β-Thalassemia: evolving treatment options beyond transfusion and iron chelation

After years of reliance on transfusion alone to address anemia and suppress ineffective erythropoiesis in β-thalassemia, many new therapies are now in development. Luspatercept, a transforming growth factor–β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading. However, many patients do not respond to luspatercept, so additional therapeutics are needed. Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis. Genetically modified autologous hematopoietic stem cell transplantation offers the potential for lifelong transfusion independence. Through a gene addition approach, lentiviral vectors have been used to introduce a β-globin gene into autologous hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400, respectively. Results from the many clinical trials for these agents will yield results in the next few years, which may end the era of relying on transfusion alone as the mainstay of thalassemia therapy.

Patient and Physician Preferences for Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) in Patients Not Candidates for Intensive Chemotherapy

Background The number of targeted antileukemic therapies for the treatment of AML has increased over the past decade. However, for patients who are not candidates for high intensive chemotherapy (HIC), a better understanding is needed of what treatment attributes patients and physicians value and how their preferences differ to potentially improve treatment satisfaction. Objective To understand the impact of treatment attributes on treatment selection, we quantified the preferences of: a) patients newly diagnosed with AML who are not candidates for HIC; and, b) the physicians who treat them. Methods A discrete choice experiment (DCE) was performed to quantify the extent to which treatment attributes impact patients' and physicians' treatment decisions in various scenarios. A literature review was conducted to identify treatment attributes important to patients with AML. Following the review, one-on-one phone interviews were conducted with patients (United States [US], n=3; United Kingdom [UK], n=3) and physicians (US, n=2; UK, n=2) to finalize the attributes and levels included in the DCE. Patients who were eligible to participate in the online survey were adults with a self-confirmed AML diagnosis, who had not relapsed or been refractory to treatment, had not received a stem cell transplant, and had not received HIC or met one of the following criteria: aged ≥75 years, diagnosis of congestive heart failure, chronic kidney disease, or other types of cancer, or ECOG score of 3 or 4. Physicians included hematologists/ oncologists treating >5 patients with AML over the past year. The web-based DCE included choice cards showing 2 hypothetical treatment profiles with 6 attributes (chance of 2-year overall survival [OS], average quality of life [QoL], risk of serious infections, risk of grade 3/4 nausea, chance of achieving transfusion independence, and duration of hospitalization per year) at varying levels. Participants chose a preferred treatment for each choice card. Conditional logit regression models were used to estimate preference weights and to analyze the impact of treatment attributes on participants' choices. Results The DCE was completed by 77 patients newly diagnosed with AML who had not received HIC (US, n=47; UK, n=30) and 145 physicians (US, n=48; UK, n=52; Canada, n=29; Australia, n=16). Mean patient age was 71.4 years; 51.9% were female. Mean (SD) time since AML diagnosis was 8.3 (8.2) months. Most physicians were hematologists (81.4%) and saw a median of 30 AML patients yearly. For patients, duration of hospitalization (decrease from 6 to 2 weeks/year) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point QoL scale) and chance of 2-year OS (increase from 15% to 40%; Figure). Based on these findings, we estimated that patients were willing to accept a decrease in 2-year OS (from 40% to 15%) or an increase in risk of serious infections (from 5% to 20%) to decrease time spent hospitalized (from 6 to 2 weeks per year). For physicians, chance of 2-year OS (from 15% to 40%) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point scale), risk of serious infections (from 20% to 5%), and risk of grade 3/4 nausea and vomiting (from 20% to 1%; Figure). Based on these findings, we estimated that physicians were willing to accept an increased risk of grade 3/4 nausea and vomiting (from 10% to 20%) in exchange for decreased time in hospital (from 6 to 2 weeks per year) and increased chance of achieving transfusion independence (from 35% to 55%) when other treatment attributes remained stable. Conclusion Significant differences in treatment attribute importance for patients with newly diagnosed AML who had not received HIC were observed between patients and physicians. Patients most valued treatments that reduced hospitalization duration while physicians most valued treatments that improved chance of 2-year OS. These differences highlight the importance of a shared decision-making process when choosing treatments for patients with AML ineligible for HIC. However, given the variability among individual patients, it may be particularly worthwhile for physicians to initiate a discussion with patients prior to treatment selection to determine what treatment attributes each patient values most. Treatment selection could then be tailored based on attributes most valued by the patient and likely lead to improved treatment satisfaction. Figure 1 Figure 1. Disclosures Zhou: Astellas Pharma, Inc.: Consultancy. Yang: Astellas Pharma, Inc.: Consultancy. Song: Astellas Pharma, Inc.: Consultancy. Marshall: Astellas Pharma, Inc.: Consultancy; Arthur JE Child Chair: Other: Indirectly related salary support. Griffin: Novartis: Patents & Royalties: Post marketing royalties from midostaurin; Astellas Pharma, Inc.: Consultancy. Saini: Astellas Pharma, Inc.: Consultancy, Honoraria. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect.

Clinical Efficacy of JAK Inhibitors in Patients with Vexas Syndrome: A Multicenter Retrospective Study

Background VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation (Bourbon et al. Blood 2021). Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, we report some clinical efficacy of JAK inhibitors (JAKi) in VEXAS patients. Patients We analyzed retrospectively 24 UBA1 mutated patients (Met41 or previously reported alternative splicing site) treated with JAKi (11 with ruxolitinib (RUXO), 11 with tofacitinib (TOFA), 1 with baricitinib, 1 with upadicitinib) in 7 French, 1 Portugese and 2 US centers. Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (C reactive protein, CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively. Results All 24 patients were males with a median age at VEXAS diagnosis of 72 years [range 54-89]. Thirteen had documented myeloid neoplasia (MN) (1 CMML-0, 1 other MDS/MPN, 10 MDS). Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). IPSS-R was very low/low/intermediate in 8/3/2 cases respectively. Median time between first VEXAS related clinical manifestations and JAKi onset was 2.45 years [0.15-5.45]. Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments [range 0-9]. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with RUXO, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi (figure A). After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the RUXO group as compared to 25% and 25 % in patients treated with other JAKi (8 evaluable patients) (p=0.0036 et 0.0055 respectively, figure B). RUXO efficacy was similar in patients with (n=9) or without (n=2) associated MN. In RUXO treated patients, median CRP and steroid dose reduction was 72.5% [range 21.5- 99.5] and 66.25% [range 0-75] respectively at 3 months. With a median follow-up of 4 months [range 1.4-12], only 1 RUXO treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi (figure C). Of the 13 patients with MN, 7 were RBC transfusion dependent at JAKi onset (6 with RUXO, 1 with other JAKi). Four of 6 patients treated with RUXO achieved RBC transfusion independence at 3 months, but not the patient treated with other JAKi. Regarding safety, severe adverse events were reported in 6 patients: 3 deep vein thrombosis, (2 with TOFA/1 with RUXO), 1 pneumonia (RUXO), 1 enterohemorrhagic E. Coli infection (RUXO), and 1 lethal legionellosis (TOFA)). Conclusion Ruxolitinib (and less often other JAK inhibitors used in this study) provides rapid response in most VEXAS patients, allowing in two third of the cases corticosteroid dose reduction/withdrawal and RBC transfusion independence in 4/6 patients with MN who were initially transfusion dependent. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of RUXO on VEXAS patients with concomitant MN will soon be studied prospectively in a Groupe Francophone des Myélodysplasies (GFM) clinical study. Figure 1 Figure 1. Disclosures Galicier: Novartis Pharma Sas, Sanofi Aventis France: Consultancy; Lilly France, Baxalta France, Sanofi Aventis France Sas: Other: Payments as Speaker for Educational Program; Shire France SA, Janssen-Cilag, Pfizer Sas: Other: Invitation to Congress. Hirsch: Novartis Pharma: Consultancy; Daiichi Sankyo Oncology: Consultancy. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding. Fenaux: Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Efficacy and Safety of Eltrombopag Combined with Cyclosporine As First-Line Therapy in Adults with Severe Acquired Aplastic Anemia: Results of the Interventional Phase 2 Single-Arm Soar Study

Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months; responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL; platelet count ≥20,000/μL; automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart; transfusion restrictions were also applied. For the primary endpoint to be considered 'clinically meaningful' at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%; 95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%; n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%; n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%; non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts; 45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3]; COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]); no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. Figure 1 Figure 1. Disclosures Vallejo: Novartis: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Finelli: Takeda: Consultancy; Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding; Alexion Brasil: Consultancy; Instituto Butantan: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals Inc: Consultancy, Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Consultancy; Roche: Consultancy; Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

Evaluation of the Long-Term Safety and Efficacy of Pegcetacoplan Treatment for Paroxysmal Nocturnal Hemoglobinuria Patients: An Extension Study

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening disease characterized by complement mediated hemolysis and thrombosis. Current C5-inhibitors, such as eculizumab and ravulizumab, are able to partially treat these symptoms by controlling intravascular but not extravascular hemolysis, manifesting as persistent anemia in up to 72% of treated patients and transfusion dependence in up to 36% of patients. Pegcetacoplan (PEG) is a Food and Drug Administration (FDA)-approved C3-inhibitor that controls both intravascular and extravascular hemolysis (IVH and EVH). In the PEGASUS phase 3, multi- center, active-comparator controlled, randomized trial (NCT03500549), improvements in hemoglobin levels from baseline to Week 16 demonstrated the superiority of PEG over eculizumab; 85% of the patients receiving PEG achieved transfusion independence when compared with the 15% of patients on eculizumab. The extension study will evaluate the long-term safety and efficacy of PEG in patients with PNH. Acute hemolytic (AH) events occurred during the PEG clinical development program. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with PEG Aims: Determine the long-term safety and efficacy of PEG for PNH treatment, as well as evaluate a treatment regimen to address acute hemolytic (AH) events in these patients. Study Design: The PEG extension study (NCT03531255) is an active, multi-center, open-label, non-randomized trial with an estimated enrollment of up to160 adult PNH patients (≥18 years), who have completed prior PEG trials - phase 1b PADDOCK (NCT02588833) and PHAROAH (NCT02264639), phase 2a PALOMINO (NCT03593200), and the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) trials. The main study will determine long-term safety and efficacy of PEG dosing on complement-mediated hemolytic activity, hemoglobin levels, and transfusion independence in PNH patients. For enrolled subjects experiencing AH episodes, a substudy to evaluate safety and efficacy of intensive SC or IV dosing of PEG acute treatments will be offered. Dose adjustments will be offered for AH subjects declining to enter the substudy, but continuing to participate in the main study. Inclusion criteria for the management of AH substudy specify that lactate dehydrogenase (LDH) levels in patients must be >2 times the upper limit of normal, accompanied by new or worsening clinical signs of hemolysis (hemoglobinuria, fatigue, decreased hemoglobin, etc.). Notable exclusion criteria include subjects who have withdrawn from a previous PEG trial, co-morbidities and infections that can enhance risk profiles for adverse events or confound study interpretation, and complement deficiency. The safety population consisting of patients that will receive at least one dose of the drug will be used for all efficacy analyses. Descriptive statistics will be used in documenting changes from baseline, along with qualitative descriptors (improved, maintained, or worsened). Intervention: Patients in the long-term extension study receive subcutaneous (SC) administration of 1080 mg PEG twice weekly, every 3 days, or 3 times weekly. For AH events substudy, patients with steady-state PEG dose of 1080 mg SC twice weekly will receive a loading dose of 1080 mg IV once, or 1080 mg SC every 24 hours for 3 doses, followed by increase in maintenance dose to 1080 mg SC every 3 days; for those receiving 1080 mg SC every 3 days, identical loading dose will be followed by subsequent maintenance dose of 1080 mg SC 3 times weekly. Primary and Secondary Outcome Measures: The study will monitor safety outcomes such as occurrence and severity of adverse events within a 2-year timeframe from baseline. Additional biomarkers include recurrent acute hemolysis, thromboembolism, laboratory and electrocardiogram (ECG) parameters. Efficacy endpoint measurements over a 48-week timeframe include mean change from baseline levels of hemoglobin, LDH, and indirect bilirubin, absolute reticulocyte counts, RBC transfusions, and functional assessment of fatigue scale scores. Results: Trial results are anticipated in 2022, upon study completion. Disclosures Hoffman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Machaidze: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weitz: Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Novartis Corporation: Consultancy, Honoraria; Sanofi Genxyme: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is a Food and Drug Administration approved C3-inhibitor that controls both intravascular and extravascular hemolysis. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with pegcetacoplan.

Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents

Background: Patients with higher-risk myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and poor prognosis with a median overall survival (mOS) of 4-6 months. Lack of response to HMA therapy, advanced age at relapse, male sex, bone marrow blasts >5% and high risk disease classification by International Prognostic Scoring System (IPSS) confer worse outcomes. Eltanexor is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound with markedly reduced brain penetration relative to selinexor in preclinical models. This is believed to result in attenuation of centrally mediated anorexia, weight loss, and nausea, allowing for more frequent dosing. Early results from a phase 1/2 study of eltanexor in patients with higher-risk HMA-refractory MDS demonstrated marrow complete responses (mCRs), hematologic improvement (HI) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee EHA 2021). Here we provide an update on baseline characteristics, blast reduction in mCR patients, extent of transfusion independence and additional subgroup analyses. Methods: This phase 1/2 study (NCT02649790) evaluated oral eltanexor monotherapy in patients with high-risk or intermediate-2 by IPSS and 5%-19% myeloblasts. Of 20 patients enrolled, 15 patients were evaluable for efficacy and constitute the population studied in this analysis; 5 patients were non evaluable for efficacy due to trial discontinuation prior to response assessment. Two doses of eltanexor were evaluated: 10 mg (n=5) or 20 mg (n=10) each given qd 5 days per week. Results: Amongst the 15 efficacy evaluable patients, there were 8 males, median age 76 years (range 62-89), 10.0% (range 7-18%) median bone marrow blasts at enrollment, and with a median of two prior regimens (range 1-4). All patients primary HMA-refractory MDS; 9 patients (60%) with high risk and 5 (33%) with intermediate-2 per IPSS, 1 with intermediate-1 per IPSS. Similarly, using the global MD Anderson Cancer Center risk prognosis model, 14 patients (93%) had intermediate-2 or high-risk MDS. The overall response rate (mCR+HI) was 53% including 47% mCRs. Additionally, 5 patients (33%) had SD. Median blast reduction in the 7 patients with mCR was 78.6% (range 55.6%, 85.7%). Four patients had hematologic improvement (HI) including 2 patients with tri-lineage HI. Of the 7 patients who achieved mCR, 4 had significant reduction in transfusion requirements with 3 of these patients achieving complete transfusion independence for 5-10 cycles. In the 10-mg cohort (n=5), all patients derived clinical benefit with 3 patients reaching mCR and 2 patients with SD. In the 20-mg cohort (n=10), 4 patients had mCR and 3 had SD. Median overall survival for all efficacy evaluable patients was 9.86 months. OS for patients who reached mCR (n=7) was significantly longer than for patients who did not reach mCR (n=8): median 11.86 vs 8.67 months (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for patients with PD (n=3, mOS=3.15 months, HR=0.23, p=0.04). Notably, mCR was seen in the 3 patients treated with >2 prior therapies and/or with secondary MDS: 1 patient with secondary MDS and 4 prior therapies; 1 with secondary MDS and one prior therapy; and 1 with de novo MDS and 3 prior therapies). Conclusions: Single-agent oral eltanexor was active in patients with higher-risk, primary HMA-refractory MDS including those with secondary MDS or with >2 lines of prior therapy. Patients with mCR had significantly longer mOS than patients without mCR and had median blast reduction of 78.6%. Further evaluation of eltanexor in MDS as a single agent and in combination with other agents is ongoing. Disclosures Lee: Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mohan: Astex: Research Funding; Incyte: Research Funding. Knupp: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Karasik: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bai: Abbvie: Current equity holder in publicly-traded company; Takeda: Current Employment, Current equity holder in publicly-traded company; Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Bhatnagar: Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Novartis: Honoraria; Sumitomo Dainippon Pharma: Research Funding.

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150)

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Novel agents for myelodysplastic syndromes

Review objective There have been several advances in the field of myelodysplastic syndromes over the past year, yielding two new US Food and Drug Administration drug approvals. The pharmacology, pharmacokinetics, clinical trials, therapeutic use, adverse effects, clinical use controversies, product description, and upcoming trials for myelodysplastic syndromes novel agents luspatercept-aamt and decitabine/cedazuridine are reviewed. Data sources This review article utilized primary information obtained from both the published studies involved in the approval of luspatercept-aamt and decitabine/cedazuridine and package inserts for the respective medications. This review article utilized secondary information obtained from National Comprehensive Cancer Network guidelines using filters and keywords to sustain information relevancy as well as key studies using the keywords, “luspatercept-aamt, myelodysplastic syndromes, decitabine, cedazuridine, hypomethylating agent, ASTX727” from scholarly journal database PubMed. Data summary Myelodysplastic syndromes consist of myeloid clonal hemopathies with a diverse range of presentation. Until recently, there have been relatively few new therapies in the myelodysplastic syndromes treatment landscape. On April 3, 2020 the US Food and Drug Administration approved Reblozyl®(luspatercept-aamt), then on July 7, 2020, the US Food and Drug Administration approved INQOVI® (decitabine and cedazuridine). Luspatercept-aamt acts as a erythroid maturation agent through differentiation of late-stage erythroid precursors. The safety and efficacy of luspatercept-aamt was demonstrated in the MEDALIST trial, a phase III trial in patients with very low-intermediate risk refractory myelodysplastic syndromes and ring sideroblasts. Luspatercept-aamt met both primary and secondary endpoints of transfusion independence of 8 weeks or longer and transfusion independence of 12 weeks or longer, respectively. Decitabine/cedazuridine has a unique mechanism of action in which decitabine acts as a nucleoside metabolic inhibitor promoting DNA hypomethylation and cedazuridine then prevents degradation of decitabine. The safety and efficacy of decitabine/cedazuridine was shown in the ASCERTAIN study, a phase III trial in patients with intermediate or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. The primary outcome evaluated was 5-day cumulative area under the curve between decitabine/cedazuridine and IV decitabine as well as additional outcomes including safety. Decitabine/cedazuridine met primary outcome and had a similar safety profile to IV decitabine. Conclusion The novel myelodysplastic syndromes agents luspatercept-aamt and decitabine/cedazuridine provide a clinical benefit in the studied populations.