Transfusion Requirements in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria with or without a History of Bone Marrow Disorder Receiving Ravulizumab and Eculizumab: Results from a Phase 3 Non-Inferiority Study Extension

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder leading to hemolytic anemia, which can occur concomitantly with bone marrow disorders (BMD), such as aplastic anemia (AA) and myelodysplastic syndrome (MDS). Accordingly, patients with PNH often require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow failure. After demonstrating a non-inferior efficacy and safety profile in two of the largest clinical trials to date, ravulizumab was approved as a treatment for adults with PNH, including patients with an underlying history of bone marrow disease, who are transfusion dependent or independent. Aims: To assess the efficacy of ravulizumab in patients with PNH with or without an underlying pathology of AA or MDS, and to investigate the impact of ravulizumab on transfusion burden as measured by number of transfusions and total packed RBC (pRBC) units transfused over a 52-week period. Methods: This phase 3 multicenter, randomized, active-controlled, open-label study (study 301, NCT02946463) enrolled complement-inhibitor-naïve patients with PNH. Patients were aged ≥ 18 years with a confirmed diagnosis of PNH by flow cytometry and lactate dehydrogenase (LDH) level ≥ 1.5x the upper limit of normal (ULN; 246 U/L). Patients received either ravulizumab or eculizumab for 26 weeks; after which all patients received ravulizumab from week 26 to week 52. Efficacy outcomes included the proportion of patients achieving transfusion avoidance (TA), number of pRBC units transfused and the number of pRBC or whole blood transfusions (WBT) received from baseline to 26 and 52 weeks of treatment. In this retrospective analysis, outcomes were analysed for the following subgroups: AA, MDS or no BMD (medical history of AA or MDS was determined by the investigator at screening). Descriptive statistics were calculated for continuous (means) and categorical variables (numbers and percentages). Formal hypothesis testing for significance between treatment groups was not performed. Results: Of the 246 patients included in the study, 79 had a history of AA (32.1%) and 13 (5.3%) had a history of MDS. Baseline characteristics were comparable between treatment groups. From baseline to week 26, a comparable proportion of patients with AA achieved TA to those with no BMD; 75.6% for patients with AA and no BMD receiving ravulizumab, and 60.5% and 73.7% for patients with AA and no BMD receiving eculizumab, respectively (Table 1). Importantly, TA was maintained through 52 weeks, with similar proportions of patients with AA (87.1‒91.3%) maintaining TA to patients without BMD (85.7‒91.5%). More specifically, 65.9% of patients with AA and 69.2% of patients without BMD achieved TA through 52 weeks of ravulizumab treatment, and 55.3% and 63.2% of patients with AA and without BMD, respectively, achieved TA on eculizumab followed by ravulizumab. The proportion of patients with MDS who achieved TA appeared numerically lower compared with patients with AA or no BMD, however, this subgroup sample size was small. Furthermore, a lower proportion of patients on ravulizumab with AA or MDS received any transfusion from baseline to weeks 26 and 52 compared with those treated with eculizumab followed by ravulizumab: for week 26, 24.4% and 57.1% for ravulizumab versus 39.5% and 100.0% for eculizumab in patients with AA and MDS, respectively, and for week 52, 29.3% and 57.1% for patients with AA and MDS receiving ravulizumab for 52 weeks versus 44.7% and 100.0% for patients with AA and MDS treated with eculizumab followed by ravulizumab. In addition, ravulizumab-treated patients with AA or MDS had numerally fewer transfusions and units of pRBC/WBT compared with those who received eculizumab followed by ravulizumab. Overall, the exploratory nature of the analysis and small sample size means that interpretation of the data is limited. Conclusions: This analysis demonstrates that majority of patients with PNH and AA who received ravulizumab avoided the need for transfusion up to 52 weeks of treatment. Patients treated with ravulizumab for the 52-week period had numerically fewer transfusions and units of pRBC/WBT transfused compared with patients who received eculizumab followed by ravulizumab. Overall, these findings support the use of ravulizumab in complement-inhibitor-naïve patients with PNH, with or without a history of BMD. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yonemura:Alexion Pharmaceuticals: Honoraria, Research Funding. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pavani:Alexion Pharmaceuticals: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

Download Full-text

Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽

10.1182/blood-2020-140777 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Regis Peffault De Latour ◽

Jeffrey Szer ◽

Austin Kulasekararaj ◽

Jin Seok Kim ◽

Caroline I. Piatek ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Naïve ◽

Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽

10.1182/blood.v116.21.2241.2241 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2241-2241

Author(s):

Hubert Schrezenmeier ◽

Robert A Brodsky ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

History Of ◽

Equity Ownership ◽

To Receive

Abstract Abstract 2241 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

A Global Registry of Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽

10.1182/blood.v114.22.3007.3007 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3007-3007

Author(s):

Robert Brodsky ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Health Care Services ◽

Clinical Symptoms ◽

Marrow Transplant ◽

Advisory Committees ◽

Care Services ◽

History Of

Abstract Abstract 3007 Poster Board II-983 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, and pulmonary hypertension. The natural history of PNH is highly variable and has previously been captured by retrospective assessment. However, the clinical presentation and prognosis of the disease has changed with the increased awareness of PNH, the increased use of more sensitive diagnostic tests, and the availability of new treatment. Specifically, the development of targeted but potentially life-long therapies, such as terminal complement blockade, necessitates the collection of long-term outcomes data in this patient population. We have established a global PNH Registry in order to redefine the natural history of PNH capturing a wide range of patients from all over the world. The goal of the present analysis is to describe the data collected for the patients in the Registry and demonstrate its use as an ongoing repository of information on symptoms, course, complications and treatment in patients with a PNH clone. The first patient was enrolled in January 2005, with data contributed from 62 clinical sites in 12 countries on 4 continents as of July 2009. Patients are included in the Registry regardless of amount of clone, bone marrow pathology, symptoms, or treatments. Sites collect data at enrollment and every 6 months including demographics, diagnostics and flow cytometry, other lab tests including LDH, medical conditions such as bone marrow pathology and major adverse vascular events (MAVE), clinical symptoms, medications and transfusions, qualitative assessments, bone marrow transplant, and mortality. Patients complete a questionnaire every 6 months including health-related quality-of-life, symptoms, and use of health care services. As of July 2009 there were 368 enrolled patients in the Registry (51% female, 49% male). Mean age at enrollment was 43.6 ±16.7, while mean age at first PNH symptoms was 35.9±16.7. At enrollment, median GPI-deficient granulocyte percentage (GPI-DG) was 80.4%, while 10% of patients had a GPI-DG <10. Of those patients with a GPI-DG <10, 81% had bone marrow pathology (62% with aplastic anemia, 16% with myelodysplastic syndrome, 3% other pathology) compared to 38% of patients with GPI-DG 350. MAVE was increased in patients with GPI-DG 350 compared to <10 (22% vs. 8%), as were LDH levels (median 1042 vs. 239 U/L). Patients with GPI-DG <10 reported high levels of significant clinical symptoms (fatigue 59%; dyspnea 52%; abdominal pain 41%) and symptom reporting was generally increased in patients with higher GPI-DG levels. Treatment in the year prior to Registry enrollment primarily consisted of transfusions (42%), anticoagulation therapy (30%), eculizumab (29%), and immunosuppression (23%), although these varied by GPI-DG level. Clinicians assessed 14% of patients with a Karnofsky score of 70 or lower (i.e., not capable of work or normal activity). Patients' assessment of their overall health, social functioning, and fatigue worsened and use of health care services increased with higher GPI-DG. At this time, median follow up is 12.8 months, although 25% of patients have been followed for at least 30 months. Two patients received a bone marrow transplant and 8 are deceased. In conclusion, preliminary data show that greater GPI-DG is associated with less underlying bone marrow pathology, more hemolysis, more thromboses, and more patient-reported symptoms. New clinical sites and geographic regions are encouraged to participate in the Registry ([email protected]). This global PNH Registry should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Brodsky: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees. Rotoli:Author Deceased: Author Deceased. Maciejewski:Celgene: Speakers Bureau; Gemzyne: Research Funding; Taligen: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua:Alexion: Membership on an entity's Board of Directors or advisory committees. Rosse:Alexion: Membership on an entity's Board of Directors or advisory committees. Karnell:Alexion: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Effect of Romiplostim on Health-Related Quality of Life in Children with Immune Thrombocytopenia and Associated Burden in Their Parents: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽

10.1182/blood.v126.23.37.37 ◽

2015 ◽

Vol 126 (23) ◽

pp. 37-37 ◽

Cited By ~ 2

Author(s):

Susan D Mathias ◽

Xiaoyan Li ◽

Melissa Eisen ◽

Nancy Carpenter ◽

Ross D Crosby ◽

...

Keyword(s):

Sample Size ◽

Board Of Directors ◽

Research Funding ◽

Stock Ownership ◽

Platelet Response ◽

Phase 3 ◽

Advisory Committees ◽

Parental Burden ◽

Response Status ◽

Parent Proxy

Abstract Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count levels and increased risk of bleeding. Symptomatic ITP in children can have a negative impact on their health-related quality of life (HRQoL) and increase their parents' burden. The effect of romiplostim (a thrombopoietin receptor agonist) on HRQoL and parental burden was evaluated in a phase 3 study of children with ITP. Methods: In a phase 3, randomized, double-blind, placebo-controlled study on efficacy and safety of romiplostim, children (<18 years) with ITP ≥ 6 months were randomized to weekly romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT), a psychometrically-valid disease-specific HRQoL instrument (Klaassen Ped Blood Cancer2007), was administered to children and/or their parents at baseline, weeks 8, 16, and 25. All three KIT versions were used: Child self-report (to assess HRQoL of children ≥7 years), Parent/Proxy (to assess HRQoL of children <7 years via parent proxy), and Parent self-report (to assess impact of children's ITP on parental burden, for children of all ages). Each KIT version contains 26 items, summarized in a single score ranging from 0 to 100. Higher Child or Parent/Proxy KIT scores reflect better HRQoL of a child with ITP, and higher Parent KIT scores reflect less parental burden. Among efficacy endpoints of the study, overall platelet response was defined as achieving a weekly platelet response (platelet count ≥ 50 x 109/L) for ≥ 4 weeks during weeks 2 to 25, and durable platelet response was defined as achieving a weekly platelet response for ≥ 6 weeks during weeks 18 through 25. As exploratory endpoints of the study, changes in KIT scores from baseline to each follow-up assessment were estimated separately by treatment group (romiplostim or placebo) and by overall/durable platelet response status (yes/no). A mixed effects repeated measures analysis was conducted to estimate the difference in changes of Child and Parent KIT scores between romiplostim group and placebo group, controlling for baseline score, child's age, child's gender, and child's race (analysis of Parent/Proxy data was not conducted due to small sample size). Results: Sixty-two patients were enrolled and randomized to receive romiplostim (42 patients) and placebo (20 patients). Mean age was 9.6 years (range: 3-17, 16 patients <7 years), 57% were female, and 66% were white. Overall and durable platelet response was achieved by 34 and 24 patients, respectively. In general, changes in KIT scores by treatment group and overall platelet response status showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim (vs placebo) and for platelet responders (vs non-responders) (see Tables 1 and 2). Results based on durable response status were similar to those based on overall response status (data not shown). In the mixed effects analysis, greater improvement from baseline to week 8/16/25 on Parent KIT score was found in the romiplostim group vs placebo (by approximately 8 points, p-value<0.05); no significant difference was found between groups for Child KIT score. Conclusion: Romiplostim treatment is associated with reduced parental burden (measured by Parent KIT score). In some instances sample sizes were small for other KIT versions; therefore, results should be interpreted with caution. Table 1. Mean Change from Baseline in KIT Scores by Treatment Arm KIT Version Assessment week (sample size for romiplostim, placebo) Romiplostim Mean (95% CI) PlaceboMean (95% CI) Child 8 (n=28,11) 16 (n=27,10) 25 (n=28,11) 9 (4, 15) 11 (5, 16) 14 (7, 20) 9 (1, 18) 8 (-3, 20) 10 (-1, 20) Parent/Proxy 8 (n=8,2) 16 (n=8,3) 25 (n=9,3) -0.9 (-7, 5) -0.4 (-12, 11) 8 (2, 13) -40 (-108, 23) -1 (-86, 84) -10 (-80, 59) Parent 8 (n=40,16) 16 (n=39,17) 25 (n=37,16) 13 (10, 17) 15 (10, 21) 18 (12, 23) 4 (-6, 13) 12 (4, 20) 13 (4, 22) Table 2. Mean Change from Baseline in KIT Scores by Overall Platelet Response KIT Version Assessment week (sample size for responders, non-responders) Responders Mean (95% CI) Non RespondersMean (95% CI) Child 8 (n=23,17) 16 (n=22,16) 25 (n=23,16) 11 (4, 18) 11 (4, 18) 16 (8, 24) 4 (-5, 12) 8 (1, 15) 8 (1, 15) Parent/Proxy 8 (n=7,5) 16 (n=8,5) 25 (n=8,6) 0.9 (-7, 9) 4 (-10, 18) 9 (1, 17) -15 (-44, 13) -4 (-31, 22) -3 (-23, 17) Parent 8 (n=30,26) 16 (n=30,26) 25 (n=29,24) 11 (7, 14) 14 (7, 20) 17 (10, 24) 10 (3, 18) 15 (9, 21) 15 (9, 21) Disclosures Mathias: Amgen: Research Funding. Li:Amgen: Employment, Other: Stock Ownership. Eisen:Amgen Inc: Employment, Other: stock ownership. Carpenter:Amgen: Employment, Other: Stock Ownership. Crosby:Amgen: Research Funding. Blanchette:Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Other: Data Safety Monitoring Board; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Blood ◽

10.1182/blood-2020-142166 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-45

Author(s):

Antonio Risitano ◽

Ilene C. Weitz ◽

Carlos M. de Castro ◽

Jean-Jacques Kiladjian ◽

Morag Griffin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Response To Treatment ◽

Publicly Traded ◽

Phase 3 ◽

Advisory Committees ◽

Post Hoc Analysis ◽

Hematologic Response ◽

Post Hoc

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin <10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH >1.5× upper limit of normal and/or ARC >150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (<3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (>6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Download Full-text

Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria: Pharmacokinetics and Pharmacodynamics Observed in Two Phase 3 Randomized, Multicenter Studies

Blood ◽

10.1182/blood-2018-99-110858 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 626-626 ◽

Cited By ~ 6

Author(s):

Regis Peffault De Latour ◽

Robert A. Brodsky ◽

Stephan Ortiz ◽

Antonio M. Risitano ◽

Jun-Ho Jang ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Day Treatment ◽

Complement Inhibitor ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Serum Free ◽

Equity Ownership

Abstract Background/Objective: In 2 large, phase 3 clinical studies, ravulizumab (ALXN1210), an innovative C5 inhibitor administered every 8 weeks, achieved noninferiority to eculizumab in complement inhibitor-naive and -experienced patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH). The objective of this analysis was to characterize ravulizumab pharmacokinetics (PK) and pharmacodynamics (PD). Potential PD differences between ravulizumab and eculizumab were also examined to explore a possible mechanistic explanation for the robust clinical results observed in the phase 3 studies. The consistent ravulizumab vs eculizumab results across all primary and secondary clinical endpoints may be attributable to more complete inhibition of free C5 (defined as serum free C5 level <0.5 μg/mL, which is associated with complete inhibition of hemolysis in vitro). Methods: Two phase 3, randomized, open-label, noninferiority studies (NCT02946463, study 301; NCT030560040, study 302) included pts ≥18 years of age with confirmed PNH. Pts in study 301 were complement inhibitor-naive, with lactate dehydrogenase (LDH) levels ≥1.5 times upper limit of normal (xULN), and ≥1 PNH-related sign/symptom at screening. Pts in study 302 were clinically stable after having been treated with eculizumab for ≥6 months, with LDH levels ≤1.5 xULN at screening. Pts received weight-based dosing regimens of ravulizumab q8w or eculizumab 900 mg q2w in accordance with PNH labeling for 183 days. Study protocols did not allow dose escalation. Coprimary efficacy endpoints in study 301 were transfusion avoidance and LDH normalization; the primary endpoint in study 302 was percent change from baseline in LDH. Serum samples for PK/PD analyses were collected on study days 1, 8, 15, 22, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, and 183. PK/PD outcomes included serum drug concentrations as well as serum free complement protein C5 and total C5. Free C5 was quantified in ravulizumab-treated pts utilizing a Gyros-based fluorescence assay, and in eculizumab-treated pts using an electrochemiluminescence ligand binding assay. Noncompartmental PK parameters were assessed for ravulizumab. Results: In study 301, 246 pts received study drug (ravulizumab, n=125; eculizumab, n=121); 195 received study drug in study 302 (ravulizumab, n=97; eculizumab, n=98). Ravulizumab met the primary objective of statistically significant noninferiority compared with eculizumab for all primary and key secondary endpoints in both studies. The PK profile of ravulizumab was similar in both studies (and when stratified by weight-based dosing [data not shown]), with Tmax of approximately 2.5 hours (Table 1). Following population PK modeling, mean (SD) post hoc terminal elimination half-life in all 222 pts was 49.7 (8.9) days. Ravulizumab steady-state therapeutic concentrations were rapidly achieved following the first dose and were sustained throughout the 183-day treatment period in both studies. Complete suppression of free C5 was attained by the end of first ravulizumab infusion (mean serum free C5 concentrations <0.5 μg/mL) and was sustained throughout the entire 183-day treatment period for all pts at all time points in both studies. In contrast, mean free C5 concentrations did not consistently remain <0.5 μg/mL with eculizumab in either study (Panels 1 and 2). In studies 301 and 302, 15 (12.4%) and 7 (7.1%) eculizumab-treated pts experienced ≥1 individual postbaseline serum free C5 level ≥0.5 μg/mL over the 183-day treatment period. In study 301, total mean (SD) C5 levels increased in the ravulizumab and eculizumab groups from 104 (24.4) and 106 (26.3) μg/mL at baseline to 183 (36.5) and 196 (38.5) respectively, at day 183. In study 302, total mean (SD) C5 levels were elevated in the ravulizumab and eculizumab groups at baseline (203 [29.5]) and 207 [37.3] μg/mL) and remained elevated at day 183 (197 [29.3] and 227 [40.2] μg/mL). Conclusions: In 2 large, phase 3 studies of PNH pts who were either naive to or receiving prior complement inhibitor therapy, ravulizumab q8w led to immediate, complete, and sustained complement C5 inhibition in all pts, whereas the effect of eculizumab q2w was less consistent. In pts treated with ravulizumab, free C5 suppression below the free C5 threshold was associated with complete inhibition of intravascular hemolysis, providing a mechanistic basis for the consistency of the point estimates for all endpoints. Disclosures Ortiz: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy. Hillmen:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Pradhan:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Wells:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding.

Download Full-text

The Relationship between Baseline Biomarkers and Efficacy of Isatuximab in Combination with Pomalidomide and Dexamethasone in RRMM: Insights from Phase 1 and Phase 3 Studies

Blood ◽

10.1182/blood-2019-128071 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3179-3179

Author(s):

Paul G. Richardson ◽

Joseph Mikhael ◽

Thierry Facon ◽

William I. Bensinger ◽

Sandrine Macé ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Phase 1 ◽

Phase 3 ◽

Advisory Committees ◽

Blood Samples ◽

Bone Marrow Plasma

Background: Anti-CD38 monoclonal antibody therapy has become an integral component of treatment for relapsed/refractory multiple myeloma (RRMM) but not all patients respond. Identification of predictive biomarkers could help clinicians identify the best treatment course for a patient. We present baseline biomarker analyses on samples from a Phase 1 (Study 1; NCT02283775) and Phase 3 (Study 2; NCT02990338 [ICARIA-MM]) clinical study that evaluated the addition of isatuximab (Isa), an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone (Pd) for the treatment of RRMM. CD38 receptor density (RD), FCGR3A (Fc immunoglobulin receptor) genotype, and bone marrow or peripheral blood immunophenotyping were evaluated as potential predictive biomarkers for a response to the Isa-Pd regimen. Methods: Both studies enrolled similar patient populations with RRMM who had received ≥2 prior lines of therapy including lenalidomide and a proteasome inhibitor. Baseline blood samples were taken prior to first treatment in both studies; in addition, a bone marrow sample was taken during screening in Study 1. In Study 1, bone marrow plasma cells were analyzed for CD38 RD. Immune cell populations (CD19+ B-cell, CD3+ T-cell, CD4+ T-cell, regulatory T-cells (Tregs) and natural killer (NK) cells [CD56+ bright CD16+ low subset and CD56+ dim CD16+ bright subset]) were characterized using blood samples and bone marrow aspirates. Blood samples from both studies were analyzed for FCGR3A genotyping (V158 and F158 high- and low-affinity alleles). Biomarker results were correlated with response, defined as at least partial response according to IMWG criteria. Results: Study 1 enrolled and treated 45 patients with Isa-Pd. Study 2 randomized 154 patients to Isa-Pd and 153 patients to Pd. Baseline patient demographics were similar for both studies and the median number of prior lines of therapy was 3 (range: 1-10) for Study 1 and 3 (2-11) for Study 2. The overall response rates (ORR) with Isa-Pd were 62.2% (28/45) in Study 1 and 60.4% (93/154) in Study 2. In Study 1, the median CD38 RD, for 31 patients with evaluable results, was 108,172 receptors/cancer cell (range: 12,950-337,335). In patients responding to Isa-Pd (n=21), the median CD38 RD value was 120,931 (48,770-337,335) receptors/cancer cell; in patients not responding to Isa-Pd (n=10), the median CD38 RD value was 85,370 (range 12,950-309,003) receptors/cancer cell. Univariate analysis in Study 1 showed no association between CD38 RD and ORR (p=0.2870). Across five Phase 1/2 clinical studies with Isa, 4/198 patients (2.0%) had a CD38 RD level below 48770, the lowest value in a responder patient. FCGR3A genotyping results were available for both studies. Across both studies, the distribution of the F158V single nucleotide polymorphism of FCGR3A gene was 42% for F/F, 42% for F/V and 16% for V/V. In both studies, responses were observed for all 3 genotypes (Table 1). In Study 1, the observed ORRs with the Isa-Pd regimen for the 3 genotypes ranged from 50.0% to 80.0%, whereas in the larger Phase 3 Study 2, the ORR was more similar across genotypes (range 56.9% to 65.5%). Median progression-free survival (PFS) ranged from 8.97 months to 14.78 months and Isa-Pd showed a PFS benefit vs Pd for all 3 genotypes (Table 1). In Study 1, 42 patients had at least one baseline peripheral blood immune biomarker value; of these, 17 patients were non-responders and 25 patients were responders. In addition, 41 patients had at least one baseline bone marrow immune biomarker measurement (16 were non-responders and 25 were responders). No significant difference was observed between responders and non-responders for the tested immune biomarkers in bone marrow during screening. P-values were 0.2817 (CD19+ B-cell), 0.6446 (CD3+ T-cell), 0.7780 (CD4+ T-cell), 0.1620 (Tregs), 0.9591 (NK cell), 0.8275 (CD56+ bright/CD16+ low NK cell), and 0.7389 (CD56+ dim/CD16+ bright NK cell). Similarly, there was no significant difference between responders and non-responders for the immune biomarkers in baseline blood samples. Conclusion: Biomarker analyses on samples from patients treated with Isa-Pd did not find a significant association between tumor response and baseline bone marrow plasma cell CD38 RD, FCGR3A genotype, or immunophenotypes in bone marrow plasma cells or peripheral blood. These results suggest there is no benefit in prescreening patients for these parameters before treatment with Isa-Pd. Disclosures Richardson: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bensinger:Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau. Macé:Sanofi: Employment. Chiron:Sanofi: Employment. van de Velde:Sanofi: Employment. Campana:Sanofi: Employment. Liu:Sanofi: Employment. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

Download Full-text

Classical Hodgkin Lymphoma Patients Have an Increased Incidence of Idiopathic Acquired Aplastic Anemia

Blood ◽

10.1182/blood-2018-99-110032 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5098-5098

Author(s):

Taylor Linaburg ◽

Adam R. Davis ◽

Noelle V. Frey ◽

Daniel J. Landsburg ◽

Stephen J. Schuster ◽

...

Keyword(s):

Bone Marrow ◽

General Population ◽

Aplastic Anemia ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Advisory Board ◽

Classical Hodgkin Lymphoma ◽

Advisory Committees ◽

History Of

Abstract Idiopathic acquired aplastic anemia (AA) is a rare immune-mediated bone marrow aplasia of unknown etiology. Interestingly, we noted several cases of AA developing after a previous diagnosis of classical Hodgkin lymphoma (HL). Due to the rarity of both HL and AA, we hypothesized that their co-occurrence represents a non-random association that may be etiologically significant. To evaluate this potential association, we analyzed the prevalence, incidence and characteristics of patients with co-occurring AA and HL at our institution and through a systematic literature review. Using a defined search of electronic medical records for patients seen at our institution between 2005 and 2018, we identified 4 patients with severe AA who were also diagnosed with HL. The prevalence of AA in patients with HL at our institution (0.2%; 4 of ~2040) was in agreement with the prevalence of AA in published cohorts of HL patients (e.g., 1 in 138 - 200; p 0.205). Using a conservative incidence measure of AA, we found that patients with HL have a striking, over 20-fold higher incidence of AA compared to the published incidence of AA in the general population (4 in 26,497 person-years vs 2.2 to ~7 in 1,000,000 person-years; p=0.0001). To determine the clinical and pathologic characteristics of AA in patients with a history of HL, we expanded our study by performing a systematic literature review. Using the search terms "Hodgkin lymphoma", "Hodgkin disease", "aplastic anemia" and "pancytopenia" in the PubMed database, we identified 7 cases of associated AA and HL diagnoses published between 1956 and 2007. Patients with other HL complications, such as post-chemotherapy myelosuppression, infections, myelodysplastic syndrome, acute leukemia, and hemophagocytic syndrome were excluded. Of the 11 total cases of AA also diagnosed with HL, the median age at AA diagnosis was 31.5 years (range of 12-49 years), with 80% of patients being male (Figure 1, Table 1). Ten of the 11 patients developed AA after or concurrent with a HL diagnosis. The median interval between HL diagnosis and AA onset was 2 months, ranging from concurrent presentation in 5 patients to a maximum of 14 years after an initial HL diagnosis. Of the 10 patients initially presenting with HL, 3 were treated with ABVD, 4 with MOPP-related regimens, and 2 patients required salvage therapy. There were no unusual hematological or other toxicities due to chemotherapy. At the time of AA diagnosis, none of the patients had marrow involvement with HL, and 5 of 10 patients were in complete remission from HL. Five patients for whom cytogenetic information was available had no cytogenetic abnormalities at AA diagnosis. Among the 4 cases from our institution, 2 had a diagnosis of marginal zone lymphoma (1 treated by splenectomy, 1 by rituximab monotherapy), and 1 had a remote history of testicular carcinoma treated by orchiectomy; all 3 cases were in remission prior to HL diagnosis. There was no family history indicative of bone marrow failure or inherited cancer syndromes. The 10 patients who developed AA concurrent with or after HL had dramatically poor outcomes, with a median survival of 14 months (range of 1 month to not reached) (Figure 1, Table 1). Of these 10 patients, 4 were treated with immunosuppression, 2 with eltrombopag, and 2 received allogeneic bone marrow transplants. Of the 4 patients who received immunosuppression, 1 evolved to MDS/AML 4 months after AA diagnosis. Five patients presented with both diagnoses concurrently: 1 was refractory to immunosuppression and achieved complete remission after receiving an allogenic bone marrow transplant, while 4 were unable to receive standard therapy for either condition. Of the historical cases, 5 of the 7 patients received supportive therapy only; the median survival for these patients was 14 months (range of 1 month to 84 months). In conclusion, the data suggest that patients with HL have a significantly higher incidence of AA compared to the general population. The underlying reason for this association is not known; however, the development of AA after HL, a unique B-cell neoplasm associated with a marked inflammatory component, without having received prior cytotoxic therapy in half of the cases, points to secondary immune dysregulation as the possible etiologic factor for AA pathogenesis. Recognition of this syndrome and improved management algorithms are needed for the management of AA presenting in patients with HL. Disclosures Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy. Schuster:Dava Oncology: Consultancy, Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Svoboda:Kyowa: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Olson:Novartis: Other: participated in 2 advisory boards in 2018; Merck: Other: participated on an advisory board in 2018; BluebirdBio: Other: participated in an advisory board in 2018.

Download Full-text

Sars-Cov-2 Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria: An Italian Multicenter Survey

Blood ◽

10.1182/blood-2021-150328 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2180-2180

Author(s):

Juri Alessandro Giannotta ◽

Bruno Fattizzo ◽

Corrado Girmenia ◽

Claudia Ielo ◽

Elisabetta Metafuni ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Recombinant Erythropoietin ◽

Advisory Committees ◽

Factor B ◽

Complement Inhibition

Abstract SARS-CoV-2 infection and vaccination have raised concerns in paroxysmal nocturnal hemoglobinuria (PNH). In fact, PNH patients carry an increased infectious risk secondary to complement inhibition treatment or associated bone marrow failure (BMF), and may therefore benefit from preventive strategies such as vaccinations. On the contrary, vaccines can be numbered among inflammatory complement amplifiers (e.g., infections, traumas, surgery), potentially triggering a disease exacerbation. In PNH patients on complement inhibitors, this phenomenon has been defined pharmacodynamic breakthrough hemolysis (BTH). Based on isolated reports of BTH following SARS-CoV-2 vaccines, we conducted a survey among 5 Italian reference centers to evaluate complications and BTH occurrence in PNH patients who completed the SARS-CoV-2 vaccination schedule from January, 2 2021 until the time of writing. Adverse events, hematologic and hemolytic parameters were recorded within 7-10 days before and after each dose of vaccine. A total of 67 patients (females/males 43/24, median age 47.6 years, range 21-90.5) were eligible for the analysis. According to the International PNH Interest Group classification, 45 patients suffered from hemolytic PNH, 20 from PNH in the context of BMF syndromes (aplastic anemia or myelodysplastic syndrome), and 2 from subclinical PNH. Fifty-five subjects (82%) were on regular complement inhibition therapy, i.e., eculizumab (N=35), ravulizumab (N=13), subcutaneous anti-C5 (N=3), anti-factor B (N=2) and ravulizumab + anti-factor D combination (N=2). Vaccines (Comirnaty/Pfizer-BioNTech N=53, mRNA-1273/Moderna N=12, and ChAdOx1 nCov-19/AstraZeneca N=2) were complessively well-tolerated, with 3 non-hematologic adverse events after the first dose (2 fever and 1 exercise-induced tachycardia, grade 1 according to CTCAE v5.0) and 2 after the second one (fever, accompanied by vomit in one patient, grade 1). During the observation period, 3 BTH and 1 hemolytic exacerbation were recorded (5.9% of patients), as detailed in Table 1. The most severe episode occurred in a young woman (Patient 3) on subcutaneous ravulizumab who experienced a hemoglobin (Hb) drop >2 g/dL, marked clinical signs of intravascular hemolysis and lactate dehydrogenase (LDH) increase >1.5 x upper limit of normal (ULN) from baseline, which is considered a clinical BTH according to the criteria proposed by the Severe Aplastic Anemia Working Party of the European group for Bone Marrow Transplantation. The patient required hospitalization for additional treatment with recombinant erythropoietin and anti-thombotic/bacterial prophylaxis. The second more severe BTH was registered in a male patient (Patient 1) on oral anti-factor B who experienced a Hb drop >2 g/dL without an overt hemolytic flare, and required hospitalization for intravenous antibiotic therapy (concomitant urinary tract infection). The remaining two patients experienced a subclinical BTH (Patient 2) and a hemolytic flare (Patient 4, not on complement inhibition). On the whole, a median delta variation from usual values of Hb and LDH of -25% (range -26+3%) and +80% (+18+105%) were observed, respectively. Of note, 3 episodes occurred after the second dose of vaccine, generally within 24-48 hours. Anti-complement drugs were not modified/discontinued in any of the 3 patients on regular treatment. Patients not experiencing BTH (94.1%) showed stable hematologic parameters after the first dose (Hb/LDH median delta variations from baseline -1%/+1%, range -14+12%/-32+40%) and the second dose of vaccine (Hb/LDH median delta variations from baseline +1%/0%, range -18+47%/-76+41%). Of note, 4 patients with a previous SARS-CoV-2 infection completed the vaccination without any complication/PNH exacerbation. In conclusion, this survey shows that BTH/hemolytic flares following SARS-CoV-2 vaccines are observed in about 6% of PNH patients, may be clinically relevant but manageable, and should not discourage vaccination. BTH has been registered mostly few days after the second dose of vaccine, suggesting a "booster" effect favoring a higher inflammatory response. Watchful clinical and laboratory monitoring is advised, in order to promptly recognize severe hemolytic flares in both treated and naïve patients. Figure 1 Figure 1. Disclosures Fattizzo: Novartis: Speakers Bureau; Kira: Speakers Bureau; Alexion: Speakers Bureau; Annexon: Consultancy; Momenta: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sica: Jazz Pharma: Consultancy; Alexion: Consultancy. Barcellini: Novartis: Other: Invited speaker, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Other: Invited speaker, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Download Full-text