Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse
Authors: Rafei Hind , Kantarjian Hagop M. , Sasaki Koji , Short Nicholas J. , Ravandi Farhad , Huang Xuelin , Khoury Joseph D. , Wang Sa A , Jorgensen Jeffrey L. , Khouri Issa F. , Kebriaei Partow , Jain Nitin , Dabaja Bouthaina S. , Alvarado Yesid , Kadia Tapan M. , Paul Shilpa , Chew Serena , Garcia-Manero Guillermo , Burger Jan A. , DiNardo Courtney D. , Daver Naval , Montalban-Bravo Guillermo , Yilmaz Musa , Ohanian Maro , Khouri Maria , Thompson Philip A. , Jacob Jovitta , Rostykus Meagan , Garris Rebecca , Konopleva Marina , O'Brien Susan M. , Jabbour Elias 
Published: November 2020

Background:
The combination of low intensity therapy with InO improved outcome compared to intensive chemotherapy and to single agent InO in Salvage 1. The sequential addition of blina may allow the administration of weekly lower dose of InO and distancing allogeneic stem cell transplant (ASCT) from the last dose of InO, while deepening the minimal residual disease response. This will lead to less veno-occlusive disease (VOD) and better long-term efficacy. The aim of this study is to evaluate the outcome of pts in first relapse treated with this combination.
Methods:
The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. InO was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 38 pts were treated, an amendment was made to incorporate 4 cycles of blina after 4 cycles of mini-hyper-CVD + InO. InO was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blina was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the pt.
Results:
From 2/2013 to 9/2019, 65 pts were enrolled and received first salvage therapy including 27 pts with mini-hyper-CVD + InO + blina. Patient characteristics and outcome are summarized in Table 1. The median age at diagnosis was 39 years (range, 18-87). Among 65 pts, 8 (12%) pts had primary refractory disease; 25 (38%), CR1 duration less than 12 months. 7 (11%) pts had prior history of ASCT. The overall response rate was 91% (CR, 66%, CRp/CRi, 25%). These rates were 100% in pts with primary refractory disease (CR 100%); 84 % in pts with CR1 duration &lt;12 months (CR 60%, CRp/CRi 24%); and 94% in pts with CR1 duration &gt;12 months (CR 63%, CRi/CRp 31%) (Table 2). Among 56 evaluable pts for minimal residual disease (MRD) assessment at morphologic response and 57 overall, 57% of pts achieved negative MRD by multicolor flow cytometry at response and 88% overall. Among 59 who achieved remission, 26 (44%) relapsed, 35 (59%) underwent allogeneic SCT in CR2, and 6 (9%) died in CR/CRp. Overall, 6 pts (9%) developed VOD; 4 after subsequent ASCT. The rate of VOD was 5/38 (13%) in pts who did not receive blina. In contrast, only 1 case of VOD was observed among the 27 pts (4%) who received the weekly lower dose of InO and sequential addition of blina; this pt had VOD post ASCT in CR2. With a median follow-up of 36 months (range, 1-87 months), 27 pts (42%) were alive, 21 of whom (32%) were in CR and MRD negative status. The median CR duration (CRD) and overall survival (OS) were 13 and 16.5 months, respectively. The estimated 3-year CRD and OS rates were 25% and 42%, respectively. Using the IPTW analysis, compared to a similar historical cohort of pts treated with standard salvage chemotherapy (n=77), the mini-hyper-CVD + InO with or without blina (n=58) resulted in significantly improved survival (P&lt;0.001). The 3-year OS rates were 54% (median not reached) and 32% (median 16 months), respectively (P=0.002).
Conclusion:
The combination of InO with mini-hyper-CVD with or without blina is highly effective and shows improved outcome compared to intensive chemotherapy in pts with ALL in first relapse, with 3-year OS rate of 42%. The risk of VOD can be minimized with fractionated lower dose InO and sequential combination of blina.

Disclosures
Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Short:Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Ravandi:AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Khouri:Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Kebriaei:Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Amgen: Other: Research Support. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alvarado:Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding. Kadia:BMS: Honoraria, Research Funding; Incyte: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy. Burger:TG Therapeutics: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau. DiNardo:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; MedImmune: Honoraria; Syros: Honoraria; Calithera: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; AbbVie: Research Funding. Konopleva:Agios: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding. Jabbour:AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding.

OffLabel Disclosure:
Inotuzumab Blinatumomab Used in combination with standard reduced intensity chemotherapy for the treatment of ALL