Search

Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy.We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing.Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed.The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response.Takeda Oncology and Amgen.

7009 Background: Ponatinib and blinatumomab are highly active in Ph+ ALL. A chemotherapy-free combination of these agents may lead to durable remissions and reduce the need for stem cell transplant (SCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or CML in lymphoid blast phase (CML-LBP) received up to 5 cycles of blinatumomab. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years. All patients (pts) received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2022, 55 pts were treated (35 ND, 14 R/R and 6 CML-LBP). Baseline characteristics and responses are shown in Table. Among 23 pts with ND Ph+ ALL evaluable for response, 22 (96%) achieved CR/CRi; 1 pt had early death due to myelosuppression from prior chemotherapy. Among 13 evaluable pts with R/R Ph+ ALL, 12 (92%) achieved CR/CRi. The CMR rates for the ND, R/R and CML-LBP cohorts were 64%, 71%, and 17% after cycle 1 and were 85%, 79%, and 33% overall, respectively. In the ND cohort, 4/17 evaluable pts (24%) achieved CMR in the peripheral blood within 1 week, and 9/15 (60%) within 2 weeks. The median follow-up is 11 months (range, 1-46+ months). Among the 35 pts in the ND cohort, 33 pts (94%) are alive and in continuous remission. Only 1 pt in the ND underwent SCT in first remission (due to persistent MRD positivity), and no relapses have been observed. The 2-year EFS and OS rates in the ND cohort are 93%. Among the 13 responding pts in the R/R cohort, 6 (46%) underwent SCT. The 2-year EFS and OS rates for the R/R cohort are 42% and 61%, and for the CML-LBP cohort are 33% and 60%, respectively. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to recurrent neurotoxicity. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission. Clinical trial information: NCT03263572. [Table: see text]

Background: Ponatinib and blinatumomab are both highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two agents may lead to deep and durable responses, thereby reducing the need for both chemotherapy and allogeneic stem cell transplant (ASCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and alanine aminotransferase and aspartate aminotransferase ≤3x the ULN. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding pts. Twelve doses of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate were administered. For pts with ND Ph+ ALL, the primary endpoint was the CMR rate. For pts with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Between February 2018 and July 2021, 43 were treated (24 ND, 14 R/R and 5 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND and R/R Ph+ ALL cohorts were 60 years (range, 34-83) and 38 years (range, 24-61), respectively. BCR-ABL1 transcripts were p190 in 67% of pts in the ND cohort and 93% in the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in salvage 2 or beyond. Among 32 pts evaluable for morphologic response, all but 1 pt (97%) responded. Notably, the one non-responding pt had R/R Ph+ ALL and had previously received ponatinib in an earlier salvage regimen. The CR/CRi rate was 100% for ND pts, 91% for R/R pts, and 100% CML-LBP pts. 84% of responding pts achieved CMR (91% in the ND cohort, 91% in the R/R cohort, and 40% in the CML-LBP cohort). The CMR rates after 1 cycle were 64%, 82% and 20% in these 3 groups, respectively. Among 10 pts in the ND cohort who had peripheral blood PCR for BCR-ABL1 evaluated on day 7 of cycle 1, 3 (30%) had already achieved CMR at this early timepoint; 5 out of 13 evaluable patients (38%) had achieved CMR by days 14-21 of cycle 1 The median follow-up is 9 months (range, 1-38+ months). Among the 24 pts in the ND cohort, 1 pt died in CR, and the rest are all in ongoing response without HSCT in first remission, with a median CR duration of 8 months (range, 1-36+ months). The estimated 2-year EFS and OS for the ND cohort is 95% (Figure 1). Among the 14 pts in the R/R cohort, 2 are too early for response evaluation, 1 did not respond, 4 underwent ASCT (3 of whom are still alive without relapse and 1 of whom relapsed post-ASCT and died), 2 did not undergo ASCT and subsequently relapsed, 1 died in CR, and 4 are in ongoing response without ASCT. The estimated 2-year EFS and OS for the R/R cohort are 53% and 39%, respectively (Figure 1). Among the 5 pts in the CML-LBP cohort, 2 relapsed (1 of whom converted to myeloid immunophenotype) and 3 are in ongoing response without ASCT. The combination treatment was well-tolerated, and most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). No pts discontinued blinatumomab due to toxicity. No early deaths were observed. Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab is a safe and effective regimen in both ND and R/R Ph+ ALL, as well as in CML-LBP. Given the particularly favorable outcomes of pts with ND Ph+ ALL who were not transplanted in first remission, these data suggest that this regimen may serve as an effective transplant-sparing regimen in this population. Figure 1 Figure 1. Disclosures Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Ascentage: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Ascentage: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Jain: Aprea Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Ravandi: Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; Cellectis S.A. ADR: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; LFB Biotechnologies: Consultancy; Dan's House of Hope: 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; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, 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; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab and ponatinib as frontline therapy for Ph+ ALL

Background: The oral Bcl-2 inhibitor venetoclax (Ven) has preclinical activity in acute lymphoblastic leukemia (ALL) and has shown encouraging response rates in combination with the Bcl-xL inhibitor navitoclax in patients (pts) with relapsed/refractory (R/R) ALL. We hypothesized that the addition of Ven to low-intensity chemotherapy with mini-hyper-CVD may improve outcomes in pts with ALL. Methods: Pts ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative B- or T-cell ALL/lymphoblastic lymphoma (LBL) or ≥18 years of age with R/R Ph-negative B- or T-cell ALL/LBL were eligible. Pts were required to have a PS of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3 x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD alternating with methotrexate and cytarabine (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. Ven was given at a dose of 400 mg daily on days 1-14 of cycle 1 and on days 1-7 of cycles 2-8. Rituximab (if CD20+ B-cell ALL) and prophylactic IT chemotherapy x 8 doses were given for the first 4 cycles. Pts with T-cell ALL received an additional 2 cycles of nelarabine (650 mg/m 2 daily on days 1-5) and peg-asparaginase (1,500 IU/m 2 [capped at 3750 IU] on day 5), without Ven, during consolidation and another 2 cycles of nelarabine plus peg-asparaginase during maintenance. Responding pts received vincristine and prednisone maintenance with venetoclax daily on days 1-14 of each 28-day cycle for up to 2 years. Results: Between 6/2019 and 12/2020, 23 pts have been treated (4 frontline and 19 R/R). Pt characteristics are summarized in Table 1. The median age in the frontline cohort was 63 yrs (range, 26-64) and in the R/R cohort was 45 (range, 21-70). In the frontline cohort 1 pt had B-ALL, 2 pts had T-cell ALL and 1 pt had T-cell LBL. In the R/R cohort, 14 had B-cell ALL, 4 had T-cell ALL, and 1 had T-cell LBL, including 2 pts with ETP ALL. Among the 19 R/R pts, the median number of prior therapies was 1 (range, 1-5) and 10 (53%) had undergone prior allogeneic stem cell transplant (alloSCT). Among the 14 R/R B-cell pts, 12 (86%) had received prior blinatumomab and 5 (36%) had received prior inotuzumab ozogamicin. Among the 4 frontline pts, 3 (75%) achieved CR. The 4 th pt achieved brief PR as best response. All responders achieved their best response after cycle 1. One pt achieved MRD negativity after cycle 1, and all 3 responders achieved MRD negativity at some point during therapy. Among the 19 R/R pts, 2 were in CR at enrollment and 17 were evaluable for morphologic response. 11 pts (65%) responded to the regimen (CR, n=8; CRp, n=2; CRi, n=1). An additional pt achieved PR. Among the 11 responders, 8 achieved best response after 1 cycle and 3 after cycle 2. 2 pts achieved MRD negativity after cycle 1, and 3 pts achieved MRD negativity at some point during therapy. Responses were similar among pts with B-cell ALL (64%) and T-cell ALL/LBL (66%) and among pts with adverse-risk karyotype (40%) and non-adverse risk karyotype (60%) [P=0.46]. The median duration of follow-up is 12.2 months (range, 2-18 months). Among the 3 frontline pts who achieved remission, 1 underwent alloSCT and is still in remission and the other 2 remain on therapy in remission. Among the 13 R/R pts who achieved remission, 6 (55%) relapsed, 4 (31%) underwent alloSCT (2 are still alive without relapse and 2 subsequently relapsed), 2 (18%) died in remission, and 1 (9%) is in remission without alloSCT or relapse. In the R/R cohort, the median PFS and OS were 6.2 and 7.1 months, respectively, and the estimated 1-year PFS and OS rates were 14% and 30%, respectively (Figure 1). Outcomes were inferior for those with adverse-risk karyotype versus others (median OS 6.0 vs 10.7 months; 1-yr OS rate: 17% vs 45%; P=0.04). Treatment was overall well-tolerated. In cycle 1, the median time to platelet recovery was 27 days (range, 0-81 days) and neutrophil recovery was 20 days (range, 0-36); in cycle, median times to recovery were 26 days (range, 17-41) and 19 days (range, 0-26), respectively. In the entire cohort, the 30-day and 60-day mortality rates were 0% and 4%, respectively. One pt in the R/R cohort died from refractory disease and sepsis on day 43. Conclusion: Low-intensity chemotherapy with hyper-CVD plus venetoclax was safe and effective in pts with Ph-negative ALL. Continued evaluation of venetoclax-based regimens in ALL, including in the frontline setting, are warranted. Figure 1 Figure 1. Disclosures Kantarjian: Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: AstraZeneca: Consultancy; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria. Thompson: Amgen: Other: Institution: Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Pemmaraju: Springer Science + Business Media: Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Clearview Healthcare Partners: Consultancy; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Plexxicon: Other, Research Funding; Samus: Other, 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; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jain: Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; TG Therapeutics: Honoraria; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Beigene: Honoraria; AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Research Funding; ADC Therapeutics: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Wierda: Janssen: Research Funding; AstraZeneca: Research Funding; Xencor: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Gilead Sciences: Research Funding; Loxo Oncology, Inc.: Research Funding; GSK/Novartis: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Borthakur: GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Ryvu: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ravandi: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Research Funding; Amgen: 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; Agios: Honoraria, Research Funding; Prelude: Research Funding; AstraZeneca: Honoraria; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kadia: Dalichi Sankyo: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Astellas: Other; Genentech: Consultancy, Other: Grant/research support; AstraZeneca: Other; Pfizer: Consultancy, Other; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.

7001 Background: Achievement of a complete molecular remission (CMR) is associated with superior outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib and blinatumomab both produce high rates of molecular remission in Ph+ ALL. The combination of these two agents may lead to durable responses and reduce the need for allogeneic hematopoietic stem cell transplant (AHSCT). Methods: This is a single-arm phase 2 study in adults with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL. Patients received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once CMR was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding patients. Twelve doses of prophylactic intrathecal chemotherapy were administered. For patients with ND Ph+ ALL, the primary endpoint was the CMR rate. For patients with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Twenty-eight patients were treated (19 FL and 9 R/R). Median age was 59 years (range, 25-83 years); 62 years (range, 34-83 years) in the ND cohort and 36 years (range, 25-61 years) in the R/R cohort. Transcripts were p190 in 69% of patients the ND cohort and 100% in the R/R cohort. Among R/R patients, 44% were in Salvage 2+. No early death within 4 weeks were observed. Overall, 95% of patients responded; the response rate was 100% in the ND cohort and 88% in the R/R cohort. Among responding patients, 86% achieved CMR: 87% in the ND cohort and 86% in the R/R cohort. Median time to CMR was 1 month (range, 1-13 months). None of the patients in the ND cohort underwent AHSCT; 4 patients (44%) with R/R disease underwent subsequent AHSCT. With a median follow-up of 14 months, the estimated 1-year overall survival (OS) rate was 94% and event-free survival (EFS) rate was 81% for the entire study population. In the ND cohort, no patients have relapsed or died, and the 1-year OS and EFS rates were both 100%. In the R/R cohort, 1-year OS and EFS rates were 88% and 55%, respectively. The treatment was well-tolerated. Most side effects were grade 1-2. No patient discontinued ponatinib due to toxicity. One patient discontinued blinatumomab due to recurrent grade 2 tremor. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab shows encouraging results in Ph+ ALL. The regimen results in high rates of CMR and durable responses, potentially obviating the need for chemotherapy and AHSCT in many patients, particularly when used as frontline therapy. Clinical trial information: NCT03263572.

Neurodegenerative disorders have been linked to an array of external factors ranging from atmospheric pollutants to diet related additives. In our study we have investigated BMAA a neurotoxin produced by cyanobacteria, which gets an easy entry into human food chain via sea food and water, Aluminium which is believed to be present more in bottled water in comparison to tap water; and MSG, a derivative of glutamate; extensively used as flavour enhancer. LD50 for the three chemicals used in this study were determined. Our results suggest that BMAA leads to a significant loss of long term memory, reduction in geotaxic response, and reduction in both, fertility and life span. Short term memory was not significantly affected by BMAA. Aluminium deposits caused loss of long and short term memory and reduction in geotaxic response. MSG caused reduction in short term memory. In combination with BMAA, MSG produced reduction in all the parameters. Dementia has a direct bearing on quality of life. Dementia can set in as early as 40 years of age in humans. This has been attributed to life-style and stress related factors. The present study establishes a direct cause and effect relationship between dementia, stress and diet. These effects are established when Drosophila melanogaster are treated with neurotoxins, singly or in combinations. Experiments are in progress to understand the mechanisms that underlie these processes.