Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve survival in relapsed or refractory acute lymphoblastic leukemia (ALL) compared to conventional chemotherapy. The combination of INO with reduced-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL is safe and highly effective (Kantarjian H et al, Lancet Oncol 2018;19(2):240-8). The addition of blinatumomab to this regimen may further improve outcomes.

Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP).

Results: 64 pts have been treated, 5 of whom were in complete remission (CR) at enrollment. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-81 years); 27 pts (42%) were ≥70 years. 28% were positive for TP53 mutation, 19% were CRLF2 positive, and 27% had adverse-risk karyotype. 33/58 pts (57%) were CD20+ and received rituximab.

Among 59 pts evaluable for morphologic response, 58 (98%) responded (CR, n=51; CRp, n=6; CRi, n=1). MRD negativity by 6-color flow cytometry was achieved in 48/62 pts (77%) after 1 cycle and 59/63 pts (94%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively.

Among 63 pts who achieved remission, 9 (14%) relapsed, 3 (5%) underwent allogeneic SCT in first remission, 30 (48%) remain on treatment or have completed maintenance, and 21 (33%) died in CR/CRp. The rate of death in CR/CRp was higher in pts ≥70 years of age vs. 60-69 years (50% vs. 22%; P=0.02). Causes of death for pts in CR/CRp included: sepsis (n=7; all in pts 70 years and older), VOD (n=3), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1), MDS/AML (n=4; 3 in pts 70 years and older) and unknown causes (n=4). 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/64 (9%) with no difference in VOD in pts who did or did not receive blinatumomab.

With a median follow-up of 37 months (range, 2-85 months), 34 pts (53%) were alive, 30 of whom (47%) were in CR and MRD negative status. The 3-year continuous remission and OS rates were 76% and 54%, respectively (Figure 1A). The 3-year continuous remission rate was 69% and 87% for pts age 60-69 and ≥70 years, respectively (P=0.25), and the 3-year OS rate was 63% and 42%, respectively (P=0.13; Figure 1B). The trend for worse survival in the pts ≥70 years was driven predominantly by the increased rate of death in CR/CRp in this older group. The outcomes of pts who did or did not receive blinatumomab were similar. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=77), mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS (54% vs 32%; P=0.007).

Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 3-year OS rate of 54%. Further optimization of this regimen with less chemotherapy in patients 70 years and older is warranted to further decrease the rate of death in remission.

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Disclosures

Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Daver:Otsuka: Consultancy; Astellas: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Pemmaraju:sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Konopleva:Ablynx: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Agios: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Merck: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Strategia Therapeutics: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. O'Brien:Astellas: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite: Research Funding; Aptose Biosciences, Inc: Consultancy; Acerta: Research Funding; Verastem: Consultancy; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy. Jabbour:AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

OffLabel Disclosure:

The use of inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients with ALL

Topics:
acute lymphocytic leukemia, blinatumomab, cardiovascular diseases, chemotherapy regimen, chronic venous disease, inotuzumab ozogamicin, older adult, phase 2 clinical trials, chromosomes, brachial plexus neuritis

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2019 by The American Society of Hematology
2019
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