Shum, M.

Abstract Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in 2 cohorts, 1 for patients with CAD and the other for those with wAIHA. In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks. Safety end points included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy end points included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and functional assessment of chronic illness therapy (FACIT)-fatigue scale. Thirteen of 13 (100%) and 10 of 11 (91%) patients with CAD and wAIHA, respectively, experienced at least 1 TEAE. Ten patients had at least 1 serious AE; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (−1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective for patients with CAD and wAIHA. This trial was registered at www.ClinicalTrials.gov as #NCT03226678.

Abstract Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who cannot tolerate or who are not eligible for autologous or chimeric antigen receptor T cell (CAR-T) therapy have limited therapeutic options and suboptimal long-term outcomes. In patients who were not eligible for HSCT, the rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) regimen (and variations using methylprednisolone or carboplatin/oxaliplatin) have shown an overall response rates (ORR) of ~50%, a complete response (CR) rate of ~25% (Gopal, Leuk Lymphoma, 2010), and a median progression-free survival (PFS) and an overall survival (OS) of 3 and 9 months, respectively (Crump, Hematol Oncol Clin N Am. 2016; Gopal Leuk Lymphoma, 2010; Ng, Br J Cancer, 2005; Sirohi, Hematology, 2007; Barton, Eur J Haematol. 2015; Moccia Leuk Lymphoma, 2017). Selinexor is an oral small molecule selective inhibitor of exportin-1 (XPO1) mediated nuclear export (SINE) compound leading to activation of tumor suppressor proteins and reduction in oncoprotein levels. It also reduces the expression of deoxyribonucleic acid (DNA) damage repair proteins and therefore potentiates DNA damage-based therapies leading to an increased death of cancer cells. Selinexor has synergistic effects with gemcitabine and cisplatin, and enhanced anti-lymphoma effects with dexamethasone. In the SADAL study (n=134), single-agent oral selinexor 60 mg twice weekly induced an ORR of 29% and a CR rate of 13% in patients with RR DLBCL. The response rates were consistent across various subgroups including patients <70 vs ≥70 years old, those with de novo and transformed DLBCL, and GCB and non-GCB subtypes of DLBCL. The median duration of response (DOR) was 9.3 months, and 23 months for patients who achieved CR. OS was 9.0 months. In June 2020, selinexor monotherapy was approved in the US for the treatment of adult patients with RR DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor in combination with R-GDP was evaluated in a Phase 1 clinical trial (SELINDA), in which patients with DLBCL received either 40 or 60 mg selinexor once or twice weekly in combination with standard dose R-GDP. The recommended phase 2 dose for further exploration was 40 or 60 mg once weekly with an ORR of 60-80%. Therefore, combining selinexor with R-GDP is expected to improve response rates, and continuation of treatment with single-agent selinexor is expected to prolong the duration of responses, improve PFS (and potentially OS) in patients with RR DLBCL. Materials and methods: XPORT-DLBCL-030 is a Phase 2/3, multicenter study. The Phase 2 portion of the study is an open-label randomized study to identify the optimal dose of selinexor (40 or 60 mg) in combination with R-GDP in patients (n=120) with RR DLBCL. Patients ≥18 years with 1-3 prior lines of therapy and ECOG performance status ≤2 who are not intended for HSCT or CAR-T therapy are randomized 1:1:1 to one of 3 treatment arms: Arm 1: selinexor 40 mg+R-GDP (S40+R-GDP); Arm 2: selinexor 60 mg+R-GDP (S60 + R-GDP); Arm 3: R-GDP. Combination treatment will be given for up to 6 cycles (21 days/cycle). After completing the SR-GDP combination therapy (EoC), patients in Arms 1 and 2 who reach at least partial response (PR), will receive weekly single-agent selinexor 60 mg (28 days/cycle) as "continuous therapy" until disease progression (PD) or unacceptable toxicity. After PD, patients will be followed up for survival. Patients in the R-GDP arm will be followed up for PD and survival. Patients who are ineligible for HSCT due to an active disease, or those who have primary refractory DLBCL, defined as no response or relapse within 6 months after ending first-line treatment, will be allowed to enroll in the study (up to 15% and 25%, respectively of all patients enrolled). The primary endpoint of the study is ORR according to the Lugano 2014 criteria. Secondary endpoints include PFS, OS, ORR-EoC, DOR and incidence and severity of adverse events. Figure 1 Figure 1. Disclosures Pinto: Takeda: Consultancy; MSD: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Canales: Sanofi: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Ma: Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Li: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arriola: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arazy: 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. 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) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease characterized by hemolysis mediated by autoantibodies directed against red blood cells (RBC). AIHA is classified as either warm (60-70%), or cold agglutinin disease (CAD, 20-25%), depending upon the temperature at which the autoantibodies show maximum binding. Warm AIHA is mediated by warm reactive autoantibodies, which are usually of the immunoglobulin G class (IgG). Almost 90% of CAD is medicated by monoclonal antibodies of IgM class. The diagnosis of wAIHA or CAD is based on the presence of hemolytic anemia, signs of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. Complement plays an important role in warm antibody AIHA. When erythrocytes are heavily coated with immunoglobulin, the amount of antigen-antibody complex can be sufficient for binding complement protein complex C1, thereby activating the classical complement pathway. CAD is almost entirely a complement-dependent disorder. Cold antibodies (IgM) temporarily bind to the RBC membrane, activate complement, and deposit complement factor C3 on the cell surface. These C3-coated RBCs are cleared slowly by the macrophages of the liver through extravascular hemolysis. Less frequently, the complete complement cascade is activated on the cell surface, resulting in the insertion of membrane attack complex C5b to C9 and intravascular hemolysis. Therefore, treatment with inhibitors of complement cascade may halt or at least attenuate acute complement mediated hemolysis in AIHA patients and improve recovery of RBC destruction. Aims: This Phase 2, open-label study is being conducted in the US and Italy to assess the safety, tolerability, efficacy, and PK of multiple subcutaneous (SC) doses of APL-2 administered daily in subjects with wAIHA or CAD. Methods: Patients with primary AIHA are eligible. Patients are required to have hemoglobin (Hb) levels <11 g/L, signs and symptoms of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. The study will recruit 12 subjects with wAIHA and 12 subjects with CAD. APL-2 270 mg/d or 360 mg/d will be administered for 48 weeks. Efficacy is assessed by change from baseline in Hb, transfusion requirements, reticulocytes, lactate dehydrogenase (LDH), haptoglobin, bilirubin, and FACIT fatigue score. Endpoints will be assessed at Weeks 8, 12, 44, and 48. Results: 2 subjects with CAD (Subject 1: 270 mg/d; Subject 2: 360 mg/d) have been treated for at least 8 weeks and up to 12 weeks; 2 subjects with wAIHA (Subject 3: 270 mg/d; Subject 4: 360 mg/d) have been treated for at least 4 weeks. Subject 1 screened with Hb (NR 13.5 g/dL-17.5g/dL) of 10.0 g/dL and reported an increase to 13.0 g/dL at Week 12, with reticulocyte (NR 30-100 10^9/L) reduction from 99.6 10^9/L at Week 2 to 56.34 10^9/L at Week 8 (screening/baseline values not available). Subject 2 had baseline Hb of 7.9 g/dL and reported an increase to 13.6 g/dL at Week 8, with reticulocyte reduction from 154.34 10^9/L at baseline to 67 10^9/L at Week 8. Subject 3 had baseline Hb of 8.0 g/dL and reported an increase to 11.2 g/dL at Week 4, with reticulocyte reduction from 223.44 10^9/L at baseline to 27.12 10^9/L at Week 4. Subject 4 did not show signs of haematological improvement by Week 4, and the principal investigator decided to discontinue the subject at Day 42. Subject 1 had LDH levels within the normal range (100-200 I/U) at screening and remained normal through the study. Subjects 2 reported a baseline LDH of 339 I/U with a reduction to within NR to 107 I/U at Week 8. Subject 3 reported a baseline LDH of 235 I/U, which was also reduced to within NR at Week 4 to 123 I/U. Subject 1 had consistent indirect bilirubin (NR 0.2-0.7 mg/dL) through the study with a baseline value of 1.5 mg/dL and a Week 12 value of 1.4 mg/dL. Subject 2 had a reduction in indirect bilirubin with a baseline value of 1.3 mg/dL and a Week 8 value of 0.5 mg/dL.To date, APL-2 has generally been well-tolerated. No significant infections have been observed. Summary/Conclusions: Interim results demonstrate that systemic inhibition of C3 with APL-2 has demonstrated positive trends in haematological parameters in patients with wAIHA and CAD as early as Week 4. To date, APL-2 has been safe and well tolerated. The study is ongoing and will enroll up to 12 subjects with wAIHA and 12 subjects with CAD. Disclosures Grossi: Apellis Pharmaceuticals: Employment, Equity Ownership. Gertz:spectrum: Consultancy, Honoraria; Medscape: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Apellis: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; janssen: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; celgene: Consultancy; Abbvie: Consultancy; annexon: Consultancy. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Stout:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background:Autoimmune haemolytic anaemia (AIHA) is characterized by haemolysis mediated by autoantibodies directed against red blood cells (RBCs). Warm antibody (wAIHA; 60%>70%) and cold agglutinin disease (CAD; 20%>25%) subclasses are defined by the immunoglobulin (Ig) isotype involved and its thermal optimum for binding RBCs. wAIHA is mediated by IgG while 90% of CAD is mediated by IgM isotypes. CAD and wAIHA outcomes can be life‐threatening, but no therapies are approved. Complement C3b deposition on RBCs plays a central role in AIHA, accelerating phagocytosis in the liver and/or spleen (extravascular haemolysis) and forming membrane attack complexes (intravascular haemolysis). By blocking formation of C3b, APL‐2, a cyclic peptide, has potential as a novel therapeutic for AIHA.Aims:To assess whether inhibiting complement C3 with daily subcutaneous (SC) doses of APL‐2 (270 mg/day or 360 mg/day) prevents intra‐ and extravascular haemolysis in AIHA subjects, reducing anaemia associated signs and symptoms.Methods:Subjects with primary AIHA were eligible for this Ph 2 open‐label study to assess the safety, tolerability, efficacy, and pharmacokinetics of APL‐2. Subjects had haemoglobin (Hb) levels < 11 g/dL, signs of haemolysis, and a positive direct agglutinin test (DAT) for IgG and/or complement C3. Twenty‐four subjects (13 CAD, 11 wAIHA) were recruited and will be treated with APL‐2 for 48 weeks. Efficacy was assessed by change from baseline in Hb, transfusion requirements, absolute reticulocyte counts (ARC), lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin (INDBIL), and Functional Assessment of Illness Therapy (FACIT) fatigue score. Data are reported after 16 weeks (Day 112).Results:Two of 13 CAD subjects withdrew; 7 of 11 remaining subjects reached Day 112. Mean Hb (standard error [SE]) increased from 8.9 (0.4) [n = 13] to 11.6 (0.5) [n = 7] g/dL, and mean LDH, ARC, and INDBIL returned within normal range. Mean FACIT scores (SE) increased 9.9 (3.4) points from baseline. Two subjects had pre‐study and 1 had on‐study transfusions (normalized to 112 days). All 13 CAD experienced ≥1 treatment‐emergent adverse event (TEAE), mainly Grade 1–2 and unrelated. Four subjects reported 10 unrelated serious adverse events (SAEs) (6 SAEs in 1 subject). Three subjects experienced 3 unrelated Grade 3 TEAEs (pneumonia, dyspnoea, hypertension); 1 subject reported 2 unrelated Grade 4 TEAEs (high calcium, high creatinine) and withdrew.Eight of 11 wAIHA subjects were DATmonoC3+ and 3 were DATmonoC3‐. Two of 3 DATmonoC3‐ withdrew for lack of response and efficacy data are reported for 8 DATmonoC3+ subjects. Six of these reached Day 112. Mean Hb (SE) increased from 9.2 (0.3) [n = 8] to 10.8 (0.5) [n = 6] g/dL, and mean ARC and INDBIL returned within normal. Mean FACIT scores (SE) increased 2.7 (2.8) points from baseline. One subject had pre‐study and 2 had on‐study transfusions (normalized to 112 days). Ten of 11 wAIHA (C3+ and C3‐) experienced ≥1 TEAE, mainly Grade 1–2 and unrelated. Five subjects reported 8 unrelated SAEs. Five subjects experienced 13 unrelated Grade 3 TEAEs (oral squamous cell carcinoma, haemolytic flare, purpura, acute kidney injury, dyspnoea, chest pain); 1 subject reported 1 unrelated Grade 4 TEAE (haemolytic flare) and withdrew. Six‐month data for 10 CAD and 6 wAIHA C3+ is planned for June 2019.Summary/Conclusion:APL‐2 increases Hb values in CAD and wAIHA C3+ within the first weeks of treatment with sustained benefit with longer exposure. APL‐2 reduces intra‐ and extravascular haemolysis shown by reductions in LDH, INDBIL, and ARC. APL‐2 appears to be safe and well‐tolerated.