Tag: Hemolytic Anemia

SUMMARY: The FDA on February 4, 2022 approved ENJAYMO® (Sutimlimab-jome) to decrease the need for Red Blood Cell transfusion due to hemolysis in adults with Cold Agglutinin Disease (CAD). CAD is a chronic and rare autoimmune hemolytic anemia estimated to impact the lives of 5,000 individuals in the U.S. and accounts for 15% of patients with Auto Immune Hemolytic Anemia. It is twice as common in women compared to men and is characterized by hemolysis triggered by exposure to cold temperatures usually 3-4 degrees C (37-39 degrees F). The median age at symptom onset is about 65 years, whereas the median age at diagnosis is about 72 years. The median survival is approximately 11 years.

Cold Agglutinin Disease is a complement-mediated disease and majority of the cases of CAD are mediated by IgM antibodies, unlike warm Auto Immune Hemolytic Anemia, which is predominantly IgG-driven. The circulating IgM antibodies in the body core are not bound to the RBC surface. However, as blood shifts toward the peripheral circulation and cools, IgM antibodies transiently bind to the RBC membrane resulting in agglutination. This in turn activates the complement cascade, binding C3b to the cell surface. As C3b-coated cells return toward the body core, IgM antibody dissociates, and the C3b-coated RBC are destroyed by receptor-specific macrophages present predominantly in the liver and to a lesser degree in the spleen, resulting in extravascular hemolysis and some element of intravascular hemolysis. The severity of hemolysis depends on the thermal amplitude, rather than the serum concentration of IgM antibodies. CAD can be Primary/Idiopathic or Secondary to different underlying disorders such as infections, lymphoproliferative disorders, immunoproliferative disorders, as well as connective tissue diseases.

Patients with CAD usually present with chronic anemia with hemoglobin levels ranging from 4.5 g/dL to 8 g/dL, and over 50% of patients require transfusion support, and therapy is often considered in 75% of the patients. In addition to hemolysis, clinical manifestations include cold-induced circulatory symptoms such as livedo reticularis, Raynaud disease, acrocyanosis and, rarely, cutaneous necrosis. Hemoglobinuria and Splenomegaly tends to be less severe. There has been no approved treatment for CAD. Therapies have included corticosteroids, alkylating agents, purine nucleoside analogs and Rituximab, with little benefit.

ENJAYMO® is a first-in-class humanized monoclonal antibody that is designed to selectively target and inhibit C1 complex in the classical complement pathway, which is part of the innate immune system. By blocking C1 complex, ENJAYMO® inhibits C1-activated hemolysis in CAD and prevents the premature destruction of normal RBC. ENJAYMO® does not inhibit the Lectin and alternative complement pathways.

CARDINAL study is an open-label, single-arm, multicenter trial conducted to assess the efficacy and safety of ENJAYMO® in patients with confirmed CAD and a recent history of RBC transfusion. In this study, eligible patients with CAD (N=24) entered Part A of the study. This consisted of a 26-week treatment period during which patients received ENJAYMO® at a dose of 6.5 g IV for patients weighing less than 75 kg, and 7.5 g IV for those weighing 75 kg or more, on days 0 and 7, after which they received an infusion every 2 weeks. After the 26-week treatment period, patients were eligible to continue to the open-label extension study (Part B). The mean patient age was 71.3 yrs and two thirds of patients had failed prior therapies. CAD diagnosis was defined as the presence of chronic hemolysis, a positive polyspecific Direct Antiglobulin Test result, a monospecific Direct Antiglobulin Test result strongly positive for C3d, a cold agglutinin titer of 1:64 or higher measured at 4°C, a Direct Antiglobulin Test result for IgG of 1+ or less, and no overt malignant disease. Patients with a diagnosis of Systemic Lupus Erythematosus (SLE) or other autoimmune disorder with antinuclear antibodies at screening, overt malignant disease, treatment with Rituximab monotherapy within 3 months before enrollment or treatment with Rituximab combined with chemotherapy within 6 months before enrollment were excluded.

The Primary end point was a composite of a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without RBC transfusion from week 5 through week 26. Secondary end points included improvements in hemoglobin level, normalization of bilirubin and LDH level, and Quality of Life, as assessed with the use of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (scores range from 0 to 52, with a higher score indicating less fatigue. The authors herein reported the results of Part A of the study.

The majority of patients (54%) met the prespecified Primary endpoint criteria with 63% of patients achieving a hemoglobin12 g/dL or more or an increase of at least 2 g/dL and 71% of patients remained transfusion-free after week five. Approximately 92% of patients did not use other therapies for CAD.

With regard to Secondary endpoints, there was a mean increase in the hemoglobin level of 2.29 g/dL at week 3, and 3.18 g/dL at the 26-week treatment assessment time point, from the mean baseline level of 8.6 g/dL. The mean bilirubin levels normalized by week 3, from a mean baseline level of 3.23 mg/dL and clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. The activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. There were no cases of meningococcal infections and none of the patients experienced thromboembolism.

It was concluded that in this pivotal study, ENJAYMO® had a rapid and sustained treatment benefit in most patients with Cold Agglutinin Disease by preventing chronic hemolysis, markedly increasing hemoglobin levels, and improving quality of life.

Sutimlimab in Cold Agglutinin Disease. Röth A, Barcellini W, D’Sa S, et al. N Engl J Med 2021;384:1323-1334

SUMMARY: The FDA on February 6, 2019, approved CABLIVI® (Caplacizumab-yhdp) for adult patients with acquired Thrombotic Thrombocytopenic Purpura (aTTP), in combination with Plasma Exchange and immunosuppressive therapy. Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently.

Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. A diagnosis of TTP is therefore based on clinical presentation and laboratory results and is confirmed by documentation of severe ADAMTS13 deficiency, with ADAMTS13 activity levels of less than 10%. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with Glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 20% of the patients with TTP will succumb to their disease. There is a persistent risk of life-threatening recurrences, which can occur as late as 10 or 20 years after an initial episode of TTP. Persistent or recurrent ADAMTS13 deficiency is a strong risk factor for recurrence.

CABLIVI® is an anti-von Willebrand Factor, humanized, bivalent, variable-domain-only immunoglobulin fragment (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX-V receptor and thus prevents microvascular thrombosis.

In a phase II study (TITAN trial), CABLIVI® given as an adjunct to Plasma Exchange significantly reduced the median time to a response, with more rapid normalization of platelet count, LDH and creatinine, and also reduced the incidence of major thromboembolic events as well as mean number of Plasma Exchange days, compared with placebo. However, patients who had persistent ADAMTS13 deficiency had a relapse soon after treatment with CABLIVI® was stopped, suggesting that monitoring of ADAMTS13 could be useful, to guide the continuation of therapy.

HERCULES trial is a multicenter, randomized, double blind, placebo controlled, phase III trial which evaluated the efficacy and safety of CABLIVI® in patients with acquired Thrombotic Thrombocytopenic Purpura. The trial also evaluated the benefit of CABLIVI® in reducing the risk of recurrence, by allowing for treatment to continue until immunosuppressive therapy resolved the underlying autoimmune disease. TTP was diagnosed based on clinical presentation (the presence of both thrombocytopenia and MicroAngiopathic Hemolytic Anemia with schistocytes seen on blood smear) and if they had received exactly one Plasma Exchange treatment. Severe ADAMTS13 deficiency was not an eligibility requirement and patients were excluded if they had suspected thrombotic microangiopathies that were not associated with TTP, such as Hemolytic Uremic Syndrome, or if they had congenital TTP.

This study randomly assigned 145 patients with TTP to receive CABLIVI® (N=72) or placebo (N=73). Patients in both groups received daily Plasma Exchange at 1 to 1.5 times the estimated plasma volume, until at least 2 days after normalization of the platelet count and Glucocorticoids (Prednisone or Prednisolone at a dose of 1 mg/kg or more of body weight per day during the daily Plasma Exchange period and continuing for the first week after the end of the daily Plasma Exchange period. Patients received CABLIVI® 10 mg IV loading bolus or placebo before the start of the first Plasma Exchange after randomization followed by 10 mg daily subcutaneously until 30 days after the last daily Plasma Exchange. Treatment was extended at 7-day intervals for a maximum of 28 days, if signs of persistent underlying disease such as suppressed ADAMTS13 activity levels were still present. The Primary outcome was the time to normalization of the platelet count, with discontinuation of daily Plasma Exchange within 5 days thereafter. Key Secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period, refractory TTP and normalization of organ-damage markers.

It was noted that the median time to normalization of the platelet count was shorter with CABLIVI® than with placebo and patients who received CABLIVI® were 1.55 times as likely to have a normalization of the platelet count as those who received placebo (P=0.01). The composite outcome event was 74% lower with CABLIVI® than with placebo (12% versus 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with CABLIVI® than with placebo (12% versus 38%, P<0.001). None of the patients in the CABLIVI® group developed refractory disease whereas 3 three patients in the placebo group did. Patients who received CABLIVI® required fewer Plasma Exchanges and had a shorter hospital stay, than those who received placebo. The most common adverse reactions in at least 15% of patients receiving CABLIVI® were epistaxis, headache, and gingival bleeding.

It was concluded that among patients with TTP, treatment with CABLIVI® resulted in a more rapid normalization of the platelet count, a lower incidence of a composite of TTP-related death, a lower incidence of recurrence of TTP or a thromboembolic event during the treatment period, and a lower rate of recurrence of TTP during the trial period, compared to placebo. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. Scully M, Cataland SR, Peyvandi F, et al., for the HERCULES Investigators. N Engl J Med 2019; 380:335-346.

SUMMARY: Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently. Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 10-20% of the patients with TTP will succumb to their disease.

Caplacizumab is an anti-von Willebrand Factor, humanized, single-variable-domain immunoglobulin (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX receptor. TITAN is an international, multicenter, phase II, randomized, placebo-controlled study, designed to assess the efficacy and safety of Caplacizumab given as an adjunct to Plasma Exchange, in patients with acquired TTP. Seventy five patients (N=75) were randomized in a 1:1 ratio to receive Plasma Exchange plus either Caplacizumab 10 mg subcutaneous or placebo, daily. The mean age was 42 years and the mean platelet count was 24,600 per cubic millimeter. Majority of the patients in both groups received concomitant glucocorticoids and 23% of the patients in the placebo group received RITUXAN® during daily Plasma Exchange compared 6% in the Caplacizumab group. The primary end point was the time to response, defined as normalization of the platelet count (150,000 per cubic millimeter or higher) and a Lactate DeHydrogenase (LDH) level that was no more than twice the upper limit of the normal range. Secondary end points included TTP exacerbations and relapses.

It was noted that the median time to a response was significantly reduced with Caplacizumab as compared with placebo (39% reduction in median time, P=0.005). The mean number of Plasma Exchange days was lower with Caplacizumab (5.9 versus 7.9 days), the mean volume of Plasma administered was lower with Caplacizumab (19.9L versus 28.3L), normalization of LDH and creatinine occurred more rapidly with Caplacizumab and Complete Remissions after initial course of Plasma Exchange was more common in the Caplacizumab group (81% versus 46%), when compared to the placebo group. Mild to moderate bleeding was more common with Caplacizumab than with placebo (54% versus 38%).

The authors concluded that the addition of Caplacizumab to Plasma Exchange induces a faster resolution of acute TTP compared with placebo and Caplacizumab maintained a platelet-protective effect during the treatment period. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. Peyvandi F, Scully M, Hovinga JK, et al. for the TITAN Investigators. N Engl J Med 2016; 374:511-522