Citations

Abstract Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed by many hematologic malignancies. SL-401 is currently being advanced through clinical trials in patients with a variety of CD123+ malignancies including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML) in remission with high relapse risk, and multiple myeloma. CD123 has been shown to be expressed on myeloproliferative neoplasm (MPN) cells as well as microenvironmental immune cells, namely plasmacytoid dendritic cells (pDCs), in the bone marrows of some patients with MPN including chronic myelomonocytic leukemia (CMML). Microenvironmental pDCs have been implicated in promoting plasma cell disorders and preliminary data suggest that pDCs could play a related role in some myeloid neoplasms. Accordingly, a therapy directed at both CD123-expressing myeloid cells and neighboring CD123-expressing pDCs could provide therapeutic benefit. SL-401 is being evaluated in patients with advanced, high-risk MPN, including systemic mastocytosis (SM), myelofibrosis (MF), primary eosinophilic disorders (PED), and CMML. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of patients with advanced, high risk MPN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, 12 ug/kg/day, or higher for days 1-3 of a 21-28 day cycle in a 3x3 design. In stage 2, patients receive SL-401 at the dose determined in stage 1. Study objectives include characterization of the safety profile, including determination of the maximum tolerated or tested dose, and detection of preliminary efficacy signals including evaluation of tumor response and progression free survival by standard criteria. As of 7/20/16, 6 patients with MPN (MF, n=3; CMML-2, n=2; CMML-1, n=1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3). The median age was 66 years (range: 42-81 years). Patients treated at all doses received 1+ to 2+ cycles (ongoing) of SL-401. The most common treatment-related adverse events (AEs) were thrombocytopenia (2/6; 33%) and fatigue (2/6; 33%); the most common ≥ Grade 3 treatment-related AEs were thrombocytopenia (2/6; 33%) and anemia (1/6; 17%); there has been no DLT. Efficacy assessments are ongoing. Patients are currently enrolling in the 12 ug/kg/day cohort. Conclusions: Initial dosing of SL-401 appears to be well-tolerated in patients with MPN and CMML, with no unexpected AEs observed. Given CD123 expression on myeloid neoplastic cells as well as microenvironmental immune cells (namely, pDCs), SL-401 may offer a novel, targeted therapeutic approach in patients with high-risk MPN and CMML of unmet medical need. Enrollment continues in stage 1 of this ongoing Phase 2 trial and updated safety and efficacy data will be presented. Clinical trial information: NCT02268253. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. McCloskey:Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer Inc: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Ali:Incyte Corporation: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Abstract Background: Cytoreductive therapy with hydroxyurea (HU) has been considered first line therapy for patients with high risk polycythemia vera (PV) and essential thrombocythemia (ET) since the results of the PVSG-08 trial demonstrated thrombotic risk reduction (Fruchtman SM et al 1997) for PV and PT1 for ET (Harrison CN et al 2005). Although HU is well tolerated by most patients and has been shown to reduce thrombotic risk in this setting, concern regarding the leukemogenic potential of this oral ribonucleotide reductase inhibitor balanced by the observation of molecular responses with interferon-α (IFN-α) led us to compare the clinical response and tolerability of pegIFN-α (PEG) and HU in a global, randomized, phase III trial. Methods : MPD-RC 112 trial (NCT01258856) enrolled patients with high risk (age >60 years, history of thrombosis, extreme thrombocytosis, symptomatic splenomegaly, uncontrolled cardiovascular risk factors), newly diagnosed (<5 years), WHO defined ET/PV that were treatment naïve (HU <3 months) and randomized (1:1) to PEG or HU. The primary endpoint was complete hematologic response (CHR) rate by European LeukemiaNet (ELN) criteria between the arms after 12 months of therapy. A planned interim analysis based on intent-to-treat with testing boundaries for efficacy and futility was conducted after 75 patients were on study for 12 months. Response assessment by ELN criteria were conducted by blinded review by 4 investigators (JM, RAM, AY, RH). Intent-to-treat analysis was conducted for efficacy endpoints (HU n=39; PEG n=36). Safety analysis included all patients who received treatment (HU n=36; PEG n=36). Results: Patients: The MPD-RC 112 trial involved 24 centers in 6 countries; enrollment began 09/2011 and concluded 7/2016 prior to full accrual due to study drug availability with 168 patients enrolled (Table 1 for 75 patients in the interim analysis). There was no imbalance between arms with respect to history of thrombosis, erythromelalgia, diabetes, hypertension, but age was significantly older on HU. This remained true when analyzing by ET/PV disease strata with the exception of diabetes which was slightly imbalanced within the PV cohort (HU 5/23, 22%; PEG 0/21, 0%; p<0.05). Response: CHR and PHR were observed in 13 (33%) and 14 (36%) patients for an overall response rate (ORR) of 69% (27/39) for HU, and 10 (28%) and 19 (53%) for an ORR of 81% (29/36) for PEG (CHR comparison p=0.60 based on z-test which did not cross either testing boundary). 10 patients randomized to HU were not evaluable for 12-month response due to never initiating treatment (n=3) or early study discontinuation for AEs (n=1), patient withdrawal (n=5), or treatment non-compliance (n=1). 3 patients were not evaluable for response on PEG due to early study discontinuation for AEs (n=1), physician decision (n=1), or patient withdrawal (n=1). Excluding patients who never initiated treatment did not impact the primary endpoint comparison (HU 13/36, 36%; PEG 10/36, 28%; p=0.45). For ET, CHR and PHR were observed in 7 (44%) and 4 (25%) patient on HU, and 6 (40%) and 6 (40%) for PEG (CHR comparison p=0.83). For PV, CHR and PHR were observed in 6 (26%) and 10 (44%) patients on HU, and 4 (19%) and 13 (62%) for PEG (CHR comparison p=0.58). Normalization of spleen by palpation at 12 months was seen in 2/7 (29%) and 5/7 (71%) of the HU and PEG treated patients with palpable spleen at baseline, respectively. Among 38 PV patients, rate of phlebotomy use at 12 months was 0/18 (0%) vs 5/20 (20%) on HU and PEG (p=0.02). From baseline to best score through 12 months, 9/28 (32%) and 12/34 (35%) patients with data on HU and PEG, respectively, had a ≥50% reduction in MPN-SAF Total Symptom Score (p=0.79). Toxicity: No Grade 4 AEs occurred in either treatment arm. Overall, Grade 3 AEs occurred in 5/36 (14%) HU patients and 16/36 (44%) PEG patients (Grade 3 hematologic: 4/36 [11%] HU vs 8/36 [22%] PEG; Grade 3 non-hematologic: 5/36 [14%] HU vs 16/36 [44%] PEG). See Table 2 for Grade 3 AEs regardless of attribution occurring in >10% of patients in either arm. Conclusions: This interim analysis does not show a clear difference in primary endpoint of CHR between HU and PEG. A comparative analysis of the quality of life and symptom burden will provide further insight into the tolerability of these agents (Mesa et al ASH 2016). The final results of this pivotal trial will provide necessary data required to firmly establish the optimal first line therapy for patients with high risk ET/PV. Disclosures Mascarenhas: CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Roche: Research Funding; Novartis: Other: DSMB , Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Harrison:Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Vannucchi:Novartis: Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Incyte: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

Abstract Intro: Multiple myeloma (MM) is an incurable malignancy that arises from MGUS, however the majority of patients with MGUS do not go on to develop MM. A deeper understanding of the biology of progression from MGUS to MM is needed to identify patients at higher risk of progression and identify potential strategies to prevent development of MM. Altered bone metabolism is common in MGUS with upregulation of the receptor-activator of nuclear kB ligand (RANKL) to osteoprotegrin (OPG) ratio. Vitamin D has a central role in bone metabolism and has recently been associated with progressive disease in several malignancies, including MM. We hypothesized that progressive alterations in the key molecules of bone remodeling would correlate with the risk group of MGUS and that correction of vitamin D deficiency would lead to improved equilibrium of selective cytokines involved in bone remodeling and metabolism. Methods: 43 patients with MGUS or smoldering myeloma were assigned to low (0 or 1 risk factor) or high (2 or 3 risk factors or smoldering multiple myeloma (SMM)) risk of progression to MM based on the IMWG consensus statement (Leukemia. 2010, June; 24(6); 1121-7). We measured 25 hydroxyvitamin D levels, IL-6, and the RANKL/OPG ratio via enzyme linked immunosorbent assay (ELISA). Patients with low levels of 25 hydroxyvitamin D were treated with 6,000 units of cholecalciferol daily for 8 weeks and then 2,000 units daily thereafter. Repeat levels of 25 hydroxyvitamin D, interleukin-6 (IL-6), and RANKL/OPG were repeated after three months of cholecalciferol therapy. Results: Total enrollment was 43 patients, with 26 patients with low risk disease and 17 patients with high risk disease. There was no significant difference in IL-6, OPG, RANKL, or the RANKL/OPG ratio levels between patients with low versus high risk disease. Patients with SMM versus patients with MGUS had higher levels of IL-6 RANKL and the RANKL/OPG ratio. 14 patients were found to have vitamin D deficiency with 25 hydroxyvitamin D <25ng/mL, 5 high risk and 9 low risk patients. There was no difference in IL-6 levels in patients with or without vitamin D deficiency. Patients with vitamin D deficiency had an increased RANKL and the RANKL/OPG ratio. With cholecalciferol supplementation in deficient patients, the average vitamin D level in deficient patients increased from 16.6 to 25.34 ng/mL while the RANKL/OPG ratio decreased (241.99 vs. 115.32, p-value .041) and the serum free light chain ratio improved (median improvement of 6, p-value=.013). Conclusions: These data provide clues that vitamin D deficiency is pervasive in MGUS . Additionally, hypovitaminosis D and its correction modulates the RANKL/OPG ratio that could play a pivotal role between osteoblasts and osteoclasts. Further study is required to determine if alterations in bone metabolism and the correction of abnormal metabolism can alter the disease course of patients with MGUS, especially serum free light chains and bone marrow plasma cells (PC) and the PC karyotype. This trial was conducted with IRB approval from the University of Kansas Medical Center. Table 1. RANKL, OPG, and RANKL/OPG ratios for SMM versus MGUS patients with 0,1, or two risk factors and patients with vitamin D deficiency versus those without vitamin D deficiency. SMM MGUS 0,1,2 p-value 25 hydroxyvitamin D<25 ng/mL 25 hydroxyvitamin D >25 p-value RANKL (pg/mL) 65500.76 13819.97 .041 50216.25 10387.77 .044 OPG (pg/mL) 180.59 164.81 .25 177.78 163.46 .60 RANKL/OPG 252.66 110.04 .06 241.99 73.25 .034 Disclosures Yacoub: seattle genetics: Membership on an entity's Board of Directors or advisory committees; sanofi: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Yacoub et al report excellent responses to pegylated interferon alfa-2a in patients with hydroxyurea-resistant/intolerant polycythemia vera or essential thrombocythemia.

Background:Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role.1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF.4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi.Methods:This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg).Results:23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets <100 K/uL, of which 8 patients had platelets <50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of > 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of > 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets <100 K/uL, had treatment duration of 6 months or more.Summary/Conclusion:Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.

Background:Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ∼6–7 month median overall survival (OS) in the relapsed/refractory (r/r) setting. Splenomegaly is a major cause of morbidity, is a poor prognostic factor and has emerged as a potential therapeutic target in CMML. Tagraxofusp (SL‐401) is a targeted therapy directed to CD123, a target expressed on CMML blasts, monocytes and neoplastic microenvironmental plasmacytoid dendritic cells (pDCs) that are part of the CMML malignant clone, as well as on a variety of additional malignancies. Tagraxofusp was approved by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is being investigated in other CD123‐expressing malignancies.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with CMML.Methods:This multicenter, open‐label, Phase 1/2 clinical trial is enrolling patients with CMML. In Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), every 28 days (cycles 5–7), and every 42 days (cycles 8 and beyond). In Stage 2 (expansion), patients receive the RP2D (12 mcg/kg).Results:20 patients with CMML (CMML‐1 [n = 12]; CMML‐2 [n = 8]) were treated with tagraxofusp, including 18 in the relapsed/refractory setting, with hypomethylating agents (HMAs) being the most commonly administered prior therapy. Median age was 69 years (range 43–80) and 80% were male. 10 patients (50%) had baseline splenomegaly (defined as spleen palpable below the left costal margin [BCM]), of which 6 had baseline splenomegaly ≥ 5 cm BCM. Most common treatment‐related adverse events (TRAEs, incidence ≥ 20%) were hypoalbuminaemia, thrombocytopenia, nausea, vomiting and fatigue. Most common ≥ grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome was reported in 3 patients (grade 1–2). 100% (10/10) of patients with baseline splenomegaly had a spleen response by physical exam: 80% (8/10) had spleen size reduction of ≥ 50% and 67% (4/6) with baseline spleen size ≥ 5 cm had spleen size reduction of ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp.Summary/Conclusion:Tagraxofusp demonstrated single agent activity in patients with CMML and splenomegaly, an area of potential unmet medical need. Given the expression of CD123 in CMML, tagraxofusp represents a rational therapeutic approach in this disease. Updated data will be presented, and a registrational trial is planned. Trial information: NCT02268253.

Abstract Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.

BACKGROUND Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double‐blind, placebo‐controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer. METHODS Patients with metastatic colorectal cancer who progressed on first‐line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28‐day cycle. Crossover was not allowed. The primary endpoint was progression‐free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1‐sided α value of .1. RESULTS One hundred eighty‐one patients were randomized (120 to regorafenib‐FOLFIRI and 61 to placebo‐FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib‐FOLFIRI than placebo‐FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53‐1.01; log‐rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71‐1.44). The response rate was higher with regorafenib‐FOLFIRI (34%; 95% CI, 25%‐44%) than placebo‐FOLFIRI (21%; 95% CI, 11%‐33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS The addition of regorafenib to FOLFIRI as second‐line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society .

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.