ALBERT

Description: Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age

Description: An immune-mediated anti-tumor response is the ultimate goal of allogeneic transplantation for relapsed, refractory malignancies. We developed a transplant protocol with less toxicity compared with standard allogeneic transplantation. We utilize multiple donor lymphocyte infusions after nonmyeloablative HLA-haploidentical stem cell transplantation for refractory disease. We have performed a total of 41 HLA-mismatched transplants with escalation of the CD3+ dose to 2×108 cells/kg using G-CSF primed product, with a conditioning regimen of 100cGy total body irradiation. Our phase I/II study had 26 with hematologic malignancies. This therapy results in loss of detectable macrochimerism. Despite this, 13 responses, six major, occurred outside of macrochimerism. We have observed a new infusion related clinical entity named haploimmunostorm (HIS), observed after infusion. This syndrome occurred in 26 out of 30 (87%) patients with a CD3+ dose more than 1×108 cells/kg. In the syndrome, a constellation of symptoms occurred, some with variable penetrance, in which hyperpyrexia and malaise were a constant feature occurring as early as 4 hrs after cell infusion (median of 14 hrs). A morbilliform rash was seen in 40% of patients. Biopsies revealed no evidence of hyperacute or acute GVHD. Diarrhea was present in a 20% of patients; biopsies taken also failed to show any evidence of GVHD. Transient elevations of liver enzymes occurred in 40% of the patients usually. Steroids were used successfully if the HIS syndrome lasted more than 72 hrs. We used a Bioplex machine and analyzed 17-separate cytokine levels serially in these patients beginning with pre-treatment levels. Cytokine level analysis showed a cluster of cytokines that had up to a 1100 fold level increase compared with baseline pretreatment cytokine levels with significant increases of at least 10 fold in IFN-g, IL-10, IL-13, IL-2, IL-5, IL-6, IL-7, IL-8, MCP-1, and MIP-1b. This syndrome appears to be immunologically based and represents neither hyperacute nor acute GVHD. This syndrome is different than an engraftment syndrome reported in some patients undergoing autologous transplant with a different cluster of cytokine elevation (IL-6, IL-8, IL-10, IFN-g, MCP-1, MIP-1b) compared with (IL-1,IL-2, IL-8, TNFa, IFNg) for engraftment syndrome Engraftment syndrome occurs at time of engraftment, opposed to HIS in which may be a rejection syndrome. HIS deviates from engraftment syndrome with absence of noncardiogenic edema, pulmonary infiltrates, renal insufficiency weight gain and encephalopathy. The skin and intestinal biopsy results are distinctly different than GVHD or engraftment syndrome. The anti-tumor responses may be due to activation of host natural killer and T-cells with increases in MCP-1, MIP-1b and IL-6, essentially breaking host tumor tolerance. In summary, we have observed a new clinical entity that was not previously seen and is a result of the donors having a relatively intact immune system at the time of cell infusion.

Description: Introduction Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed 〉6 months after receiving a rituximab-containing regimen was initiated. Methods Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed 〉6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status

Description: Background: Y90 Ibritumumab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients (pts) who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has never been studied. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. In this prospective, single-arm, open-label, multicenter phase II trial, we assessed the response rate and safety of a short induction course of BR for 4 cycles followed by consolidation with 90YIT for chemotherapy-naïve pts with FL. Methods: Consenting pts greater than 18 years with chemotherapy naïve FL (grade 1-2 and 3a) requiring treatment were eligible for this study. All pts had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375mg/m2. One week later, bendamustine 90mg/m2 was administered on days 1 and 2, and rituximab 375mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Pts were restaged 4-6 weeks after the last dose of BR. Pts were considered eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was give 6-12 weeks after completion of the last cycle of BR. The primary endpoint of this study is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: Forty-two pts were enrolled in this study: 38 pts initiated study treatment, and 4 were screen failures. Median age was 58 years [range 31-74]. The study enrolled FLIPI low (18%), intermediate (47%), high (34%) risk pts; 32 of 38 (84%) were Grade 1-2 and 6 (16%) were Grade 3a. Response rates after 4 cycles of BR: Thirty-eight pts have completed 4 cycles of BR and 38 are evaluable for response. Twenty-two of 38 evaluable pts achieved a CR/CRu (58%) and 15 of 38 pts had a PR (39%) for an overall response rate (ORR) of 97%. One pt had stable disease (SD). Response rates after BR followed by 90YIT: Thirty of 38 BR-treated pts have received 90YIT and are evaluable for the primary endpoint of CR/CRu. Of the 38 BR treated pts, two in CR were unable to receive 90YIT due low platelets, one was not eligible to receive 90YIT due to achievement of SD only, one declined treatment, and four are not yet evaluable for response. Twenty-five of 30 evaluable pts are in CR/CRu (83%), 4 remain in PR (13%) after 90YIT and one progressed during 90YIT, for an ORR of 96%. Of the 14 pts who had a PR after BR, 7 (50%) converted to a CR/CRu immediately after 90YIT, with three (21%) additional conversions to CR/CRu in follow-up, the latest occurring 16 months after 90YIT. Grade 3-4 hematologic toxicities during BR included: lymphopenia (36%), neutropenia (8%), thrombocytopenia (3%), leukopenia (3%). Non-hematologic toxicities included grade 2 phlebitis (14%) and grade 3 hyperglycemia (8%), hyponatremia (3%), diarrhea (3%), infusion-related reaction (3%), headache (3%), rectal hemorrhage (3%). Grade 3-4 hematologic toxicities after 90YIT included: neutropenia (33%), leukopenia (36%), thrombocytopenia (36%), lymphopenia (14%), anemia (3%). Non-hematologic toxicities included skin infection (3%). Median neutrophil recovery was 8 weeks [range 8 to 12] and median platelet recovery was 9 weeks [range 5 to 36] after Y90IT. There have been no incidences of neutropenic fever. One pt developed chronic myelogenous leukemia, occurring 11 months after treatment with BR followed by Y90-IT. There have been no cases of myelodysplasia or acute myelogenous leukemia. Conclusions: In this nearly final analysis, the CR/CRu rate of pts completing all study therapy (BR followed by 90YIT) is 83%, the ORR is 96%, and the conversion rate from PR to CR/CRu is 71%. We conclude that sequential treatment with BR followed by Y90IT is highly effective and safe, and should be considered as a frontline treatment option for FL. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Description: Background: We have previously reported initial high response rates of the BRAF inhibitor, vemurafenib, in patients (pts) with relapsed or refractory hairy cell leukemia (HCL) (Tiacci and Park et al. NEJM 2015). However, complete response (CR) rates were low at 35-40% with detectable minimal residual disease (MRD) in most patients, and a longer follow up revealed a relapse rate of 50% (Park JH et al. Blood 2018, 132;392). Based on the recent data suggesting improved CR rate in combination with rituximab in relapsed HCL (Tiacci et al. Blood 2016, 128:1214), we initiated a phase II clinical trial to investigate the efficacy of vemurafenib and obinutuzumab in patients with newly diagnosed HCL (NCT03410875). Methods: Adult pts with previously untreated HCL who met the treatment initiation criteria (i.e. ANC

Description: BACKGROUND: Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated results from a phase 1 study on the safety and efficacy of each of these agents when combined with intensive chemotherapy in patients with newly diagnosed AML, as well as data regarding the rate of measurable residual disease (MRD)-negative complete remissions (CRs), mutation clearance and molecular profiling. METHODS: In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with induction therapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib until the end of study. For patients who proceed to allogeneic hematopoietic stem cell transplant (HSCT), mIDH inhibitor treatment is discontinued prior to transplant and is not resumed post-transplant. mIDH1/2 variant allele frequency (VAF) is assessed in bone marrow mononuclear cells using Digital PCR Technology (Sysmex-Inostics Inc). IDH1/2 mutation clearance (IDH-MC) is defined as a reduction in the mIDH1/2 VAF to a level below the limit of detection of this assay (0.02-0.04%) for ≥1 on-treatment time point on or after Day 28 of induction. MRD in bone marrow aspirates is analyzed using multi-parameter flow cytometry. Baseline co-occurring mutations are identified with a 95-gene next generation sequencing panel targeted to hematologic malignancies. RESULTS: As of May 1, 2018, 134 patients had been treated: 47 with ivosidenib (median age 63 years, range 24-76) and 87 with enasidenib (median age 63 years, range 27-77; Table 1). Secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 33/87 (38%) patients with mIDH2 and in 16/47 (34%) patients with mIDH1. The most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS for patients with IDH1 mutations; and DNMT3A, SRSF2 and ASXL1 for patients with IDH2 mutations. Ivosidenib or enasidenib combined with induction and consolidation was well tolerated, based on the frequency of grade ≥3 non-hematologic adverse events (Table 2) and hematologic recovery (Table 3). Times for ANC and platelet count recovery were nominally longer in patients with sAML. Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 26/28 (93%) patients with de novo AML and 6/13 (46%) patients with sAML (Table 4). Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT. Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 33/45 (73%) patients with de novo AML and in 20/32 (63%) patients with sAML (Table 4). Thirty-seven patients received ≥1 cycle of consolidation therapy, 6 patients received maintenance directly after induction and 11 patients received maintenance after consolidation. Thirty-three patients proceeded to HSCT. Longitudinal VAF data are available for 31 ivosidenib-treated patients and 60 enasidenib-treated patients. In patients who achieved a CR, IDH-MC was observed in 41% (9/22) of those with mIDH1 (Table 5) and in 30% (11/37) of those with mIDH2 (Table 6). Flow cytometry assessments are available for 21 patients achieving a CR: MRD-negative CRs were observed in 89% (8/9) of those with mIDH1 and in 58% (7/12) of those with mIDH2. CONCLUSION: Ivosidenib or enasidenib in combination with induction and consolidation therapy has an acceptable safety profile with robust remission rates, MRD-negative CRs, and mutation clearance in a population of older, high-risk patients with mIDH AML. The clinical benefit of adding ivosidenib or enasidenib to induction, consolidation and maintenance therapy for patients with newly diagnosed mIDH AML will be further evaluated in a randomized phase 3 trial. Disclosures Stein: Celgene: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Fathi:Jazz: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria. Mims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Pratz:Boston Scientific: Consultancy; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Stone:AbbVie: Consultancy; Merck: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Agios: Consultancy, Research Funding; Sumitomo: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Otsuka: Consultancy; Jazz: Consultancy; Fujifilm: Consultancy; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ono: Consultancy; Orsenix: Consultancy. Döhner:Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding. Pollyea:Celgene: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: 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; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. McCloskey:Amgen Pharmaceuticals: Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: 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; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Lowenberg:Clear Creek Bio Ltd: Consultancy, Honoraria; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ossenkoppele:Roche: Consultancy, Honoraria; Karyopharm: Consultancy, Research Funding; Genmab: Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Lersch:Celgene: Employment. Nabhan:Agios: Employment. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Hua:Agios: Employment, Equity Ownership. Almon:Agios: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; AbbVie: Research Funding; AROG: Research Funding.