Abstract
Background: Inotuzumab ozogamicin (INO) and blinatumomab are effective in the treatment relapsed/ refractory B-cell acute lymphoblastic leukemia (ALL) and improve overall survival (OS) in this setting. The use of these agents in older adults with newly diagnosed B-cell ALL may allow for use of less chemotherapy and improve remission durations and OS compared to standard therapies.
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/m 2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m 2 on day 3 of cycle 1 and 0.8-1.3mg/m 2 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/m 2 on day 2 and 0.3 mg/m 2 on day 8 of cycle 1; 0.3 mg/m 2 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). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m 2 and 2.7 mg/m 2, respectively.
Results: 75 pts have been treated. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-87 years); 30 pts (40%) were ≥70 years. 39% were positive for TP53 mutation, 19% had Ph-like ALL (with 6 of the 8 Ph-like pts being CRLF2+ by flow), and 25% had adverse-risk karyotype.
Among 69 pts evaluable for morphologic response, 68 (99%) responded (CR, n=61; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 57/71 pts (80%) after 1 cycle and 71/74 pts (96%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively.
Among 74 pts who achieved remission, 10 (14%) relapsed, 4 (5%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 32 (43%) remain on treatment or have completed therapy, and 28 (38%) died in remission. Overall, 9 pts (12%) developed MDS/AML; in 7 of these cases the myeloid malignancy was TP53-mutated and in the 2 other cases, both the ALL and subsequent AML shared mutations in myeloid mutations (RUNX1, SRSF2, and TET2). Notably, 6 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/75 (8%) with no difference in VOD in pts who did or did not receive blinatumomab.
With a median follow-up of 56 months (range, 1-111 months), the 5-year continuous remission and OS rates were 76% and 47%, respectively (Figure 1A). Outcomes were superior for those 60-69 years of age versus those who were ≥70 years (5-year OS rates: 58% and 31%, respectively; P=0.04) and for those without poor-risk cytogenetics (e.g. KMT2A rearranged, low hypodiploidy/near triploidy, complex cytogenetics) versus poor-risk cytogenetics (5-year OS rates: 56% and 25%, respectively; P=0.01). Pts ≥70 years of age were more likely to die in remission (20/29 [69%] vs. 19/45 [42%] in pts 60-69 years of age; P=0.03), which was a major driver of the poor survival in this age group. The 5-year OS for pts age 60-69 years with non-poor risk cytogenetics, age 60-69 with poor risk cytogenetics, age ≥70 with non-poor risk cytogenetics and age ≥70 with poor risk cytogenetics were 68%, 37%, 42% and 0% respectively (Figure 1B). Neither Ph-like ALL nor the presence of a TP53 mutation significantly impacted OS (P=0.26 and P=0.34, respectively).
Conclusion: Low-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 98% and a 5-year OS rate of 47%. Even with this relatively reduced-intensity regimen, deaths in remission (usually due to infection) occur, primarily in pts ≥70 years of age. A strategy using the combination INO and blinatumomab, without any chemotherapy, is being explored in this population.
Short: NGMBio: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: BMS: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria. Jain: Janssen: Honoraria; TG Therapeutics: Honoraria; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kadia: Genfleet: Other; AstraZeneca: Other; Genentech: Consultancy, Other: Grant/research support; Jazz: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Aglos: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Dalichi Sankyo: Consultancy; BMS: Other: Grant/research support; Cellonkos: Other; Pfizer: Consultancy, Other; Astellas: Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; Amgen: Other: Grant/research support. Khoury: Kiromic: Research Funding; Stemline Therapeutics: Research Funding; Angle: Research Funding. Wang: Stemline Therapeutics: Honoraria. Alvarado: Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Sun Pharma: Consultancy, Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Trovagene: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo: Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Konopleva: AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, 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; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; AstraZeneca: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding. Pemmaraju: Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; LFB Biotechnologies: Consultancy; Celgene Corporation: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Affymetrix: Consultancy, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Roche Diagnostics: Consultancy; Sager Strong Foundation: Other; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Wierda: Miragen: Research Funding; GSK/Novartis: Research Funding; Loxo Oncology, Inc.: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Xencor: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.
Blinatumomab and inotuzumab as frontline therapy for B-cell ALL
