Updated Results from a Phase II Study of Hyper-CVAD with Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia
Authors: Short Nicholas J. , Kantarjian Hagop , Ravandi Farhad , Huang Xuelin , Thompson Philip A. , Ferrajoli Alessandra , Kadia Tapan M. , Jain Nitin , Alvarado Yesid , Yilmaz Musa , Khoury Joseph D. , Jorgensen Jeffrey L. , Wang Sa A , Kornblau Steven M. , Konopleva Marina , Garcia-Manero Guillermo , Garris Rebecca , Schroeder Heather M , Milton Anna , Rivera Juan , Banks Glenda , Jabbour Elias J. 
Published: November 2021

Abstract
Background: Blinatumomab is highly effective therapy for both the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and persistent or recurrent measurable residual disease (MRD) after initial ALL therapy. We hypothesized that early incorporation of blinatumomab in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival.
Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m 2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Beginning with pt #10, those with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD.
Results: 38 evaluable pts have been treated. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 38 evaluable pts are summarized in Table 1. Median age was 37 years (range, 17-59 years). At least one high-risk feature was present in 21 pts (55%), including TP53 mutation in 27%, CRLF2+ in 19%, and an adverse-risk karyotype in 32%. 84% of pts received ofatumumab or rituximab.
Among 32 pts with active disease at study entry, 100% achieved CR, with 81% achieving CR after the first cycle (Table 1). MRD negativity by 6-color flow cytometry was achieved in 22/26 responding pts (85%) after 1 cycle and 37/38 pts (97%) overall. The 60-day mortality rate was 0%.
With a median follow-up of 27 months (range, 11-55 months), the 3-year continuous remission and OS rates were 80% and 83%, respectively (Figure 1). Overall, 5 pts (13%) relapsed, 13 (34%) underwent allogeneic SCT in first remission (including 2 additional pts who relapsed post-SCT), 1 died in CR (possible pulmonary embolism), and 19 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features and no relapses have occurred beyond 2 years from the start of treatment. OS with hyper-CVAD plus blinatumomab compares favorably to a historical cohort of pts treated with hyper-CVAD plus ofatumumab (3-year OS 83% versus 66%, respectively; P=0.2).
Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 16 (42%) pts had a neurological adverse event of any grade due to blinatumomab. Four pts (11%) developed grade 3 neurologic toxicity related to blinatumomab, all of which was transient and reversible. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia).
Conclusion: Hyper-CVAD with sequential blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with an overall MRD negativity rate of 97% and a 3-year OS rate of 83%. This study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with ALL and also shows that reduction of chemotherapy in this context is feasible.
Figure 1 Figure 1.

Disclosures
Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding. Thompson: Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Janssen: Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Kadia: Astellas: Other; Genentech: Consultancy, Other: Grant/research support; Sanofi-Aventis: Consultancy; Cellonkos: Other; Pfizer: Consultancy, Other; Pulmotech: Other; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Novartis: Consultancy; BMS: Other: Grant/research support; AstraZeneca: Other; Liberum: Consultancy; Ascentage: Other; Genfleet: Other; Jazz: Consultancy; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Jain: Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Incyte: Research Funding; Servier: Honoraria, Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; Pfizer: Research Funding; Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Wang: Stemline Therapeutics: Honoraria. Konopleva: KisoJi: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.

OffLabel Disclosure:
Blinatumomab in the frontline setting for B-cell ALL