ALBERT

Description: After failure of DNA methyltransferase inhibition (DNMTi) there is no standard of care therapy for high-risk myelodysplastic syndromes (MDS), and median survival for higher risk disease is less than 6 months (Prebet et al, JCO 2011; Jabbour et al, Cancer 2015). Pevonedistat, a first in human small molecule inhibitor of the NEDD8 activating enzyme (NAE), downregulates Cullin ring ligases (CRL) which interferes with the shuttling and degradation of proteins in the proteasome and leads to accumulation of CRL substrates. Combining pevonedistat (Pev) with azacitidine (AZA) resulted in synergistic cell killing in in vitro and xenograft models of acute myeloid leukemia (AML) (Smith et al, Blood 2011), elicited favorable response rates in treatment naïve elderly or unfit AML patients (Swords et al Blood 2018), and is currently under study in treatment-naïve MDS. The study presented herein (NCT03238248) investigates the utility of adding pevonedistat to azacitidine (PevAz) after DNMTi failure in MDS and MDS/MPN overlap syndromes. Methods: In this on-going single-arm phase II study, MDS and MDS/MPN patients were eligible if they were refractory to DNMTi treatment, progressing after at least 2 cycles of therapy; had failed to achieve a complete remission (CR) after at least 4 cycles of DNMTi therapy; or had relapsed after an initial response to DNMTi therapy. Enrolled subjects received AZA 75mg/m2 sc/iv daily on days 1-5 and Pev 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle. Survival is the primary endpoint and is assessed at regularly scheduled study visits and every 3 months after ending protocol-directed therapy. Hematologic and bone marrow response rates are secondary endpoints. Responses to treatment are determined by the MDS International Working Group (IWG) response criteria (Cheson et al, Blood 2006) or for MDS/MPN, by the modified MDS/MPN IWG response criteria (Savona et al, Blood 2015). Results: As of the data cutoff on 15 MAR 2019, 23 subjects (21 with MDS, 2 with MDS/MPN) had enrolled and initiated treatment. Subjects had previously been treated with AZA (n=11/23), decitabine (n=11/23), and ASTX727 (n=4/23); some subjects had been treated with more than one DNMTi prior to enrollment. Median number of cycles of any prior DNMTi therapy was 7 (range 2-35). 65% of subjects were female. Median age at enrollment was 67 years (range 51 - 85). 65% had Intermediate-2 or High risk disease by IPSS at time of enrollment. Median number of PevAz cycles completed prior to the data cutoff was 4 (range 1-19). One subject had not reached the first response assessment at the time of the data cutoff and data was unavailable for one subject. The overall response rate including complete and partial remission, hematologic improvement and clinical benefit (CB) was 42.9% (9/21), and CR rate (including 1 CR + 4 marrow CR) was 23.8% (5/21) with a median duration of response (DOR) of 8.7m (range 2.8m-15.7m). An additional 38.1% (8/21) had stable disease as best response (Table 1). The most common Grade 〉2 adverse events (any attribution) include thrombocytopenia (39%), anemia (35%), leukopenia (26%), neutropenia (22%), infections (17%), and febrile neutropenia (13%). Six subjects experienced Grade ≤ 2 elevations in AST/ALT and 4 had Grade ≤ 2 elevation in bilirubin, whereas only one subject experienced Grade 〉 2 LFT abnormality (increase in ALT). There was one death on study due to intracerebral hemorrhage related to a previously undiagnosed metastatic carcinoma. PevAz treatment was discontinued in other subjects due to disease progression (n=7), adverse event (n=1), lack of response (n=1), or to pursue allogeneic stem cell transplant after achieving a satisfactory response to PevAz (n=3). Ten subjects were continuing PevAz therapy on study as of the data cutoff. Summary: PevAz was well-tolerated in MDS and MDS/MPN patients who had previously failed DNMTi, with the most common adverse events of cytopenias, which are a common feature of these diseases. 5/21 subjects achieved CR/mCR with meaningful DOR, and the ORR of 42.9% exceeded expectations for MDS patients with previous failure of DNMTi therapy; both MDS/MPN patients responded with CR and CB. For these patients whose treatment options are limited and prognosis very poor, these preliminary data are especially encouraging and warrant further investigation. This therapy combination is being tested in a phase 3 study in treatment naïve high risk MDS, CMML and low-blast AML. Disclosures Watts: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Byrne:Karyopharm: Research Funding. Bradley:AbbVie: Other: Advisory Board. Savona:Sunesis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties.

Description: Diseases that infiltrate the bone marrow disrupt erythropoiesis leading to anemia. In multiple myeloma (MM), anemia severity can be correlated with degree of marrow infiltration by myeloma cells. Infiltrating MM may impair the function and structure of erythroblastic islands (EBIs), the marrow erythropoietic niches. An EBI consists of a central macrophage surrounded by colony-forming units-erythroid/proerythroblasts (CFU-E/pro-EBs) and their progeny, the differentiating erythroblasts. Cytokines produced by MM cells, such as Fas ligand (FL), tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL), can induce erythroid cell apoptosis. Physical displacement of the erythroid cells away from central macrophages by MM can destroy the EBIs. Non-erythrotoxic therapies that kill MM cells while sparing erythropoietic cells allow quantification of erythropoiesis and marrow MM infiltration before and after treatment of newly diagnosed MM patients. Marrow biopsies from 15 newly diagnosed MM patients were obtained before and after 4 courses of non-erythrotoxic induction therapy with bortezomib, dexamethasone, and lenalidomide (Richardson et al, Blood 2010). CBCs and serum MM paraprotein quantifications were obtained with the marrow biopsies and before each course of therapy. No patient had renal insufficiency, iron or cobalamin deficiency, erythropoietin (EPO) therapy, or RBC transfusion. At diagnosis, percentages of marrow space occupied by MM and erythroid cells were negatively correlated. Percentages of marrow space infiltrated by MM (range = 2.3 - 72.3%) were also negatively correlated with hemoglobin (Hb), hematocrit (Hct) and RBCs. One patient had a partial response: marrow myeloma decreasing from 27.5% to 5.3%. All other patients had reductions in marrow myeloma to 〈 2.2%. The 8 patients with 〈 30% MM infiltration at diagnosis had no change (-1.4% to 1.8%) in marrow space occupied by erythroid cells following therapy, whereas 7 patients with 〉 35% MM infiltration at diagnosis increased marrow space occupied by erythroid cells following therapy (3.4 to 19.2%). Hb, Hct, and RBCs did not change during therapy in patients with 〈 30% MM infiltration, but those with 〉 35% myeloma infiltration at diagnosis had progressive increases in Hb, Hct, and RBCs during therapy. These clinical data were used to study the relationship between marrow infiltration by MM and erythropoiesis. Mathematical models of MM infiltration effects on marrow EBI structure/function were developed and tested in simulations. A previously developed hybrid discrete-continuous model of erythropoiesis based on EBI (Eymard et al, J Math Biol 2015) was extended to a larger area of marrow containing multiple EBIs. In the model, CFU-E/proEBs have 3 fates-- self-renewal, differentiation, and apoptosis--that depend upon factors produced systemically, such as glucocorticoids and EPO, and locally, such as stem cell factor and bone morphogenetic protein 4 by central macrophages and FL by mature erythroblasts. Intracellular regulatory networks were modeled with ordinary differential equations and extracellular concentrations by partial differential equations. Under normal conditions, EBIs achieve a steady-state that produces new RBCs at rates which maintain normal Hb, Hct and RBCs. At early times after the section of bone marrow is infiltrated by small foci of proliferating MM cells, EBI function is not affected. With further proliferation, infiltrating MM cells occupy more marrow space, inducing erythroid cell apoptosis by producing FL, TNF or TRAIL and by displacing erythroid cells from central macrophages, thereby destroying EBIs. However, central macrophages of destroyed islands persist or are replaced by differentiation of monocyte-macrophage precursors. After MM cells are killed by therapy, the residual macrophages can interact with burst-forming units-erythroid (BFU-E), thereby reestablishing EBIs. If the MM infiltrate is not sufficiently reduced after a course of therapy, it can physically interfere with the macrophage-BFU-E interaction, preventing the reestablishment of an EBI and full recovery of RBC production until a subsequent therapy reduces the infiltrate sufficiently that the EBI is reestablished. The model is consistent with the clinical data and may apply to other marrow infiltrative diseases including myelofibrosis, systemic infections, or other malignancies. Disclosures No relevant conflicts of interest to declare.

Description: Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib. Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patients Secondary Objectives: Hematologic response, symptom assessment Methods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1. Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1). Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction Ibrutinib was FDA approved for relapsed or refractory (R/R) marginal zone lymphoma (MZL) based on a phase II clinical trial that showed an overall response rate of 48% (Noy et al, Blood 2017). However, factors associated with response to ibrutinib in R/R MZL and outcomes of patients after progression on ibrutinib are unknown. Given the poor survival in other B-cell lymphomas such as mantle cell lymphoma (MCL) after progression on ibrutinib (Martin P et al, Blood 2016), we sought to evaluate clinicopathologic characteristics predictive of ibrutinib failure in R/R MZL, and describe outcomes of patients who experienced progression on ibrutinib therapy. Methods We performed a multicenter retrospective study of MZL patients treated at 19 US medical centers. Eligible patients were ≥ 18 years diagnosed with MZL from 2010-2019, who received ibrutinib for R/R MZL. Patients achieving a complete response (CR) or partial response (PR) with ibrutinib were considered ibrutinib responders, while those who had stable disease (SD) or progression of disease (PD) were classified as non-responders. The primary endpoint was to evaluate factors predictive of primary progression (PD) on ibrutinib. Secondary endpoints include evaluation of predictors of overall survival (OS) and progression-free survival (PFS) following ibrutinib therapy, assessment of outcomes based on the sequencing of ibrutinib therapy, and evaluation of outcomes following ibrutinib failure. PFS was defined as time from the start of ibrutinib therapy until lymphoma relapse/progression or death from any cause, censoring at last clinical assessment if no progression or death. OS was defined as time from the start of ibrutinib treatment until death or last follow-up. A multivariable Poisson regression analysis was performed to model ibrutinib progression on the clinicopathologic factors (see Table). To identify significant predictors for OS and PFS, we used a multivariable Cox model. Results 101 patients with R/R MZL received ibrutinib, of whom 99 had sufficient data for inclusion in the analysis. Among these patients, 63% (n=62) had CR/PR to ibrutinib (ibrutinib responders, CR=17, PR=45) and 37% (n=37) had no response (ibrutinib non-responders, SD=25, PD=12). The median duration of follow-up was 1.8 years (range=0.1-5.4 years) and 2 years (range=0.2-6.3 years) for ibrutinib responders and non-responders, respectively. Baseline characteristics of the R/R MZL patients stratified by ibrutinib response are shown in the Table. Among all the baseline factors examined for association with ibrutinib progression, only primary refractory disease (refractory to frontline therapy, RR=3.78, 95%CI=1.36-10.45, p=0.01) was predictive of a higher probability of primary progression on ibrutinib on multivariable analysis. The median OS was significantly better for responders (NR [not reached], 95%CI=3.2-NR) compared to non-responders (3.4 years, 95%CI=1.4-NR) (Figure 1A). Achieving CR/PR with ibrutinib (HR=0.22, 95%CI=0.09-0.52) and lack of complex cytogenetics (HR=0.22, 95%CI=0.08-0.59) were predictors of superior PFS. Similarly, ibrutinib response (HR=0.13, 95%CI=0.03-0.53) and lack of complex cytogenetics (HR=0.19, 95%CI=0.04-0.87) were predictors of better OS. There was no difference in PFS or OS based on the timing of ibrutinib administration (second vs third vs fourth line and beyond, Figure 1B and 1C). The median post ibrutinib relapse/progression OS (PROS) for patients who initially responded then progressed on ibrutinib (secondary progression, n=19) was 4 years (Figure 1D). The median PROS for patients who had no response to ibrutinib were stratified according to SD vs PD. The median PROS for those who had SD was NR and those with PD was 0.1 year (Figure 1E). Conclusion This is the largest series of R/R MZL patients treated with ibrutinib. A history of primary refractory disease was predictive of primary progression on ibrutinib, while the presence of complex cytogenetics was associated with inferior PFS and OS. In contrast to MCL, the outcomes of patients who progress on ibrutinib in R/R MZL are not poor except for the primary progression cohort (those with PD as the best response to ibrutinib). Improving therapeutic options for patients who experience PD with ibrutinib treatment represents an urgent unmet need and these patients should be prioritized for evaluation of novel therapeutic approaches. Figure Disclosures Epperla: Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Reddy:Genentech, BMS: Research Funding; KITE Pharma, Abbvie, BMS, Celgene: Consultancy. Caimi:Genentech: Research Funding; Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding. Greenwell:Lymphoma Research Foundation: Research Funding; Acrotech Biopharma LLC, Kyowa Kirin: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Olszewski:Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Awan:Genentech: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Consultancy; Celgene: Consultancy; Blueprint medicines: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy. Barta:Monsanto: Consultancy; Atara: Honoraria; Seattle Genetics: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria. Grover:Genentech: Research Funding; Tessa: Consultancy. Bartlett:Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed Therapeutics: Research Funding; Acerta: Consultancy; BTG: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding. Christian:Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Herrera:Pharmacyclics: Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy.