Abstract: The search for predictions of species diversity across environmental gradients has challenged ecologists for decades. The humped-back model (HBM) suggests that plant diversity peaks at intermediate productivity; at low productivity few species can tolerate the environmental stresses, and at high productivity a few highly competitive species dominate. Over time the HBM has become increasingly controversial, and recent studies claim to have refuted it. Here, by using data from coordinated surveys conducted throughout grasslands worldwide and comprising a wide range of site productivities, we provide evidence in support of the HBM pattern at both global and regional extents. The relationships described here provide a foundation for further research into the local, landscape, and historical factors that maintain biodiversity.

Abstract: Tredennick et al . criticize one of our statistical analyses and emphasize the low explanatory power of models relating productivity to diversity. These criticisms do not detract from our key findings, including evidence consistent with the unimodal constraint relationship predicted by the humped-back model and evidence of scale sensitivities in the form and strength of the relationship.

Abstract: Background: Recent reports suggest that the use of erythropoietic stimulating agents (ESA) may adversely affect survival when used in the management of patients with certain solid tumors. Anemia is common in patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL). The use of erythropoietin (EPO) in this group of patients may be beneficial; however, the impact of EPO on the survival of patients with hematologic malignancies is unknown. Objective: To evaluate the effects of EPO on rate of transfusions, survival and remission rates in patients with ALL, LL and BL treated with Hyper-CVAD. Methods: We evaluated 109 pts with newly diagnosed acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) who participated in a randomized trail comparing EPO (40,000 units SQ weekly within 14 days of starting chemotherapy) vs. standard of care. Both arms received blood transfusions as per institutional guidelines. Results: From September 2003 to July 2008, 109 pts were included in the study, 5 patients were excluded from the survival analysis because they did not receive study drug (1) or for violation of the study (4), randomized to no EPO but received EPO. The median age of patients was 41 years (range: 15–84), the majority had ALL (82 pts, 79%). Median baseline Hgb was 8.8 g/dl (range 6–12.6). There was no difference in the complete remission rate or survival between the 2 groups (Table 1). Seventy-six patients (38 in each arm) who remained in the study for at least 5 months were evaluable for number of transfusions during that period of time. Patients randomized to EPO received significantly less number of transfusions than patients that did not receive EPO [N=, 16 units (range 6–32) versus 19 units (range 11–40)], p = 0.026 (Mann-Whitney U test). Five patients (deep vein thrombosis = 3; pulmonary embolism =1; and CVA = 1) in the EPO group and 2 patients (deep vein thrombosis =2) in the NO EPO group developed possible related adverse events over 6 months of evaluation (p= 0.285) EPO (N= 54) No EPO (N= 50) P value Complete remission, n (%) 51 (94) 48 (96) 0.873 Survival at 1 year (%) 80 81 NS Survival at 2 years (%) 75 70 Survival at 3 years (%) 72 70 Conclusions: The use of EPO appears not to have a negative impact on remission rate or survival in patients with ALL, LL or BL receiving HyperCVAD treatment, while EPO significantly decreased the number of transfusions required. There was no significant increase in the risk of thrombotic events associated with EPO.

Abstract: Background: The combination of low intensity therapy with inotuzumab ozogamicin improved survival compared to intensive chemotherapy and to single agent inotuzumab ozogamicin in first salvage (Jabbour et al. Cancer. 2018 (in press)). The incidence of veno-occlusive disease (VOD) is minimized with weekly divided dosage and reduced dose of inotuzumab ozogamicin per cycle. Blinatumomab single agent improves survival in relapsed / refractory ALL compared to that of standard chemotherapy. The sequential addition of blinatumomab to mini-hyper-CVD + inotuzumab ozogamicin might further improve survival and minimize the risk of veno-occlusive disease (VOD) by allowing a reduction of inotuzumab dose and spacing allogeneic stem cell transplant (ASCT) from the last dose of inotuzumab. Methods: Patients with relapsed / refractory Philadelphia chromosome negative ALL were eligible. 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. Inotuzumab ozogamicin 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 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin 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; blinatumomab 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 patient. Results: From 2/2013 to 5/2018, 84 patients were enrolled and treated including 17 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 31 months (range, 0.1-64.1). Patient characteristics and outcome are summarized in Table 1. The median age was 35 years (range, 9-87), and 23% of patients had received prior ASCT. The overall response rate was 80% (CR, 58%, CRp/CRi, 21%). These rates were 92% in S1 (primary refractory, 100%; CR1 duration 〈 12 months, 82%; CR1 duration 〉 12 months, 100%) and 56% in S2, and 60% in S3 or higher. Among 64 evaluable patients for minimal residual disease (MRD) assessment, 51 patients (80%) achieved negative MRD by 6-color flow cytometry with higher rates of negative MRD at 85% in salvage 1. Thirty four patients (40%) received ASCT. Three-year CR duration and overall survival (OS) rates were 49% and 33%, respectively (Figure 1). The median OS was 25 months, 6 months, and 7 months in salvage 1, salvage 2, and salvage 3 or more, respectively (p=0.001). Historical comparison showed median OS of 14 months and 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab and inotuzumab ozogamicin single agent, respectively (p=0.001) (Figure 2). Among the 79 evaluable patients, VOD was observed in 9 (11%). The incidence of VOD was reduced from 9/61 (15%) with single dose of inotuzumab ozogamicin to 0/18 (0%) with weekly divided dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 3 patients underwent ASCT (2, haploidentical transplant; 1, cord blood transplant). Conclusion: The combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with fractionated inotuzumab ozogamicin dosing. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding. Short:Takeda Oncology: Consultancy. Jain:Verastem: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Kadia:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding.

Abstract: 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

Abstract: Background: Liposomal vincristine has been approved as salvage chemotherapy for patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Replacement of regular vincristine with liposomal vincristine might lead to improve outcome with reduced neurotoxicity in patients with newly diagnosed ALL. Methods: Patients ≥18 years with newly-diagnosed B-cell ALL were eligible for the clinical trial consisting of hyper-CMAD (cyclophosphamide 300 mg/m2 IV every 12 hours on Days 1-3; liposomal vincristine 2 mg/m2 IV on Day 1 and day 8; doxorubicin 50 mg/m2 IV on Day 4; dexamethasone 40 mg IV daily on Days 1-4 and Days 11-14) (odd cycles 1, 3, 5, 7) alternating with high-dose methotrexate 1000 mg/m2 IV on Day 1, and cytarabine 3 gm/m2 IV every 12 hours on Days 2 and 3 (even cycles 2, 4, 6, 8). Rituximab 375 mg/m2 IV on Days 1 and 8 for courses 1-4 was administered in CD-20 positive ALL. TKI (imatinib or dasatinib) were concomitantly administered in patients with Philadelphia chromosome positive (Ph+) ALL. Overall survival (OS) was defined as time interval from the start date of hyper-CMAD to the date of death. Progression-free survival (PFS) was defined as time interval from the start date of hyper-CMAD to the date of relapse or death, whichever comes first. Results: Twenty-seven patients have been treated so far. Baseline patient characteristics are described in table 1. Median age is 53 years (range 23-80). Eleven patients (41%) had CD-20 positive ALL, and 17 (63%) had Ph+ ALL. Median follow-up is 12 months (3-22) with a median of 4 cycles (1-8) administered Of 17 patients with Ph+ ALL, 15 patients were received additional dasatinib and 2 imatinib. Twenty-six (96%) achieved complete response (CR). Early death was observed in 1 patient (4%) with Ph+ ALL. Of the 26 patients evaluable for response, 22 (100%) achieved CCyR (3 patients, diploid at start; 1 patient, not performed), and 23 (88%) achieved negative MRD by multicolor flow cytometry. Of the 16 evaluable Ph-positive patients, MMR was observed in 15 (94%) and CMR in 10 (63%). Three patients in CR1 underwent allogeneic stem cell transplantation (ASCT). At the last follow-up, 23 (85%) patients are alive. Four (15%) patients died: 1 from sepsis on C1D10; 1 from unknown cause on C1D135; 1 from post-transplant complications; and 1 from disease progression at the third salvage chemotherapy. Median time to platelet and neutrophil recovery for cycle 1 was 24 and 19 days, respectively. To date, 3 patients relapsed; 1 patient with t(4;11) relapsed at C5D36; 1 Ph-positive patient relapsed post C8 with no maintenance therapy; 1 patient with positive MRD 2 months prior to morphologic relapse while on maintenance therapy C10D32. At the last follow-up, 23 (85%) patients are alive. Four (15%) patients died: 1 from sepsis on C1D10; 1 from unknown cause on C1D135; 1 from post-transplant complications; and 1 from relapse and disease progression at the third salvage chemotherapy. The 1-year PFS and OS rates were 77% and 87%, respectively. Conclusions: The combination ofliposomal vincristine withHyper-CMAD is safe and effective with high response rates in patients with newly diagnosed ALL. Table 1. Patient characteristic and outcome N (%)/ Median [range] N= 27 Age (yrs) 53 (23-80) Age ≥ 60 10 (37) Male 12 (44) PS 2-3 2 (7) WBC (x 109/L) 17.1 (1.4-372.1) CNS disease 6 (22) CD20 positivity 11 (41) Cytogenetic Abnormality, No. (%) Diploid 3 (11) Philadelphia chromosome 17 (63) Hypodiploid 2 (7) Hyperdiploid 1 (4) t(4;11) 3 (11) Misc 1 (4) Overall response, No. (%) CR 26/27 (96) Early death 1/27 (4) CCyR 22/22 (100) MRD by Flow 23/26 (88) MMR:BCR/ABL 15/16 (94) CMR:BCR/ABL 10/16 (63) Figure 1. Progression-free survival and overall survival Figure 1. Progression-free survival and overall survival Disclosures Chahoud: American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. DiNardo:Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract: Background: Outcome of patients with R/R ALL is very poor. INO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve clinical outcome. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as 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). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Results: Forty-eight patients (23 men, 25 women) have been enrolled so far. Patient characteristics and outcome are summarized in Table 1. Median age is 35 years (range 9-87). Median follow-up is 9.4 months (range, 1-27), and patients received a median of 2 cycles (1-8). Of 46 evaluable patients (2 patients, too early to assess response), 5 patients (11%) were refractory to mini-hyper-CVD + INO and died of progressive disease. Early death was encountered in 7 (15%) patients. The overall response rate was 74%: 24 (52%) CR, 8 (17%) CRp, and 2 (4%) marrow CR. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (n=6; 1 in a patient who had prior allo-SCT; 1 at D35 of CAR T-cell; and 3 post allo-SCT following INO therapy). Four (9%) patients were switched early to maintenance therapy due to poor performance status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Nineteen (41%) patients proceeded to receive allo-SCT. At the last follow-up, 20 (43%) patients are alive in response; 2 (4%) too early to assess response; 4 (8%) relapsed post transplantation. 22 (43%) patients died: 7 early death; 5 refractory disease; 5 post relapse after subsequent salvage, 1 post-transplantation VOD, 3 due to post-transplant complications, and 1 in response to IO due to sepsis and multiple organ failure. The 1-year PFS and OS rates were 60% and 46%, respectively. Median survival for patients with CR/CRp/marrow CR was 18 months versus 1 month in patients with refractory disease (p 〈 0.001). Median survival was 17 months in patients with S1, 6 months in patients with S2 and 7 months in patients with S3+ (Figure). Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Table 1. Patient characteristics and outcome Median (range) / No. (%) N=48 Age (yrs) 35 [9-87] Male 23 (48) Performance Status (ECOG) ≥2 7 (15) Salvage Status S1 S1, Primary Ref S1, CRD1 〈 12m S1, CRD1 〉 12m S2 〉 S3 24 (50) 4 11 9 11 (23) 13 (27) Karyotype Diploid T(4;11) Misc IM/ND 11 (23) 5 (10) 24 (50) 8 (17) CD22, (%) 96 [26-100] CD20 ≥ 20% 10 (21) Response CR 24 (52) CRp 8 (17) CRi 2 (4) ORR 34 (74) No response 5 (11) Early death 7 (15) Too early 2 Figure 1. Survival by salvage number Figure 1. Survival by salvage number Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.