Diagnosis Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Ravulizumab Provides Durable Control of Intravascular Hemolysis and Improves Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Follow-up of Study 301 and Comparisons with Patients of the International PNH Registry

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare chronic blood disorder characterized by uncontrolled terminal complement activation, leading to intravascular hemolysis (IVH), major adverse vascular events (MAVEs; including thrombotic events), organ damage and increased morbidity and mortality. Where available, ravulizumab is considered the standard of care for patients with PNH, providing immediate, complete and sustained inhibition of terminal complement activity. In study 301 (NCT02946463), complement component 5 (C5) inhibitor-naïve patients with PNH reported elevated levels of lactate dehydrogenase (LDH) and low hemoglobin (Hb) concentrations at baseline, alongside a history of MAVEs and need for transfusions. In such patients, ravulizumab provides durable control of IVH, reported for up to 2 years. Objectives: To report ravulizumab treatment outcomes for up to 6 years in C5 inhibitor-naïve patients with PNH from study 301 and compare survival with untreated patients of the International PNH Registry (NCT01374360). Methods: C5 inhibitor-naïve patients with PNH and high-disease activity (HDA; LDH level ≥ 1.5 × the upper limit of normal [ULN] and at least one sign or symptom of PNH) (N = 246) were randomized to receive ravulizumab or eculizumab. After the primary evaluation period (26 weeks), patients received ravulizumab for the 5-year open-label extension (OLE) period. LDH level change from baseline, the proportion of patients experiencing MAVEs, and transfusion avoidance were evaluated. Cox-proportional hazards regression analyses compared survival of patients treated with ravulizumab with untreated patients with HDA and clone size ≥ 5% at PNH Registry enrollment. Covariates comprised age at PNH diagnosis, gender, Hb concentration, estimated glomerular filtration rate, PNH clone size, transfusion history and medical history of MAVEs and bone marrow disease at baseline (i.e., date of ravulizumab treatment initiation [study 301] or PNH Registry enrollment). Transfusion history ( p = 0.05), age at PNH diagnosis and gender were included in the final adjusted model. Results: Ravulizumab treatment data were available for 244/246 patients (median [range] follow-up: 46.8 [0.4-69.3] months). At baseline, all 246 patients had LDH levels > 1.5 × ULN; at 26 weeks, 87.1% of patients achieved LDH levels ≤ 1.5 × ULN, which was maintained in 79.3% of patients at last follow-up (day 2045 [n/N = 42/53]; highest proportion reported at day 225 [n/N = 92/97; 94.9%]). At baseline, 17.1% of patients had a history of MAVEs (MAVE rate: 3.4 per 100 patient-years [PYs]). The proportion of ravulizumab-treated patients who experienced MAVEs was low throughout the study (n = 11 [4.5%], 13 events, MAVE rate: 1.4 per 100 PYs), with 9 patients (3.7%) reporting MAVEs during the OLE (11 events, MAVE rate: 1.3 per 100 PYs). Prior to randomization (≤ 6 months of study entry), 24.8% of patients did not need transfusions; at 26 weeks, this increased to 73.6% and was maintained in 53.9% of patients for the entire OLE with the highest proportion not requiring transfusions reported during the final 6 months of the OLE (75.7%). In addition, units transfused reduced from 1019 prior to randomization to 110 during the final 6 months of the OLE. Overall, 33 patients (13.4%) discontinued ravulizumab treatment during the entire study period (30 [12.2%] during the OLE). Reasons for discontinuation were death (n = 8), patient choice (n = 7), physician decision (n = 5), pregnancy (n = 4), adverse event (n = 3), lost to follow-up (n = 1) and other (n = 5). When compared with 413 untreated patients, ravulizumab was associated with an adjusted survival probability (95% confidence interval [CI]) of 84.1% (77.4, 91.3) at 4 years (hazard ratio [95%CI]: 0.14 (0.06, 0.32), p < 0.001; Figure 1) and mortality was 3.5-fold lower than that observed in untreated patients in the PNH Registry. Conclusions: This study reports the longest duration of ravulizumab treatment exposure in C5-inhibitor-naïve patients with PNH (925.7 PYs) to date. For up to 6 years, ravulizumab provided effective long-term control of IVH, evidenced by the maintenance of LDH ≤ 1.5 × ULN and low incidence of MAVEs and death. No new safety signals were identified and ravulizumab improved survival compared with untreated patients in the PNH Registry, further supporting the use of ravulizumab as the first-line treatment of choice for patients with PNH, where available.

Disease Management and Outcomes in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Analysis of Observational Data from the United States

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic disease characterized by complement-mediated hemolysis, thrombophilia, bone marrow failure (BMF), and renal disease. PNH is clinically heterogeneous, and hospitalization and regular blood transfusions may be needed. Treatment with currently approved C5 inhibitors (C5i), eculizumab and ravulizumab, have shown efficacy in intravascular hemolysis control and reduction in thrombosis risk. Yet, in routine clinical practice, a limited number of patients receive C5i in the United States. Moreover, less than 70% of patients treated with eculizumab continue to receive treatment 1 year following PNH diagnosis. If the disease is managed inadequately, patients may experience prolonged morbidity, increased frequency and severity of symptoms, and early mortality. There is limited real-world evidence available on PNH disease management. Aim: To better understand the disease management and consequences of PNH. Methods: In this retrospective observational study, we analyzed 1227 patients aged ≥18 years in the TriNetX network who were diagnosed with PNH on or after 1 January 2007 and had ≥180 days of post-diagnosis follow-up data (97% were based in the United States). Patients were followed from 1 January 2007 to 6 May 2023. Disease management and outcomes were analyzed for all patients, including those with chronic anemia who were complement-inhibitor naïve. Chronic anemia was defined as hemoglobin <10 g/dL without any hemoglobin measure of ≥10 g/dL between 3 months prior to PNH diagnosis (index date) and 6 months after diagnosis. PNH-related hospitalization was defined by specific International Classification of Diseases codes. The baseline period was defined as 1 year prior to PNH diagnosis. Event rates were estimated for hospitalization (recurrent), transfusions (recurrent), BMF, and death. Rates are adjusted for exposure time (time between diagnosis and end of follow-up) and reported as per person-year with 95% confidence intervals (CIs). Results: In the overall cohort, 58% of patients were female, and the median (interquartile range) age was 56 (38-68) years. During a median 35 (19-62) months of follow-up, 322 (26%) patients received blood transfusions and 172 (14%) patients received C5i. Median time to C5i initiation since diagnosis was 1 (0-10) month with a median treatment duration of 14 (0-49) months. Out of 1227 patients, 50 (4%) had chronic anemia and were complement-inhibitor naïve. The median length of follow-up in this subgroup was 14 (7-43) months. Most of these patients (96%) had PNH with bone marrow disorder subtype. Median hemoglobin and lactate dehydrogenase levels at baseline were 8 (7-8) g/dL and 313 (218-489) U/L, respectively. Out of these 50 patients, first-line treatment was initiated a median of 1 (1-6) month after diagnosis, with anticoagulants and corticosteroids being the most frequently prescribed. During follow-up, 32 (64%) of these patients experienced ≥1 hospitalization (rate 0.78, 95% CI 0.62-0.95) with a median of 3 (2-9) days stay for the first hospitalization. Anemia (42%), abdominal pain (36%), and infections (9%) were the leading causes of admission. In addition, 26 (52%) patients were transfusion dependent (rate 1.52, 95% CI 1.30-1.77) and 30 (60%) experienced BMF (rate 0.71, 95% CI 0.48-0.99). Moreover, 21 (42%) of these patients died during follow-up (rate 0.19, 95% CI 0.12-0.28). Discussion: These findings indicate that complement-inhibitor naïve patients with chronic anemia have substantial disease burden, including frequent hospitalization, high transfusion dependency, and early mortality. In addition, the results show that only a minority of patients in this cohort received C5i. Study limitations include that mortality is likely to be underestimated, as only in-hospital deaths are captured in these data. The small sample size limits the drawing of robust conclusions. However, overall, these findings support the need to address PNH disease burden and improve disease management.

Anticoagulation Use and Patient Outcomes in Paroxysmal Nocturnal Hemoglobinuria: A Province-Wide Retrospective Review

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder caused by somatic mutations in hematopoietic stem cells and is characterized by hemolysis, bone marrow failure, and thrombosis. Thrombotic events are the leading cause of morbidity and mortality in PNH, but little has been published about the role of prophylactic anticoagulation to prevent thrombotic events, and the ideal anticoagulant for patients who do experience thrombosis. Additionally, to our knowledge, bleeding outcomes in patients on prophylactic and therapeutic dose anticoagulants have not been examined. Our objective was therefore to examine our practice patterns regarding the use and outcomes of anticoagulation in PNH patients in our province. Methods: This multi-center, retrospective cohort study examined the epidemiology, management, thrombotic and bleeding complications of 31 adult patients with PNH in the province of Alberta, Canada during the period of January 1, 2000, to December 31, 2022. Patients were identified by International Classification of Diseases (ICD)-9 codes from hospital discharge summaries and ambulatory clinic records. Chart reviews were performed to collect patient demographics, clinical and laboratory characteristics, use of anticoagulation including agent and dose, and thrombotic and bleeding complications. Results: The median age of the cohort was 50 (interquartile range, IQR 35-70) years and 10 (32%) patients were male. Concurrent aplastic anemia and myelodysplastic syndrome were present in 15 (48%) and 3 (10%) patients, respectively. Disease presentation included thrombosis in 4 (13%) patients and bleeding in 5 (16%) patients. The majority of patients (74%) were treated with a complement inhibitor, most commonly eculizumab. Over the study period, 7 (23%) patients experienced 10 thrombotic events, including venous thromboembolism in 6 (60%) patients and arterial thromboembolism in 4 (40%) patients. The most common vascular sites of thrombosis were deep vein thrombosis of the lower extremity (3 patients) and stroke (2 patients). Of the 10 thrombotic events, 3 (30%) occurred while the patient was receiving a complement inhibitor. Thrombosis occurred at a median of 4.5 months from PNH diagnosis and the average granulocyte clone size at the time of thrombosis was 40.1% (IQR 11.3-82.9%). Of these 10 thrombotic events, 2 occurred on therapeutic-dose anticoagulation. In total, 8 (26%) patients experienced 13 bleeding events, 4 (13%) meeting criteria for ISTH major bleeding. The average platelet count at the time of bleeding was 96 (IQR 79-139). Of the 13 bleeding events, 5 occurred on an antiplatelet, 2 occurred on prophylactic-dose anticoagulation, and 2 occurred on therapeutic-dose anticoagulation. Thirteen (42%) patients were on anticoagulation: 7 (23%) patients on primary prophylaxis and 6 (19%) patients on secondary prophylaxis. For primary prophylaxis, 4 patients received a direct oral anticoagulant (DOAC), 3 at a prophylactic dose and 1 at a therapeutic dose, and 3 patients received warfarin at a therapeutic dose. Six (86%) patients on primary prophylaxis were also receiving a complement inhibitor. With regards to secondary prophylaxis, 2 patients received a DOAC, 3 patients received warfarin, and 1 patient received low molecular weight heparin. All secondary prophylaxis was given at a therapeutic dose. Five (83%) patients on secondary prophylaxis were also receiving a complement inhibitor. Of patients on a DOAC, 1 patient experienced a breakthrough arterial thromboembolism (stroke), and no patients experienced a breakthrough venous thromboembolism. Conclusion: Thrombosis in PNH is common and prevention is key to prevent long-term morbidity and mortality. Our practice patterns indicate that DOACs are being used in our province as primary prophylaxis, even in patients who are concurrently being treated with a complement inhibitor. DOACs are also being used more frequently than other anticoagulants as secondary prophylaxis, despite there not being robust data for DOAC use in this patient population. DOACs appear to be effective against VTE with no occurrence of breakthrough venous thrombosis. Major bleeding complications were observed at a higher rate than has been described in the literature and therefore the use of anticoagulants in this patient population must be weighed against the bleeding risk.

Unraveling the Clinical Spectrum: A Case Study of Classic and Aplasia-Related Paroxysmal Nocturnal Hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare nonmalignant clonal disorder of hematopoietic stem cells characterized by a phosphatidylinositol glycan protein A (PIGA) gene mutation. This mutation results in the deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, on the cell surface, rendering red blood cells (RBC) susceptible to complement-mediated destruction. This leads to hemolytic anemia, thromboses, and bone marrow failure. Here we describe two cases of PNH presenting to a tertiary care center. Case 1 A 29-year-old male with a history of polysubstance use presented to the Emergency Department with a 2-day history of progressively worsening left lower quadrant abdominal pain. CT abdomen pelvis showed multiple renal infarcts and findings suggestive of pneumatosis intestinalis. A complete blood count (CBC) revealed pancytopenia with a leukocyte count (WBC) of 3 x 10 9/L, hemoglobin (Hb) of 94 g/L, and platelet count (Plt) of 48 x 10 9/L. Lactate dehydrogenase (LDH) was elevated (900 IU/L), haptoglobin level was low ( <8mg/dL), and direct antiglobulin test (DAT) was negative. Urine was positive for hemosiderin, and flow cytometry showed RBCs (6.7%), granulocytes (97.97%), and monocytes (89.02%) with PNH phenotype. Bone marrow biopsy (BMB) was negative for dysplasia and fibrosis with normal hematopoiesis but showed increased erythroid precursors. Enoxaparin was started for thromboses and levofloxacin for neutropenia. Treatment for PNH was initiated with a loading dose of ravulizumab and meningococcal vaccination. The patient was lost to follow-up after receiving the first maintenance dose. Case 2 An 81-year-old female with a medical history of hypertension and coronary artery disease was hospitalized for gradually worsening shortness of breath and fatigue ongoing for 2 months. She reported easy bruising but denied a history of obvious bleeding from any orifice. Physical exam was significant for petechial rash in her lower extremities. Labs revealed pancytopenia (WBC 1.44 x 10 9/L, Hb 68 g/L, Plt 8 x 10 9/L), low reticulocyte count, LDH of 276 IU/L, and negative DAT. BMB showed marked aplasia, and she became transfusion dependent. Subsequently, flow cytometry revealed PNH phenotype in 1.45% of RBCs, 54% granulocytes, and 54% monocytes. Eculizumab therapy was started for the diagnosis of PNH. However, her transfusion requirements did not decrease. She developed iron overload and showed positive conversion on DAT. Darbepoetin alfa and romiplostim were added. Her Hb stabilized at >70g/L in 3 years, following which she only required romiplostim to maintain Plt >20,000 ( Graph 1). After 5 years, she opted to discontinue all treatment. She is being followed up regularly and has since remained stable. Discussion The two cases above are reflective of how PNH can present in different ways, ranging from the classic triad of symptoms to those with subclinical findings associated with other underlying conditions, such as aplastic anemia or myelodysplastic syndrome. The introduction of complement inhibitors completely changed the natural history of PNH, as patients' median survival shifted from 15-20 years to align with age-matched controls. Indications for treatment include severe anemia, thrombosis, or PNH symptoms like dyspnea, fatigue, and painful paroxysms. Currently, eculizumab and ravulizumab are the only FDA-approved drugs for PNH treatment. Ravulizumab is non-inferior to eculizumab, with the added advantage of less frequent dosing (every 8 weeks versus 2 weeks). Regular monitoring for hemolysis is warranted with treatment. Many patients require long-term therapy, which continues to be a significant challenge, even with the spaced dosing of ravulizumab. Eculizumab protects from terminal complement-mediated damage preventing intravascular hemolysis. However, these cells are still deficient in CD55, making them vulnerable to opsonization by C3 and premature removal in the spleen. As a result, >50% of PNH patients receiving treatment show positive conversion on DAT, as seen in case 2. Heparin is preferred in acute thrombotic states. Most hematologists recommend anticoagulation till a few months after starting complement inhibition.

Efficacy of SB12 (Eculizumab Biosimilar) in Asian and Non-Asian Patients with Paroxysmal Nocturnal Hemoglobinuria: Subgroup Analysis of a Global Phase III Randomized Controlled Trial

Background SB12 is a humanized monoclonal antibody biosimilar to reference eculizumab (ECU) which received marketing authorization in Europe in May 2023 after a comprehensive biosimilarity demonstration including non-clinical and clinical assessments. The pivotal SB12 Phase III study demonstrated equivalent clinical efficacy by evaluating lactate dehydrogenase (LDH) and comparable safety, pharmacokinetics, pharmacodynamics, and immunogenicity between SB12 and ECU in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Jun Ho Jang et al., eJHaem 2022). Objective To analyze the efficacy of SB12 in Asian and non-Asian patients with PNH from the pivotal phase III study. Methods A total of 50 adult patients with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor (naïve) were randomized. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25), to receive 600 mg of SB12 or ECU intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). Patients were switched to ECU or SB12 at Week 26, and switched treatment was provided until Week 50. The primary endpoints included LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. In addition, equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints included the LDH profile over time. Overall, post-hoc analysis in Asian and Non-Asian (based on race) patients who received either ECU or SB12 during the study period was conducted for the aforementioned efficacy endpoints. Results Asian patients were 27 (54.0%) of total 50. Overall, 15 (60%) Asian patients and 10 (40%) Non-Asian patients were randomized to TS1 and 12 (48%) Asian patients and 13 (52%) Non-Asian patients were randomized to TS2. Baseline demographic and disease characteristic were comparable between the two treatment sequences, with no significant differences between the treatment sequences by race between Asian and Non-Asian patients. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU in Asian (SB12 − ECU: -12.02, 95% CI [−126.87, 102.83]) and Non-Asian patients (SB12 − ECU: 76.12, 95% CI [−56.75, 208.99]) lied within the pre-defined equivalence margins (Table). The 90% CI of ratio of time-adjusted AUEC of LDH between SB12 and ECU in Asian patients (SB12/ECU: 1.01, 90% CI [0.92, 1.10]) lied within the pre-defined equivalence margin and was also comparable in Non-Asian patients (SB12/ECU: 1.15, 90% CI [0.90, 1.46]). The overall LDH profile during the study period was also comparable between Asian and Non-Asian patients. No patient developed anti-drug antibodies during the study period and no patient discontinued due to lack of efficacy. While the limited sample size suggests for caution, the comparable efficacy results by Asian and Non-Asian subgroups are also comparable to previously published results in the overall population (Jun Ho Jang et al., eJHaem 2022), with no significant differences identified. Conclusion SB12 showed comparable efficacy to ECU in complement-inhibitor naïve PNH patients in both Asian and Non-Asian subgroups. No patient developed anti-drug antibodies nor discontinued due to lack of efficacy during the study period.

Insights from Trajectories of PIGA-Mutated Clones in Paroxysmal Nocturnal Hemoglobinuria

Background: Patients with paroxysmal nocturnal hemoglobinuria (PNH) exhibit clonal expansion of hematopoietic cells deficient in glycosylphosphatidylinositol-anchored proteins (GPI-APs). Mutations in PIGA gene, involved in the biosynthesis of GPI-APs, result in the loss of GPI-APs from hematopoietic cells. However, PIGA mutations alone are insufficient to drive this clonal expansion. The pathogenesis of clonal expansion in PNH remains elusive, while several hypotheses or factors have been proposed, including immune attacks with concomitant aplastic anemia (AA) or additional mutations offering intrinsic growth advantage. Recently high-sensitivity flow cytometry and next-generation sequencing have allowed us to evaluate the clonal dynamics and architecture more precisely. The method has the potential to clarify the trajectories of PIGA mutated clones before the significant clonal expansion or the diagnosis, thereby to gain insight into the pathogenesis of the clonal expansion in PNH. Methods: To estimate the trajectories of PIGA-mutated clones, we constructed phylogenetic trees using whole genome sequencing (WGS) data of single cell-derived colonies of bone marrow samples from two PNH patients (53 colonies for Case 1 and 75 for Case 2). We used the targeted-sequencing and exome sequencing to detect driver mutations after isolating GPI-deficient and GPI-positive cells using flow cytometry. Results: Case 1 was diagnosed with AA at the age of 28. He developed hemoglobinuria at the age of 40 and was diagnosed with PNH at the age of 45. Bone marrow and peripheral blood samples were collected when he was 47 years old. The PNH clone sizes in granulocytes and red blood cells were 88.7% and 46.1%, respectively. Targeted-sequencing revealed six PIGA mutations in GPI-deficient cells and three BCOR mutations in GPI-positive cells. Case 2 was diagnosed with AA at the age of 33 and with PNH at the age of 34. Bone marrow and peripheral blood samples were collected when she was 59 years old. The PNH clone sizes in granulocytes and red blood cells were 98.6% and 96.3%, respectively. We previously identified chromosomal abnormalities in chr12, with the breakpoint located in an HMGA2 gene (Inoue et al. Blood. 2006). Targeted-sequencing detected no other driver mutations than single PIGA mutation and the HMGA2 mutation.In Case 1, Phylogenetic tree analysis constructed with WGS of single cell-derived colonies revealed multiple PIGA-mutated and BCOR-mutated clones that expanded independently of each other. All BCOR-mutated clones were identified in the GPI-positive population. In Case 2, all PIGA-mutated clones harbored the HMGA2 mutation, while no GPI-positive populations acquired the HMGA2 mutation.In both cases, the numbers of passenger single nucleotide variants per year were higher in PIGA-mutated clones than in PIGA-unmutated clones (16 vs. 11 mutations/year for Case 1 and 14 vs. 12 for Case 2). Assuming that variant acquisition rates per cell division are similar in both clones, the result suggests that PIGA-mutated clones had growth advantage against PIGA-unmutated clones.The acquisition of PIGA mutations was estimated to have occurred more than ten years prior to the PNH diagnosis. In Case 1, following the AA diagnosis, both PIGA-mutated clones and BCOR-mutated clones started expansion simultaneously, which suggests an association with immune attacks. Interestingly, even wild type clones expanded after AA diagnosis, suggesting bottle-neck effects of post-AA hematopoietic recovery. In Case 2, PIGA-mutated clones began expanding more than ten years before the AA diagnosis. Either a subclinical immune attack that might have existed before the diagnosis of clinical AA or the concomitant HMGA2 mutation conferred survival advantage for PIGA-mutated clones in Case 2. Conclusions: This estimation of the trajectories of the PIGA-mutated clone indicates that the pathogenesis of clonal expansion exhibits heterogeneity between two PNH patients.

OMS906, a Novel Alternative Pathway MASP-3 Inhibitor, Normalizes Hemoglobin Levels and Increases Clone Size in Treatment-Naïve PNH Patients

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disorder characterized by hemolytic anemia in combination with various degrees of marrow failure. PNH is driven by dysregulation of the complement system where the absence of CD55 and CD59 cell surface proteins leads to red blood cell (RBC) lysis. Untreated PNH can lead to debilitating anemia, thrombosis, fatigue, and increased mortality. Terminal complement inhibition attenuates intravascular hemolysis (IVH) but inevitably leads to extravascular hemolysis (EVH). Proximal and alternative pathway (AP) inhibition block both IVH and EVH, as demonstrated with C3, Factor B, and Factor D inhibitors. Mannan-binding lectin-associated serine protease-3 (MASP-3) activates pro-Factor D, thus activating the AP upstream of Factor D. OMS906 is a highly selective humanized mAb that binds to and inhibits MASP-3. In a Phase 1 study in healthy subjects, OMS906 was well tolerated and provided substantial MASP-3 inhibition. In the present study, safety and efficacy of OMS906 were evaluated in complement-inhibitor treatment-naïve patients with PNH. Methods: This is an ongoing, single-arm, open-label, Phase 1b proof-of-concept clinical trial (NCT05889299; EudraCT 2022-002450-22) evaluating safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OMS906 in adults with PNH. Eligibility criteria include: confirmed PNH diagnosis by flow cytometry (RBC clone size >10%); complement-inhibitor treatment-naïve or inadequate response to C5 inhibitors; and baseline hemoglobin (Hgb) <10.5 g/dL. Patients received 5 mg/kg subcutaneous (SC) OMS906 every 4 weeks, the lowest exposure cohort in this study. Primary endpoints are safety and tolerability. Secondary endpoints include changes from baseline in Hgb and lactate dehydrogenase (LDH) levels, RBC clone size, and absolute reticulocyte count; achievement of Hgb ≥12 g/dL or an increase of ≥2 g/dL; and transfusion independence. Planned enrollment was approximately 10 patients. Results: This pre-specified interim analysis included data available as of July 20, 2023. All patients (N=11) included in this analysis were complement-inhibitor treatment-naïve (55% female; mean age 41 years [range 27-72]). The majority of patients (64%) received RBC transfusions in the 12 months prior to OMS906 treatment. Co-existing conditions included iron deficiency (n=6), chronic renal failure (n=3), aplastic anemia (n=2), and myelodysplastic syndrome (MDS; n=2). At baseline (N=11), mean Hgb was 7.0 g/dL (median 6.4 g/dL, range 3.9-10.4 g/dL) and LDH was 1835 U/L (median 1831 U/L, range 905-3480). To date, all patients have received ≥2 doses of OMS906 with 4 patients having received ≥6 doses. OMS906 was well tolerated. The most common adverse events (AEs) in ≥20% of patients were increased thrombocytopenia (36%), neutropenia (27%), and itching (27%). No patients experienced clinical breakthrough hemolysis. There were no major adverse vascular events, treatment-related serious AEs, discontinuations, or deaths. Following initiation of OMS906, mean Hgb increased from baseline by 3.1 g/dL ( P<0.001) at 4 weeks (N=11), and by 9.5 g/dL ( P=0.016) at the latest timepoint of 24 weeks (n=3) [Figure 1]. Among patients receiving ≥2 doses, all but 3 experienced gender-specific normalization of Hgb levels. The remaining patients had MDS (n=2) or marrow failure (n=1). No patients required transfusions following OMS906 treatment. Mean LDH levels decreased from baseline by 1483 U/L (>80%; P<0.001) at 4 weeks (N=11) and by 1939 U/L ( P=0.004) at 24 weeks (n=3). Three patients had increases in LDH, suggesting initiation of hemolysis at the end of a dosing period. Mean absolute reticulocyte counts decreased from baseline by 87,000-122,000 ×10 9/L at all timepoints. Mean PNH RBC clone size increased by up to 38.6% (n=6; P=0.016) versus baseline. Conclusion: In this interim analysis, MASP-3 inhibitor OMS906 was well tolerated with no safety signals of concern. Once-monthly SC OMS906 resulted in clinically meaningful, beneficial effects on Hgb, LDH, and RBC clone size in treatment-naïve PNH patients. OMS906 dose escalation guided by occurrence of subclinical hemolysis is being evaluated with the goal of achieving quarterly dosing.

Early Mortality in Paroxysmal Nocturnal Hemoglobinuria.

The elevated mortality risk among patients with paroxysmal nocturnal hemoglobinuria (PNH) has been suggested to derive from a high risk of thromboembolism (TE); however, the risks of coexisting cardiovascular risk factors are not well described. We studied mortality associated with PNH taking comorbidity and treatment into account. Patients with PNH (n=115) were identified in the1977-2016 Danish National Patient Register (DNPR). For each patient with PNH, we identified 50 age- and sex-matched general population comparators. Using the Kaplan-Meier estimator and Cox regression, we compared the overall survival of patients with comparators. Cumulative incidences were used to analyze the effects of comorbidity and the causes of death. One-year survival among patients and comparators was 92.2% and 99.4%, and after 10 years, it was 68.4% and 85.8%, respectively. Early mortality was associated with older age, higher levels of comorbidity, and solid malignancies prior to PNH diagnosis. The leading causes of death were infections and associated hematological diseases. Patients with early mortality were less likely to have received treatment with eculizumab and/or warfarin. Cardiovascular risk factors were evenly distributed between patients and comparators at diagnosis. We conclude that early mortality in PNH is associated with older age, cardiovascular comorbidity, and hematological malignancies.

Hemosiderin induced acute kidney injury requiring hemodialysis in patients with paroxysmal nocturnal hemoglobinuria: A case report.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease with features of hemolytic anemia, thrombosis, and bone marrow failure. Due to intravascular hemolysis and hemoglobinuria, renal dysfunction is often accompanied in PNH patients. A 25-year old woman presenting gross hematuria after coronavirus disease 2019 infection was admitted to our medical center. She had mild nausea and headache. She was diagnosed with iron deficiency anemia few years ago and had no other underlying disease. Her laboratory findings showed acute kidney injury (AKI) and severe anemia, with evidences of hemolysis. Renal biopsy was done to determine the cause of renal failure and the result was acute tubular necrosis with deposition of golden pigments, hemosiderin. With pathologic result and laboratory finding of hemolysis, we did flow cytometry for PNH, and the patient was finally diagnosed with PNH. With AKI and oliguria, the patient started to take hemodialysis. After taking 5 sessions of hemodialysis, the patient's renal function was recovered from AKI. With diagnosis of PNH, the patient is now being treated with complement C5 inhibitor. This challenging case tells us that we should consider the first manifestation of PNH as a cause of severe AKI requiring hemodialysis in a patient with anemia and evidence of hemolysis.

Severe hemolytic exacerbations of Chinese PNH patients infected SARS-CoV-2 Omicron.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, bone marrow failure, thrombophilia. COVID-19, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with many variants including Omicron. This study collected demographic and clinical data of 20 PNH patients with SARS-CoV-2 Omicron infection. They all were with high disease activity, and LDH level exceeded any documented since the diagnosis of PNH, and those reported in the literature for previously stable treatment with complement inhibitors. D-dimer level elevated in 10 patients. 2 patients developed mild pulmonary artery hypertension. Glomerular filtration rate declined in 5 patients. 1 patient developed acute renal failure and underwent hemodialysis. Anemia and hemolysis were improved in 5 patients treated with eculizumab. Hemolytic exacerbation of PNH with COVID-19 is severe and eculizumab may be an effective treatment.

Characteristics of paroxysmal nocturnal hemoglobinuria patients in Brazil: A retrospective administrative claims database analysis of PNH patients in Brazilian public healthcare system.

Few studies have reported the profile of patients with paroxysmal nocturnal hemoglobinuria (PNH) and their care in the Brazilian health system. To describe clinical and epidemiological characteristics of patients with PNH in the Brazilian public health system including procedures performed, associated comorbidities and visits to health care professionals. In a real-world observational, retrospective, population-based cohort study, anonymized secondary data provided by the Department of Informatics of the Brazilian Unified Health System (DATASUS) were analyzed. Patients were considered eligible if they had at least one procedure coded with the ICD-10 code D59.5 from January 1, 2008 to December 30, 2018. In total, 675 individual PNH patients were identified (52.4% female; prevalence of 1:237,000 people). Around 15.8% of the patients included had myelodysplastic syndrome and about half of the sample had other aplastic anemias and/or other bone marrow failure syndromes. Portal vein thrombosis (I82 ICD code) was reported in 4.3% of patients. Regarding hospitalizations, 263 individual PNH patients had 416 inpatient admissions with the ICD code for PNH (D59.5) on admission. Twelve deaths occurred during the study period, of which two had the PNH ICD code related with the cause of death, while another three deaths were associated with acquired hemolytic anemia (D59.9), unspecified aplastic anemia (D61.9) and acute respiratory failure (J96.0), respectively. Despite its limitations, this statistical analysis of data extracted from DATASUS reasonably describes PNH patients in Brazil and its variations across different regions of the country. Comorbidities frequently associated with PNH such as portal vein thrombosis were not as common in our study, but it is assumed that several thrombotic events at specific sites were coded under the broader I82 ICD code. The frequency of visits to different health professionals, including hematologists, increased after the diagnosis of PNH. Among hospitalized PNH patients, the mortality rate was 4.5%.

Changes in Hematologic Lab Measures Observed in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with C5 Inhibitors, Ravulizumab and Eculizumab: Real-World Evidence from a US Based EMR Network

Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disorder, can be treated with C5 inhibitors (C5i) such as eculizumab or ravulizumab. This retrospective study is the first to describe real-world treatment patterns and changes in hematologic PNH-monitoring laboratory tests among C5i-treated US patients. Data were extracted from TriNetX Dataworks Network and included patients with a PNH diagnosis between 1 January 2010, and 20 August 2021. Patients were stratified into three cohorts based on their C5i usage: eculizumab, ravulizumab (prior eculizumab), and ravulizumab (eculizumab naïve). Hematological markers (hemoglobin [Hb], lactate dehydrogenase [LDH], and absolute reticulocyte count [ARC]) and relevant clinical events (e.g., breakthrough hemolysis [BTH], complement-amplifying conditions [CAC], thrombosis, infection, and all-cause mortality) were captured any time within 12 months post-index treatment. Of the 143 (eculizumab), 43 (ravulizumab, prior eculizumab), and 33 (ravulizumab, eculizumab naïve) patients, mean age across cohorts was 42-51 years, 55-61% were female, 63-73% were White, and 33-40% had aplastic anemia. Among all cohorts 12 months post-C5i treatment, 50-82% remained anemic, 8-32% required ≥1 transfusion, and 13-59% had BTH, of which 33%-54% had CACs. Additionally, thrombosis was seen in 7-15% of patients, infection in 20-25%, and mortality in 1-7%. These findings suggest many C5i-treated patients experience suboptimal disease control.

Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Ravulizumab can effectively treat ischemic enteritis caused by paroxysmal nocturnal hemoglobinuria.

Ischemic colitis is a common disease with a good prognosis; however, complications can occur in the presence of a serious underlying disease. Herein, we present a case report in which characteristic findings on lower gastrointestinal endoscopy led to a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). An 82-year-old woman visited our hospital for chronic heart and renal failure. She had a history of breast cancer, myocardial infarction, and hemorrhoidal fistula and was initially hospitalized for ischemic colitis. Subsequent lower gastrointestinal endoscopy revealed extensive ulcerative lesions in the ascending, transverse, and descending colon. Histopathologically, small vessels exhibited multiple fibrin thrombus formations. Based on histopathological and endoscopic results, the presence of an underlying disease was suspected. Flow cytometric analysis showed that erythrocytes and granulocytes had 5.5 and 86.4% CD55- and CD59-negative cells, respectively. The patient was ultimately diagnosed with PNH and considered severely ill, given the ischemic colitis-induced abdominal pain and the need for red blood cell transfusions (4-6 units per month). Accordingly, the patient was administered ravulizumab. Ischemic enteritis did not relapse following ravulizumab administration, and transfusion dependence improved. If a patient with ischemic colitis presents atypical lower gastrointestinal endoscopic findings, it is important to explore the presence of an underlying disease.

Investigational workout for the diagnosis of paroxysmal nocturnal hemoglobinuria

Investigational workout for the diagnosis of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria with sagittal vein thrombosis as the initial presentation

Introduction: Paroxysmal nocturnal hemoglobinuria is a rare disease that presents with a variety of symptoms including hematuria, thrombosis, and other non-specific symptoms. Venous thrombosis is not uncommon in paroxysmal nocturnal hemoglobinuria (PNH). However, a thromboembolic event as the presenting symptom of PNH is rare and can be life-threatening, when affects the sagittal veins in the brain. Case Report: A 28-year-old female presented to the facility with left-sided hemiparesis. Initial workup revealed a right-sided subacute hemorrhagic infarct of the parietal lobe, and magnetic resonance imaging (MRI) venography demonstrated extensive venous thrombosis involving the sagittal, straight, and transverse sinuses, with secondary edema in the involved hemisphere. Thrombotic events may affect up to 50% of PNH patients and account for at least one-third of mortality in PNH. Although disease presentation in PNH is variable, cerebral venous sinus thrombosis as the first thrombotic event in disease presentation along with the absence of hematuria makes this case unique. High suspicion of thrombosis and a differential diagnosis of PNH should be considered in young patients presenting with these symptoms, even in the absence of hematuria. Ravulizumab has significantly reduced thrombotic events, and these therapies should be immediately commenced upon high suspicion of thrombosis. Allogeneic hematopoietic stem cell transplantation offers the only curative approach for PNH to date. Conclusion: Paroxysmal nocturnal hemoglobinuria is a very rare and life-threatening disease. Hematuria is not always present in this disease. Complement inhibitor therapy should be started immediately upon confirmation of the diagnosis to decrease future thrombotic events. Paroxysmal nocturnal hemoglobinuria patients may need allogeneic hematopoietic stem cell transplantation, which is the only curative approach available today.

Treatment Outcomes of Complement Protein C5 Inhibition in 509 Patients with Paroxysmal Nocturnal Hemoglobinuria in the United Kingdom

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare hematological disorder. Affected individuals experience chronic intravascular hemolysis and an increased tendency to thrombosis. Clinical symptoms can include hemoglobinuria, dysphagia, abdominal pain, breathlessness, erectile dysfunction, fatigue and lethargy. Inhibition of terminal complement by targeting the complement protein 5 (C5) is currently the standard care used to treat PNH in the UK. Eculizumab and ravulizumab, bind to C5, stopping its cleavage to C5a and C5b and thereby preventing terminal complement activation and its consequences. Method: A retrospective analysis of case records of all patients with PNH treated with eculizumab or ravulizumab in the UK since May 2002 was performed. Clinical features at presentation and diagnosis, prior history of bone marrow failure (BMF) as well as outcomes whilst on C5 inhibition (C5i) were collected. Results: 509 patients with PNH (237 male and 272 female) have been treated with eculizumab or ravulizumab between May 2002 and July 2022. Mean age at diagnosis was 43 years and 11 months. A history of BMF was documented in 246 patients (48.3%) of which 215 had aplastic anemia (42.2%) and 31 (6.1%) had myelodysplastic syndrome. One hundred and thirty five patients (26.5%) had experienced thrombosis prior to commencing C5 inhibition. There were 192 documented thromboses in these 135 patients with 73 (38.0%) being intra-abdominal and 57 (29.7%) being arterial (mainly myocardial infarction and stroke). Symptoms experienced by patients at diagnosis include anemia: 358 (70.3%), fatigue: 316 (62.1%), hemoglobinuria: 225 (44.2%), breathlessness: 114 (22.4%), abdominal pain: 92 (18.0%), dysphagia: 36 (7.1%) and erectile dysfunction: 32 of the 237 male patients (13.5%). The median time from developing symptoms to diagnosis of PNH was 5 months (interquartile range 0-18, available in 454 cases) with 86 (16.9%) patients being originally referred to a different specialty, mainly urology, for investigation. Sixty-four (12.6%) patients were misdiagnosed with an alternative condition before the correct diagnosis of PNH was made. Four hundred and seventy-four, (93.1%) patients have been treated with eculizumab with 77 (16.2%) requiring higher doses than is recommended in the summary of product characteristics due to pharmacokinetic breakthrough hemolysis. In 2021 ravulizumab became available for use on the National Health Service and 237 patients treated with eculizumab have switched to ravulizumab. The majority of patients have had no adverse clinical issues but 3 patients have reverted back to eculizumab due to side effects. Thirty-five patients (6.9%) presented after 2021 and have been treated with ravulizumab alone. The median PNH granulocyte clone size at initiation of C5i was 85.5% (interquartile range 67-95%, available in 494 cases). Indications for complement inhibition: hemolytic disease: 325 patients (63.8%), thrombosis: 93 patients (18.3%), other complication due to PNH: 27 patients (5.3%), pregnancy: 26 patients (5.1%), pre-allogeneic bone marrow transplantation: 14 patients (2.8%), exceptional cases after discussion at a joint service meeting: 17 patients (3.3%), indication unknown: 7 patients (1.4%). Mean hemoglobin levels 12 and 24 months after initiating C5i were 107.7g/l (in 421 patients) and 108.6g/l (in 374 patients) respectively. In the most recent 12 months on C5i 123 out of 446 (27.6%) patients needed transfusions with 94 of the 123 (76.4%) requiring 3 or more transfusions. There were 23 thrombotic events on C5i (4.5%). Over the 20-year period, 91 patients have died equating to a 79.0% survival rate (Figure 1). Infection was implicated in the cause of death in 44 individuals (48.4%). There have been 11 cases of Neisseria Meningitidis septicemia in 10 individuals over 3,130 years of treatment with C5i and 1 death from this, equating to a meningococcal infection rate of 1 event per 284 years and 6 months. Clonal evolution to acute leukemia occurred in 7 cases (1.4%) and to myelodysplastic syndrome in 10 cases (2.0%). Conclusions: We report 20 years of C5i experience from the UK, for patients with PNH. Our experience of treatment with C5i confirms the continued long-term safety and efficacy of eculizumab and ravulizumab. Overall survival remains high on C5i and complications such as thromboses, meningococcal infection and clonal evolution are uncommon events. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost to Treat Newly Diagnosed Patients with Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Analysis

Background Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder that renders affected patients’ red blood cells susceptible to premature destruction (i.e., hemolysis) and can lead to excess morbidity. Current pharmacological treatments for PNH include not only eculizumab, launched in 2007, but more recently approved treatments such as ravulizumab and pegcetacoplan. Even among patients treated with currently available therapies, suboptimal C5 inhibition or exacerbating factors such as infections may result in breakthrough hemolysis or other PNH-related complications. Given the evolving treatment landscape and challenges in treatment and diagnosis, it is unclear what the total and setting-specific costs and health care utilization are among patients newly diagnosed with PNH. Objectives To determine healthcare resource utilization and costs for newly diagnosed patients with PNH. Methods United States (US) adults with a new ICD-10 diagnosis of PNH (D59.5) from April 2016 to December 2020 identified in the OptumLabs claims data were included. The date of the first claim with a PNH diagnosis was defined as the index diagnosis date. Patients were required to have at least 6 months of continuous enrollment before the index diagnosis date to identify newly diagnosed patients and at least 6 months of continuous enrollment after the index diagnosis date for analysis. Comorbidity was measured with the National Cancer Institute (NCI) comorbidity index. All-cause healthcare resource utilization (HCRU), all-cause costs, PNH-related HCRU (defined as claims with an ICD-10 code of D59.5 in any position), and PNH-related costs were measured on a per-patient per-month (PPPM) basis for inpatient admissions, emergency department (ED) visits, office visits, and other outpatient visits for the 6-month follow-up period. The PPPM frequency of blood transfusions and utilization of bone marrow transplant were also assessed. The cost and HCRU results were age-weighted to be representative of the US population. Results Of the 749 patients with an ICD-10 diagnosis of PNH (D59.5) during the selected timeframe, 381 were newly diagnosed patients who met all inclusion criteria. In the unweighted sample, approximately half of the patients (50.9%) were female, with an average age of 61.3 (SD = 17.8), and the average NCI Comorbidity Index was 0.57 (SD = 0.65). Of the 381 patients in the weighted sample, 149 (39.1%) had an inpatient admission. Of these inpatient admissions, 86 (57.7%) were PNH-related. For patients with at least one inpatient admission, the mean length of stay (LOS) was 2.2 days (SD = 3.0) and the median LOS was 1.0 days. One hundred twenty-three (32.3%) PNH patients had an emergency department (ED) visit in the first 6 months after the index diagnosis, 12 of which (9.8%) were PNH-related. Nearly all patients had office visits (97.9%) or other outpatient visits (96.6%) in the 6-month follow up period. Blood transfusions occurred in 18.6% of the PNH population, while bone marrow transplant was relatively rare (result suppressed due to small cell size). (Table 1) The PPPM total cost for newly diagnosed patients was $10,480, or $125,758 per patient per year. Of these costs, 39.0% ($4,090 PPPM) were for pharmacy costs (including infusion costs), 33.9% ($3,551 PPPM) were for inpatient costs, 6.4% ($672 PPPM) were for office visits, 0.9% ($94 PPPM) were for ED visits, and 19.8% ($2,073 PPPM) were for other outpatient visits. The total PNH-related cost was $4,763 PPPM, accounting for 45% of the total cost. PNH-related pharmacy costs for eculizumab and ravulizumab, including administration, accounted for 60.2% ($2,868) of PNH-related costs (no pegcetacoplan use was observed since it was approved in 2021). PNH-related inpatient costs accounted for 28.0% ($1,333), office visits accounted for 3.6% ($172), and other outpatient visits accounted for 8.1% ($386) of total PNH-related costs. ED visits were rarely flagged with the PNH ICD-10 code, with less than 0.1% of PNH-related costs coming from the ED. (Figure 1) Conclusions Despite new treatment options available for PNH, HCRU and associated costs remain high with 39.1% of PNH patients having an inpatient visit in the first 6 months after diagnosis. Nearly one in five newly diagnosed PNH patients still require at least one blood transfusion in the follow-up period, signaling further unmet medical need in PNH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Allogenic Hematopoietic Stem Cell Transplant in Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Study from Pakistan

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of clonal hematopoiesis1 .The resulting abnormalities in complement regulatory proteins can manifest as hemolysis, thrombosis, and marrow failure2. The management and clinical outcomes of patients with PNH significantly changed with the development of complement inhibitor therapies3. Allogenic Hematopoietic stem cell transplant (HSCT) despite being the sole curative option for PNH is not recommended as first line therapy owing to its toxicities 4,5. Current indications for HSCT include a suboptimal response to eculizumab, severe AA/PNH, clonal evolution to myelodysplastic syndrome (MDS), or acute myelogenous leukemia2. However, in low and middle income countries (LMIC) where complement inhibitor therapies are not available, allogenic HSCT still remains the only treatment option for classical PNH as well as for PNH in the setting of another specified bone marrow disorder. Objective: To analyze the efficacy and safety of Allogenic HSCT in patients with paroxysmal nocturnal hemoglobinuria (PNH). Study design: Observational, retrospective study. Place and duration of study: Armed Forces Bone Marrow Transplant Centre/ National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) Rawalpindi, Pakistan, from June 2008 till February 2022. Methodology: From June 2008 till February 2022, a total of 65 patients of PNH were registered at AFBMTC/NIBMT. Out of these16 patients underwent allogenic HSCT and were included in the final retrospective analysis. PNH diagnosis was confirmed by flow cytometry by the demonstration of GPI-negative cells in at least two cell lineages i.e neutrophils, red blood cells (RBCs) in 62.5% (n=10) patients and by fluorescent aerolysin (FLAER)-based assay in 37.5% (n=6) patients. Median time from diagnosis to transplant was 380 days. All patients received HLA identical sibling donor HSCT. Stem cell source was Bone marrow harvest (BMH), BMH plus peripheral blood stem cell (PBSC) and PBSC alone in 81% (n=13), 12.5% (n=2) and 6% (n=1) patients respectively. Graft versus host disease (GVHD) prophylaxis was with Antithymocyte globulin (ATG) + Cyclosporin (CSA) in patients receiving NMA conditioning or ATG + CSA + short term Methotrexate (MTX) in those receiving MAC. Results: Median age of the study cohort was 24 years (range, 18 to 42 years) and all were male. 68.7% (n=11) patients received immunosuppressive therapy before HSCT with partial or no response. History of thrombosis prior to HSCT was present in only one patient (cPNH). Allogenic HSCT done for classical PNH (cPNH) in 75% (n=12) patients and for PNH in the setting of another specified bone marrow disorder (PNH/AA) in 25% (n=4) patients. Patients with classical PNH received Myeloablative conditioning (MAC) i.e Flu150Bu12.8IV (75%, n=9), Bu16Cy120 (8.3%, n=1), or Flu150Cy200 (8.3 %, n=1) except for one patient who received Flu150Cy160. Patients with PNH/AA, received non myeloablative conditioning (NMA) i.e Flu150Cy120, except for one who received Flu150Bu12.8IV. Out of 16 patients, 94% (n=15) patients achieved successful engraftment with full donor chimerism. One patient (cPNH) had Primary graft failure. Median time to neutrophil and platelet engraftment was day +12 and day +22 respectively. Disease relapse was monitored by donor chimerism till Day +180 post BMT and thereafter by peripheral blood counts. PNH clone post BMT was not tested. Incidence of acute GVHD grade I/II involving skin and gut, was 25% (n=4). No incidence of chronic GVHD was noted. One patient (PNH/AA) had secondary graft failure on Day +46. With a median post-transplant follow-up of 15 months (range, 4 to 157) overall survival (OS) was 93.7% and disease-free survival (DFS) was 87.5%. Conclusion: In resource constrained, LMIC, where complement inhibitor therapies are currently unavailable, allogenic HSCT remains the valid option for treatment of PNH, with good overall survival rate and acceptable treatment related toxicites. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Experience and Patient Characteristics from Opera: A Real-World Study of Pegcetacoplan Treatment

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Chronic hemolysis leads to anemia, which can result in persistent fatigue and dependance on transfusions, affecting the overall quality of life (QOL) of patients with PNH. Pegcetacoplan (PEG; US brand name Empaveli®) is the first approved C3 inhibitor for US adults with PNH. Although clinical trials have assessed the efficacy of PEG, which include patient-reported outcomes, there is no information on the use of PEG in a real-world setting. Aims To provide the first report of trends in hemoglobin (Hb) values and baseline QOL (measured by patient-reported fatigue and cognitive impairment) from OPERA, a descriptive, observational exploratory outcomes study, presenting the first real-world data describing PEG treatment for adults with PNH post-approval. Methods This single site opt-in study recruited patients in the US, following a valid PEG prescription from a licensed medical professional. Patients ≥18 years of age, diagnosed with PNH and prescribed PEG, were electronically consented and then enrolled to participate in the OPERA study, as approved by the internal review board. OPERA collected information from routine care and did not direct or suggest any medical interventions. In this observational setting, Hb lab values were reported (by the patient/site) at varying timepoints when available. Participants self-reported QOL status from baseline over a 12-month period through monthly phone calls and quarterly online patient-reported outcome measures (PROMs). During monthly phone calls, participants were asked to report their most recent Hb levels (typical normal range: male, 13.6-18 g/dL; female, 12-16 g/dL) if available from their regular primary care visits in the previous month. Online PROMs collected data using validated QOL instruments including the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (0-52 total score) and the Patient-Reported Outcomes Measurement Information System (PROMIS) scale for Cognitive Abilities (23.27-67.09 t-score). Lower scores on each measure represent greater levels of fatigue or cognitive impairment. Results Participants enrolled in OPERA with a 30-70% monthly range to opt-in. Of 17 participants enrolled with available baseline Hb values, mean (range) age was 45.76 (20-70) years, and 8 were female. No OPERA participants were previously enrolled in a PEG clinical trial. All participants were prescribed and received the label recommended dose of PEG (1080 mg, twice weekly). All participants reported prior treatment with either eculizumab, ravulizumab or both, before starting PEG. Additional dosing information and time since PNH diagnosis can be found in the Table. The mean (SD) baseline Hb levels from 17 OPERA participants was 8.90 (2.19) g/dL, which was similar to the mean (SD) baseline Hb levels (8.69 [1.08] g/dL) for 41 patients in the previously published phase 3 PEGASUS (NCT03500549) trial. Among 4 participants with available data after 1 month of PEG use, mean (SD) Hb levels increased to 11.95 (1.84) g/dL (mean change from baseline +2.83 (1.35) g/dL) which was similar to the mean (SD) Hb levels of 11.55 (1.62) g/dL seen in 40 PEGASUS participants after 1 month of treatment. QOL data was available at baseline in 12 participants and the mean (SD) baseline FACIT-Fatigue score was 30.25 (15.63), which was similar to the mean (SD) baseline FACIT-Fatigue score of 32.2 (11.4) from the PEGASUS trial, but below the reported mean FACIT-Fatigue population norm of 43.6 (Cella, et al. Cancer. 2002). Additionally, the mean (SD) PROMIS-Cognitive Abilities t-score for patients with available QOL data (n=12) was 43.57 (9.11), which is lower than the published population norm of 50 (Saffer, et al. Psychiatry Research 2015). Conclusions This first real-world study of adults with PNH receiving PEG indicates a positive trend in Hb levels in participants after 1 month of use. These early experiences are similar to previously reported changes in Hb levels after PEG treatment in phase 3 clinical trials (Hillmen et al, NEJM 2021). At baseline, participants with PNH report a considerable amount of fatigue and cognitive impairment, indicating poor QOL with previous C5 inhibitor treatment. More research is needed to corroborate the findings of this first analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal