraria, Research Funding; Sumitomo Pharma: Honoraria; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; HUYA/IQVIA Services Japan: Honoraria; IQVIA/Genmab: Honoraria; Eisai: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria; IQVIA/Incyte: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Astra-Zeneca: Honoraria, Research Funding; Sanofi: Honoraria. Tsujimura:Janssen: Honoraria; Eisai: Honoraria; Chugai: Honoraria; Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria. Takayama:Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer: Honoraria; Asahi Kasei Pharma: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Takada Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Yoshida:Chugai: Honoraria, Research Funding; Eisai: Honoraria; Jannsen: Honoraria; Nihonsinyaku: Honoraria; Ohtsuka: Honoraria; Symbio: Honoraria; Takeda: Honoraria; Dainihonsumitomo: Honoraria; Kyowa Kirin: Honoraria, Research Funding. Takamatsu:Chugai Pharmaceutical: Research Funding; AstraZeneca: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical: Honoraria. Maruyama:CHUGAI PHARMACEUTICAL: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo: Research Funding; Ono Pharmaceutical: Consultancy; Bayer Pharma: Research Funding; Kyowa Kirin: Research Funding; Solasia Pharma: Consultancy; HUYABIO: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Regeneron Pharmaceuticals Inc.: Research Funding; Chugai Pharmaceutical: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Yakuruto: Consultancy. Nagai:AstraZeneca: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria; Sumitomo Pharma: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; IQVIA: Research Funding; Labcorp: Research Funding; Parexel: Research Funding; Eli Lilly and Company: Honoraria; Chugai: Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Mudi Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Solasia: Research Funding; lncyte: Research Funding; Daiichi-Sankyo: Research Funding.