Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP.

Immune thrombocytopenia (ITP) is a disorder characterized by low platelets due to increased clearance and decreased platelet production. While ITP has been characterized as an acquired disorder of the adaptive immune system, the resulting platelet autoantibodies provide ancillary links to the innate immune system via antibody interaction with the complement system. Most autoantibodies in patients with ITP are of the IgG1 subclass, which can be potent activators of the classical complement pathway. Antibody-coated platelets can initiate complement activation via the classical pathway leading to both direct platelet destruction and enhanced clearance of C3b-coated platelets by complement receptors. Similar autoantibody interactions with bone marrow megakaryocytes can also result in complement injury and ineffective thrombopoiesis. The development of novel therapeutic complement inhibitors has revived interest in the role of complement in autoantibody-mediated disorders, such as ITP. A recent early-phase clinical trial of a classical complement pathway inhibitor has demonstrated efficacy in a subset of ITP patients refractory to conventional immune modulation. In this review, we will analyse the role of complement in refractory ITP.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 µmol/L on-treatment versus 52.1 µmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.

Sutimlimab improves quality of life in patients with cold agglutinin disease: results of patient-reported outcomes from the CARDINAL study.

Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks' patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0-47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0-51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017.

Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria.

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11%-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four-times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase 3 studies, ravulizumab was noninferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor-naive patients], 4.0% vs 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs 5.1%). In the current analysis, patient-level data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase 3 PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 µg/mL); four (80.0%) were temporally associated with complement-amplifying conditions (CACs). Of the 22 events occurring in eculizumab-treated patients, eleven were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CACs only. Five events were unrelated to free C5 elevation or reported CACs. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. Clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.

Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series.

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hematologic disease characterized by chronic complement-mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL-2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open-label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment-emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6-8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well-tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.

A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia.

The combination of rituximab, cyclophosphamide, and dexamethasone (RCD) is highly effective in the treatment of warm autoimmune hemolytic anemia (WAIHA) associated with chronic lymphocytic leukemia (CLL). We treated a cohort of patients with relapsed/refractory WAIHA, without CLL, with RCD. The primary objective was to evaluate the overall response (OR) of RCD therapy. Complete response (CR) was defined as a hemoglobin (Hgb) ≥12 g/dL. Partial response (PR) was defined as Hgb 10-11.9 g/dL or ≥2 g/dL increase in Hgb. Sustained response was defined as Hgb ≥10 g/dL with no treatment changes. A total of 16 patients with relapsed/refractory WAIHA received RCD (7 primary WAIHA, 9 secondary WAIHA) for a median of 4 cycles (range: 2-6). The median pretreatment Hgb was 10.0 g/dL (range: 4.3-12.2). The median best Hgb achieved was 12.5 g/dL (range: 10.6-15.1) with a median of 2 cycles until best Hgb response. The OR was 94% (11 CR, 4 PR). Two immunocompromised patients were admitted for infections during RCD treatment. There were no deaths during the treatment or follow-up period. Following a response to RCD, 4 patients received noncorticosteroid immune modulation therapy and 4 patients continued on corticosteroid therapy. Seven patients received no additional treatment.

Thrombotic Microangiopathy in Cancer.

Thrombotic microangiopathy (TMA) is a rare but often devastating complication of cancer and cancer treatment. The syndrome is defined by thrombocytopenia (i.e., a platelet count of < 150,000/mcL or > 30% decrease from baseline), microangiopathic hemolytic anemia, and some evidence of organ damage. Among the nine recognized groups of disorders causing TMA, the focus of this article will be on cancer and cancer treatment-related causes of TMA. This review will discuss the pathophysiology of TMA in cancer, chemotherapy-associated TMA, transplant-associated TMA, and newer therapeutic modalities.

Ethnic and racial difference in Helicobacter pylori infection in patients with immune thrombocytopenia treated at a major urban medical center.

Immune thrombocytopenia (ITP) is an autoimmune disorder with a complex immunopathology and pathogenesis characterized by thrombocytopenia and bleeding manifestations. The disorder is separated into primary (idiopathic) ITP and secondary ITP, when associated with other immune or lymphoproliferative disorders and certain chronic infections. Helicobacter pylori (H. pylori) is a recognized bacterial cause of ITP. In regions with high prevalence of infection, bacterial eradication has resulted in improvement in platelet count. However, the prevalence of H. pylori infection and response to antimicrobial therapy in North American ITP patients is reportedly low. We evaluated the prevalence of H. pylori infection in ITP patients diagnosed and treated at a large urban medical center. Eighty-two patients were screened for H. pylori, by stool antigen (n = 54), H. pylori breath test (n = 11), and H. pylori antibodies (n = 16), of which 15 (18.3%) were white non-Hispanic (WNH), 55 (67%) Hispanic (H), 8 (9.8%) Asian (A), and 4 (4.9%) African-American (AA). Of the screened patients, 36/82 (43.9%) tested positive for H. pylori. The prevalence of H. pylori infection within the represented ethnic groups was 2/15 (13%) WNH, 29/55 (52.7%) H, 3/8 (37.5%) A, and 2/4 (50%) AA. There was a significant difference in prevalence of infection comparing WNH and H patients (p = 0.007). There were 36 treated patients, with H. pylori eradication documented in 26 patients. Fifteen of the 26 patients were evaluable for response with 8 of 15 (53%) having clinical responses, 6 complete responses, and 2 partial responses. Our study demonstrates an increased prevalence of H. pylori infection in the Hispanic ITP population with a reasonable platelet response among patients with H. pylori eradication.

Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Eculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of paroxysmal nocturnal hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce. METHODS: We designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. RESULTS: Of the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to be increased. Low-molecular-weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Twenty cord-blood samples were examined for the presence of eculizumab; the drug was detected in 7 of the samples. A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples. CONCLUSIONS: Eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications. (ClinicalTrials.gov number, NCT01374360.).

Life-threatening delayed hyperhemolytic transfusion reaction in a patient with sickle cell disease: effective treatment with eculizumab followed by rituximab.

BACKGROUND: Hyperhemolysis in sickle cell disease is a rare and potentially life-threatening complication of transfusion. STUDY DESIGN AND METHODS: In this article we report a case of delayed hemolytic transfusion reaction with resultant hyperhemolysis triggered by an anti-IH autoantibody with alloantibody behavior. RESULTS: The anti-IH was reactive at room temperature as well as 37 °C, but only weakly reactive with autologous red blood cells. Initial cold agglutinin titer was 512. The profound, life-threatening, intravascular hemolysis was rapidly and dramatically reduced with the Complement 5 (C5) inhibitory antibody, eculizumab. The auto/allo cold agglutinin was subsequently suppressed with rituximab treatment. CONCLUSIONS: Eculizumab, a potent C5 inhibitory antibody, can be a rapid and effective therapy for hyperhemolytic transfusion reactions when given in a sufficient dose to fully block the activation of complement C5.

Adding ascorbic acid to arsenic trioxide produces limited benefit in patients with acute myeloid leukemia excluding acute promyelocytic leukemia.

Arsenic trioxide (ATO) is highly effective in acute promyelocytic leukemia (APL), but despite its multiple mechanism of action, it has no activity in acute myeloid leukemia (AML) that excludes APL (non-APL AML). Ascorbic acid (AA) and ATO induces apoptosis in AML cell lines by depleting intracellular glutathione and generation of reactive oxygen species. In this study, we evaluated the effect of ATO plus AA in patients with non-APL AML. The study enrolled patient aged 18 or older with relapsed or refractory AML (non-APL) after conventional chemotherapy or previously untreated patients 55 years or older who were unfit for standard induction chemotherapy for AML. Intravenous ATO (0.25 mg/kg/day over 1-4 h) was given with intravenous AA (1 g/day over 30 min after ATO) for 5 days a week for 5 weeks (25 doses). Eleven AML patients were enrolled, including six previously untreated elderly patients aged 66-84 years in whom five had antecedent hematological disorder (ADH). Among 10 evaluable patients, one achieved a CR one a CRi and 4 patients had disappearance of blasts from peripheral blood and bone marrow. Five of the six responders were seen in previously untreated elderly patients. ATO related toxicity was mild. The combination of ATO and AA has limited clinical meaningful antileukemia activity in patients with non-APL AML.

Pegcetacoplan: A New Opportunity for Complement Inhibition in PNH.

Pegcetacoplan is the newest inhibitor of the complement system to be approved by the FDA and EMA for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). The cyclic peptide inhibitor of C3 was evaluated in several clinical trials in PHN leading to its approval. The focus of this paper will review the efficacy and safety of Pegcetacoplan (PEG), and considerations for use in patients with PNH.