ALBERT

Description: Key Points Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may involve pseudohyperkalemia and perinatal edema. This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.

Description: Background: FOXP3 is a transcription factor of central importance to the inhibitory function of CD4+, CD25+ FOXP3+ T regulatory cells (Tregs). Tregs function as critical inhibitory immunoregulatory cells and have been reported to be increased in tumor-bearing individuals, inhibiting optimal T effector mediated anti-tumor cytotoxicity. Treg depletion targeting CD25, a surface marker of Tregs as well as activated T cells, has been validated in pre-clinical models as a promising adjunctive therapeutic approach to improving T cell mediated therapy and is currently being explored in clinical trials. However, because CD25 expression is not limited to Tregs, CD25-directed therapies may also result in the undesired depletion of effector T cells. Although FOXP3 expression is more restricted to Tregs as compared to CD25, its intranuclear localization has made it challenging to target therapeutically. Vaccination of mice against FOXP3 using FOXP3 mRNA-transfected dendritic cells has been explored and can elicit FOXP3 specific CTL mediated cytotoxicity. This work implies that FOXP3 mRNA-transfected dendritic cells process FOXP3 and present FOXP3 derived peptides on the cell surface. Direct expression of FOXP3 derived peptides on the surface of Tregs has however, not been previously demonstrated. Methods: We utilized mass spectrometry to investigate if FOXP3 derived peptides presented within MHC class I complex are expressed on the surface of Tregs. CD4+, CD25+ T cells were isolated from healthy donors using magnetic bead selection to enrich for Tregs. Surface class I MHC was immunoprecipitated using a pan-MHC class I anti- HLA-A, HLA-B and HLA-C antibody and associated peptides were eluted from their MHC complex using acid elution. Peptide and fragment masses were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the spectra of resulting epitopes were matched to known protein sequences by SEQUEST. Results: Four unique FOXP3 derived peptides were identified from the primary donor samples enriched for FOXP3+ cells as described. Predictive HLA binding algorithms demonstrate that the peptides identified are predicted binders to the specific HLA alleles of the original donors. No FOXP3 derived peptides were identified from the CD4+, CD25- T cell fraction analyzed to date. Conclusions: This work directly demonstrates for the first time to our knowledge that, although FOXP3 is an intra-nuclear transcription factor, FOXP3 derived peptides are presented within class I MHC on the surface of Tregs, representing a targetable Treg associated surface protein complex. Disclosures Levy: Bullet Biotechnology, Inc.: Consultancy.

Description: Introduction: Non-myeloablative conditioning combining total lymphoid irradiation (TLI) with rabbit anti-thymocyte globulin (ATG) has been shown to have a low incidence of non-relapse mortality (NRM) for patients with myeloid neoplasms (Benjamin Biol Blood Marrow Transplant 2014). As with other reduced intensity conditioning regimens, relapse remains the primary cause of treatment failure following allo-HCT using TLI-ATG conditioning. Cytokine induced killer (CIK) cells derived from peripheral blood culture with interferon (IFN)-γ, interleukin (IL)-2, and anti-CD3, have demonstrated anti-tumor effects in vitro, and have been safely administered in a phase I/II study of patients with post-transplant relapse with low incidence of acute GVHD (Laport Biol of Blood and Marrow Transplantation 2011). In an effort to promote conversion to full donor chimerism and reduce the risk of relapse following TLI/ATG conditioning for patients with myeloid neoplasms, we evaluated the addition of donor derived cytokine induced killer (CIK) cells post-HCT. Methods: Here we report interim results for 37 patients enrolled to date in an unplanned analysis. Day+90 full donor chimerism (FDC) was the primary endpoint. Secondary endpoints include overall survival and incidence of acute GVHD. Median age is 64 years (range 37-74) with primary disease of de novo MDS (19, 51.3%), secondary AML (6, 16.2%), MPN (2, 5.4%), and therapy (t-) related myeloid neoplasm (10, 27%; including 4, t-MDS; 4, t-AML; 2, t-MDS/MPN overlap). Of patients with MDS or MDS/MPN overlap, 54% had intermediate-2 IPSS risk classification. Fifteen (40.5%) patients had a morphological complete remission at the time of HCT. Twenty-three (62%) donors were unrelated. Results: Median CD34+ dose was 7.2e6/kg (range 2.3-17e6/kg). Ten patients (27%) did not receive CIK cells; causes included CD34+ cell dose below the threshold for culture inoculation (n=4), acute graft versus host disease (n=2), fever with concern for active infection at the time of scheduled infusion (n=1), or logistical reasons (n=3, including lack of donor consent for CIK infusion, transplant delay, and reagent unavailability). Of the 27 patients receiving CIK cells, 23 received the target dose of 1e8/kg CD3+ CIK product, at a median time of 26 days (range 24-31) post peripheral blood stem cell (PBSC) infusion. The median CD3+, CD3+CD56+, CD3+CD8+NKG2D+, CD8+CD45RO+ cell culture content was 97%, 13%, 51%, and 41%, respectively. Median followup time for living patients is 420 days. Day+90 FDC, defined by 95% or greater donor-type peripheral blood CD3+ cells, was 29%. The incidence of acute GVHD grade II-IV and grade III-IV in the total cohort is 21.6% and 5.4%, respectively. The incidence of chronic GVHD is 19%. Of the 27 patients receiving CIK product, the incidence of acute GVHD grade II-IV is 7.4% with no acute grade III or IV events to date and 22% chronic GVHD. On an intention to treat analysis of enrolled patients, one year NRM 10.5% (95% CI: 0.8%-22.1%) and one year cumulative incidence of relapse 46.3% (95% CI: 28.4%-64.1%) are not significantly different compared to our historical cohort (5.2%, 95%CI: 2.0%-8.4% and 53%, 95%CI: 45.9%-60.1%) respectively. The 1-year OS by intention to treat of 68.6% (95%CI: 54%-87%) is similar to our historical control, 60.8% (95%CI: 54.3%-68.2%, p=0.76). The 1-year OS in the 27 CIK recipients is 75% (95%CI: 59.3%-94.7%). Conclusion: CIK infusion was found to be safe and feasible. There was no increase in grade III-IV acute GVHD or chronic GVHD risk. There was a statistically non-significant trend towards increased one-year survival in our cohort. The potential benefit on overall survival remains to be further evaluated with additional patient enrollment and longer followup. However, given the favorable safety profile of CIK cells, future strategies to enhance efficacy such as repeat dosing or modification of CIK cells are worth potential exploration. Disclosures Benjamin: Amgen, Inc.: Employment, Equity Ownership. Rezvani:Pharmacyclics: Research Funding.

Description: Co-senior authors Andrew Brunner and Andrew H. Wei contributed equally to this work Background: MBG453 is a high-affinity humanized anti-TIM-3 (T-cell immunoglobulin domain and mucin domain-3) IgG4 antibody in development for the treatment of MDS, AML, and other malignancies. TIM-3 is an immune checkpoint with a complex regulatory role in both adaptive and innate immune responses and is also preferentially expressed on leukemic stem and progenitor cells, making it a potential target in MDS and AML. MBG453 has been shown to enhance immune cell-mediated killing of AML cells in vitro. Hypomethylating agents (HMAs) have been shown to increase immune checkpoint expression in MDS and AML, providing rationale to study the combination of HMAs with MBG453. Methods: Patients with Revised International Prognostic Scoring System (IPSS-R) high or very high-risk (HR) MDS and newly diagnosed, or relapsed/refractory (R/R), AML following ≥ 1 prior therapy who were not candidates for standard chemotherapy and who were HMA naive were enrolled in this multi-center, open label phase Ib dose-escalation study (NCT03066648). Escalating doses of MBG453 were administered i.v. every 2 weeks (Q2W; days 8, 22) or every four weeks (Q4W; day 8) in combination with decitabine (20 mg/m2; i.v. days 1-5). The primary objectives were to characterize the safety and tolerability of MBG453 in combination with decitabine and to identify recommended doses for future studies. Secondary objectives included assessing preliminary efficacy and pharmacokinetics of the combination. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs). Adverse events (AEs) were graded using NCI-CTCAE v4.03. The International Working Group criteria for MDS (Cheson et al, 2006) or AML (Cheson et al, 2003) were used to assess efficacy. Results: As of March 25, 2019, 17 HR-MDS, 4 chronic myelomonocytic leukemia (CMML), and 38 AML patients have received decitabine and MBG453 at 240 mg Q2W (n=22), 400 mg Q2W (n=21), or 800 mg Q4W (n=16). MTD has not been reached. Median age was 70 years (range 23-87 years). 24 patients are ongoing (duration of exposure 1.1 to 18.6 months) with 35 patients discontinued (disease progression [n=19, 32%], AE [n=1, 2%], patient/physician decision [n=13, 22%], death [n=2, 3%]). There was one DLT consisting of a grade 3 ALT elevation that was corticosteroid responsive. The most common treatment emergent grade 3/4 AEs were febrile neutropenia (39%), neutropenia (34%), thrombocytopenia (31%), and anemia (29%). A total of 8 patients (14%) developed ≥ grade 2 suspected immune related AEs (irAEs) considered to be MBG453 related; 4 of whom (7%) presented with grade 3/4 events: ALT elevation (n=2), arthritis (n=1), and GGT increase (n=1). No study treatment-related deaths were observed. 16 HR-MDS and 31 AML patients have had post-baseline disease response assessments. Median duration of decitabine and MBG453 is 3.9 months (range 0.7-18.6 months). Evidence of activity with MBG453 in combination with decitabine has been seen at doses ranging from 240 mg Q2W to 800 mg Q4W. 8 of 16 (50%) HR-MDS patients achieved mCR or CR. None of the responding HR-MDS patients has had disease recurrence with exposure durations currently ranging from 3.4 to 18.6 months; two patients in mCR underwent allogeneic stem cell transplant. 4 of 14 (29%) newly diagnosed AML patients have achieved a response of PR or better (2 PR, 2 CR), with 3 additional patients exhibiting ≥ 50% bone marrow blast reduction, and 10 of 14 (71%) continuing on study. 5 of 17 (29%) R/R AML patients have achieved a response of CRi, with 5 additional patients exhibiting ≥ 50% bone marrow blast reduction. Exposure durations for all AML responders currently range from 2.1 to 17.9 months. Median onset of response among all patients was 2.0 months. TIM-3 expression was detected on leukemic cells, with modulation of TIM-3 expression following treatment with decitabine. Conclusions: In this ongoing study in patients with HR-MDS and AML, the combination of MBG453 and decitabine was safe and well tolerated, and exhibited evidence of anti-leukemic activity with encouraging preliminary response rates occurring at a median of 2 cycles, with durability in both HR-MDS and AML. These findings validate TIM-3 as a promising therapeutic target in MDS and AML and support further clinical development of MBG453 in combination with HMAs in patients with MDS and AML. Disclosures Borate: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy. Porkka:Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Knapper:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Tolero: Consultancy; Daiichi Sankyo: Honoraria; Pfizer: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; AbbVie: Other: Advisory boards; Daiichi Sankyo: Other: Advisory boards. 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. Wermke:Novartis: Honoraria, Research Funding. Janssen:Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Other: Founder of the HematologyApp which is supported by BMS, among others, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Pfizer, among others; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Incyte, among others; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, among others; MSD: Other: Founder of the HematologyApp which is supported by MSD, among others; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Daiichi-Sankyo, among others; Roche: Other: Founder of the HematologyApp which is supported by Roche, among others; Takeda: Other: Founder of the HematologyApp which is supported by Takeda, among others. Traer:AbbVie: Consultancy; Notable Labs: Equity Ownership; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy. Chua:Alfred Hospital, Melbourne, Australia: Employment. Narayan:Takeda: Other: Employment (spouse); Merck: Other: Equity ownership (spouse); Genentech: Other: Equity ownership (spouse). Tovar:Hospital Clinic Barcelona: Employment. Kontro:Amgen: Consultancy; Astellas: Consultancy; AbbVie: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sun:Novartis Institutes for BioMedical Research: Employment; Novartis: Other: Novartis stock owner (stock share as long-term employee incentive). Longmire:Novartis Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Szpakowski:Novartis Institutes for Biomedical Research: Employment, Other: Novartis Stock. Liao:Novartis: Employment. Patel:Novartis Pharmaceuticals: Employment. Rinne:Novartis: Employment; N-Of-One, Inc: Consultancy. Brunner:Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Wei:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: MBG453 is an investigational anti-TIM-3 antibody that is being evaluated in hematological malignancies and solid tumors

Description: Background T cell redirection strategies, such as CAR-T and bispecific antibodies (bsAb), are rapidly changing the way in which we approach and treat cancer. While CAR-T and bsAb have shown impressive clinical efficacy in a limited number of cancers, both strategies are ultimately limited by on-target toxicity that currently restricts application to B-cell lineage tumors as the number of genuinely tumor-specific surface antigens is extremely limited. BsAb also suffer from off-target toxicity relating their ability to directly active T-cells severely restricting the therapeutic window. We sought to solve these inherent problems with the current generation bsAb by re-designing the molecule to alter the mechanism of T-cell activation. By splitting the T-cell engaging VHVL antibody paratope between two separate molecules we created two molecules that formed an active T-cell engaging unit through protein domain complementation following proteolytic activation. Each antibody could target independent surface antigens vastly increasing targeting permutations. Thus, these two antibodies functioned as an "antibody circuit" permitting Boolean type logic to precisely control T-cell activation in multi-dimensional targeting space. We selected AML as model cancer to develop T-cell Engaging Antibody Circuits (TEACs) due to the highly characterized surface antigen landscape and the clear challenges and limitations of single-antigen targeting approaches. Results We first screened 10 AML cell lines for candidate surface antigens based upon prior studies of surface antigen display (Perna F et al, 2016) and identified CD33, CD123, CD49d, CD70, CD71, CD38, CLEC12A, Flt3, CD24, CD244, TIM3 and CCR1 as promising targets. We developed a secondary TEACs screening assay where the two TEAC molecules contained either a FITC or biotin binding domain and paired these to commercial FITC or biotin conjugated antibodies targeting the antigens above. We screened 72 TEAC pairs against the 10 cell lines which identified optimal antigen target combinations which included CD33xCD123, CD33xCLEC12A, CD33xCD49d and CD33xCD24. Using a FRET-based fluorescent peptide assay to identify peptide linkers susceptible to proteases we found MMP2 to be highly expressed in AML samples and thus designed all our TEACs with this cleavage site. We next generated IgG4 format TEACs targeting CD33, CD123, CLEC12A and CD24 that included the MMP2 cleavage activation site and tested these as TEAC pairs in vitro. This screen identified the CD123xCD33 as the most active TEAC pair which was active in 9/10 cells lines. To assess potential safety concerns, we tested TEACs and CD123 and CD33 BiTEs individually and as pairs on PBMCs and on plate-immobilized molecules. These data demonstrated that BiTEs were extremely active against healthy monocytes and also activate T-cells non-specifically once plate-immobilized. In contrast CD123xCD33 IgG TEACs pairs did not activate T-cells when plate-immobilized and did not target healthy monocytes.Finally, we examined the activity of both CD33 BiTEs and CD123xCD33 TEACs on primary patient AML samples. We conducted FRET based assays which confirmed high activity of MMP2 cleavage site on all primary AML samples. When we examined T-cell activation, CD123xCD33 TEACs were active in all CD123+ CD33+ AML samples evaluated with an EC50 of 30ug/ml. Conclusion These data suggest T-cell engaging antibody circuits is a new approach that could be safely applied toward AML. TEAC agents do not directly activate T-cells and CD123xCD33 TEAC pairs do not activate PBMC or monocytes. However, CD123xCD33 TEACs show strong activity against AML cell lines and primary CD123+CD33+ AML cells. Disclosures Millar: Revitope Oncology: Equity Ownership. Minshull:Atum Biotechnology: Employment, Equity Ownership. Narayan:Takeda: Other: Employment (spouse); Genentech: Other: Equity ownership (spouse); Merck: Other: Equity ownership (spouse). Graubert:Biogen: Other: Spouse Employee; Calico Life Sciences: Other: Research Support; Janssen Pharmaceuticals: Other: Research Support. Cobbold:Gritstone Oncology: Equity Ownership; Revitope Oncology: Consultancy; Revitope Oncology: Equity Ownership.

Description: Introduction In 2008, the World Health Organization defined a new classification of myeloid and lymphoid neoplasms with eosinophilia that result from gene rearrangements of PDGFRA, PDGFRB, and FGFR1. While rearrangements involving PDGFRA and PDGFRB generally respond well to imatinib, those associated with FGFR1 are typically aggressive and require treatment with allogeneic hematopoietic stem cell transplantation (SCT). Here we present the case of a patient with a previously unreported fusion of PCM1-FGFR1. The patient was treated with an Oral, potent, selective, and irreversible small-molecule inhibitor of FGFR 1- 4 (futibatinib (TAS-120)) under an expanded access program, resulting in the first reported instance of complete hematologic and cytogenetic remission using futibatinib in an FGFR-driven myeloid neoplasm. Results A 55-year-old male presented with dyspnea and fatigue and was found to have peripheral eosinophilia (3,660/microliter) and thrombocytopenia (46,000/microliter). Diagnostic bone marrow biopsy was notable for a hypercellular (cellularity 〉95%), erythroid dominant marrow with increased eosinophilic forms and increased pronormoblasts. Break-apart fluorescence in situ hybridization (FISH) studies revealed an FGFR1 gene rearrangement in 11.3% of nuclei (normal 〈 5.7%). The nature of the rearrangement was shown to be a paracentric inversion of chromosome 8p based on the distinct gap between the 5'FGFR1 and 3'FGFR1 probes in metaphase FISH (Figure 1). A validated, targeted next generation sequencing assay for fusion transcript detection (heme fusion assay) revealed a previously unreported PCM1-FGFR1 fusion transcript (40 unique fusion reads), with an in-frame fusion of PCM1 (exons 1-36) to FGFR1 (exons 11-18). No additional clonal markers were identified. The patient was not considered an SCT candidate due to medical comorbidities and was enrolled on a single-patient protocol expanded access program for futibatinib. He was initially treated with prednisone for control of his eosinophilia, and then started on oral therapy with futibatinib (20 mg daily). Within 1 month of initiation of futibatinib, prednisone was tapered without recurrence of eosinophilia and with improvement in platelet count (169,000/microliter). After 6 months, repeat bone marrow biopsy showed a moderately hypocellular marrow with maturing trilineage hematopoiesis. Additionally, the paracentric inversion of chromosome 8p was no longer observed in metaphase FISH, consistent with cytogenetic remission. Furthermore, the PCM1-FGFR1 fusion transcript was no longer detectable by heme fusion assay. The patient has experienced grade 2 skin rash requiring brief dose interruption (7 days) followed by dose reduction to 16 mg daily, on which he remains. He has also experienced grade 2 hyperphosphatemia, a known side effect of futibatinib, which is adequately controlled with sevelamer. The patient continues on futibatinib, with ongoing evidence of hematologic and cytogenetic remission after 11 months of therapy. Conclusions To our knowledge, this case represents the first report of a PCM1-FGFR1 fusion driving a myeloid neoplasm with eosinophilia. Treatment with futibatinib has resulted in hematologic and cytogenetic remission, with treatment successfully ongoing after 11 months. Our findings support further exploration of FGFR inhibitors as a therapeutic strategy for myeloid/lymphoid neoplasms driven by FGFR1 rearrangement, particularly in individuals who are not candidates for SCT. A phase 2 study of futibatinib in patients with FGFR1 driven myeloid/lymphoid neoplasms is planned. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Chen:Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Incyte: Consultancy; Abbvie: Consultancy. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Narayan:Genentech: Other: Equity ownership (spouse); Merck: Other: Equity ownership (spouse); Takeda: Other: Employment (spouse). Benhadji:Taiho Oncology: Employment. Hobbs:Incyte: Consultancy, Research Funding; Merck: Research Funding; Jazz pharmaceuticals: Consultancy; Celgene: Consultancy; Bayer: Research Funding; Agios: Consultancy.

Description: Background: While novel agents have allowed for successful outpatient treatment of patients with multiple myeloma (MM), multi-agent infusional chemotherapy regimens continue to have a role, particularly in high burden disease states. However, the use of platinum-based regimens is limited in patients with renal insufficiency and renal failure. We have been using a modified hyperCVAD regimen, termed HyperCD (Table 1), with omission of vincristine, and inclusion of a proteasome inhibitor (PI, either bortezomib or carfilzomib) in these aggressive clinical presentations for rapid tumor reduction. Here we present our experience with this treatment modality, with analysis of treatment outcomes and toxicities in the renal insufficiency subset. Methods:We performed a single-center chart review of all MM patients at our institution with available electronic medical records who received at least one HyperCD cycle in the setting of concurrent renal insufficiency (defined by estimated eGFR

Description: Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged 〉60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults 〉60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.