Clinical Profile and Long-Term Outcomes of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab in a Real-World Setting: High Frequency of Anemia Despite Decreased Intravascular Hemolysis

Background: Eculizumab, an anti-C5 antibody, was approved for the treatment of patients (pts) with symptomatic paroxysmal nocturnal hemoglobinuria (PNH) in 2007 and has been the standard of care for over a decade. However, published data on real-world outcomes of eculizumab-treated pts with PNH are limited. The aim of this study was to describe the clinical profile of pts with PNH treated with eculizumab by characterizing their short- and long-term laboratory and clinical outcomes. Methods: This retrospective study (Versmold et al, Blood 2020) used preexisting medical records of eculizumab-treated pts with PNH (treatment duration ≥24 weeks [wks]) treated at the University Hospital Essen, Germany prior to April 2018. Anonymized data were collected via electronic case report forms. Laboratory data were extracted from the hospital computer system. Lactate dehydrogenase (LDH), hemoglobin, absolute reticulocyte count (ARC), and bilirubin profiles were assessed at baseline (12 months before treatment) and during the treatment phase (up to 13.2 years [yrs] follow-up). Breakthrough hemolysis (BTH) was defined as ≥1 new symptom or sign of intravascular hemolysis (including fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction in the presence of elevated LDH [≥2 × the upper limit of normal (ULN)] after reduction of LDH to ≤1.5 × ULN). Extravascular hemolysis was defined as persistence of reticulocytes >100 × 10 9/L with bilirubin >1 × ULN and positive direct Coombs test or reticulocytes >100 × 10 9/L with bilirubin >1 × ULN and ≥1 positive C3c or C3d test. Complete hematologic response was zero blood transfusions with hemoglobin ≥12 g/dL and LDH ≤1.5 × ULN and major hematologic response was zero blood transfusions with hemoglobin ≥12 g/dL and LDH >1.5 × ULN within any 24-wk window (Risitano et al, Front Immunol 2019). Transfusion-dependence was ≥2 blood transfusions within any 24-wk period. Pts transferred from other centers or within 24 wks of treatment were excluded due to missing baseline data. Results: The study included 56 pts with PNH (mean age: 42.9 yrs [± 17.6]; 46.4% female) treated with eculizumab for ≥24 wks (mean follow-up: 5.24 yrs [± 3.25]) during the study period. The median duration from diagnosis to starting eculizumab was 1.57 yrs. Overall, 18 pts (32.1%) had aplastic anemia at diagnosis, 10 (17.9%) had symptoms of high disease activity, and 34 (60.7%) had a blood transfusion in the prior 12 months. The most reported disease-related symptoms at baseline were anemia (28.6%), fatigue (26.8%), thrombosis (21.4%), dyspnea (17.9%), dysphagia (10.7%), erectile dysfunction (10.0%), kidney complications (8.9%), abdominal pain (8.9%), and hemoglobinuria (7.1%). Mean hemoglobin (n=44) was 9.67 g/dL [± 2.06] and LDH in the past 12 months (n=47) was 1480 U/L [± 1010]. During the first 24-wk treatment phase, 37% (20/54) of pts had LDH >1.5 × ULN, 31% (14/45) had ARC >1.5 × ULN, and 17% (8/47) had hemoglobin ≥12 g/dL (Figure). Among pts with response data, 15% (7/47) had complete hematologic response and 2% (1/47) had major hematologic response within 24 wks. Documented BTH with symptoms occurred in 11% (6/56). Moreover, 23% (13/56) of pts were transfusion-dependent, increasing to 39% (22/56) when including pts who had ≥1 transfusion during the first 24 wks of treatment. Six pts (11%) received a higher-than-labeled dose (600 mg intravenous [IV] weekly for 4 wks, 900 mg IV 1 wk later, then 900 mg IV every 2 wks thereafter) of eculizumab. Over the long term (ie, between 25 and 246 wks), 11.1-34.7% of pts received blood transfusions and 7.0-21.7% had LDH >1.5 × ULN in any 24-wk window; whereas 36.1-72.7% had ARC >1.5 × ULN (Figure). Moreover, 65.8-77.3% of pts had hemoglobin <12 g/dL within any 24-wk period and 69.0-77.2% did not meet the criteria for major or complete hematologic response during any 24-wk period from wks 25 to 246. During the treatment phase, no meningococcal infections were reported. Conclusions: In this long-term real-world study, a considerable proportion of pts with PNH treated with eculizumab did not achieve optimal clinical outcomes with an ongoing burden of disease (ie, low hemoglobin level with high reticulocyte count due to extravascular hemolysis, BTH, etc.). Future exploration of other therapies that improve pt outcomes could help to address remaining unmet medical needs. Figure 1 Figure 1. Disclosures Alashkar: Alexion: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria; Bluebird Bio: Honoraria. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Xu: F. Hoffmann-La Roche AG: Current Employment. Liu: Genesis Research: Current Employment. Katz: F. Hoffman-La Roche Ltd: Current Employment. Shang: F. Hoffman-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Roeth: Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bioverativ, a Sanofi company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Kira: Consultancy, Honoraria.

MO929KIDNEY TRANSPLANTATION IN MONOCLONAL IMMUNOGLOBULIN DEPOSITION DISEASE: A REPORT OF 6 CASES

Background and Aims Monoclonal immunoglobulin deposition disease (MIDD) is a systemic rare condition that usually leads to end stage renal disease. Treatment of patients with a bortezomib-based regimen followed by autologous stem cell transplantation (ASCT) has been increasingly used, with improvements in the response rates and the renal graft outcomes in kidney transplant recipients Method Retrospective study of 6 patients diagnosed of MIDD with complete response but not renal response after hematologic treatment that underwent kidney transplant in our institution between 2010 and 2019. Results A total of 6 patients (5 women) were analyzed, with mean age at diagnosis of 47 years (range 40-53). At presentation their mean eGFR was 18 mL/minute (range 9-25) and mean proteinuria of 5.5 g (range 0.290-12.5). The deposit was kappa type except in 1 case (heavy and light lambda type chains). In all of them there was an absence of monoclonal component in blood and urine but positive immunofixation in 5 cases (2 only in urine). 3 started chronic hemodialysis during admission and the others at 3, 5 and 44 months after diagnosis. As hematological treatment, all received bortezomib followed by ASCT, being under complete hematological response at the time of kidney transplant. It was performed at 28 months on average from ASCT (range 11-42), with mean kappa/lambda ratio of 2.6 (range 1.33-3.75). 3 patients received induction with thymoglobulin and 3 with basiliximab, followed by triple therapy with tacrolimus + prednisone + mTOR inhibitor (4 patients) or mycophenolate (2 patients). During a median follow-up of 20,5 months from kidney transplant and 54 months from ASCT, 1 patient experienced hematologic relapse and 2 had hematologic progression (one of them with MIDD relapse in the allograft) requiring treatment. The patient with organ relapse received Daratumumab monotherapy achieving complete hematologic response but graft failure. The other 5 patients had functional graft with median serum creatinine 1.68 mg/dl. Conclusion In patients with MIDD and sustained complete hematologic response, a kidney transplant can be considered. The optimal approach to treatment of hematologic relapse or recurrence of MIDD after kidney transplant remains to be determined

Impact of hematologic complete response in the treatment of sporadic late-onset nemaline myopathy associated with monoclonal gammopathy

Monoclonal gammopathy of undetermined significance (MGUS) may be associated with pathologies with severe neuromuscular manifestations such as sporadic late-onset nemaline myopathy (SLONM). We describe a difficult to diagnose case of SLNOM with marked clinical improvement after achieving gammopathy complete hematologic response.

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

P0140RENAL PATHOLOGICAL CHANGES AFTER SUCCESSFUL TREATMENT OF LCDD USING CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE: A CASE REPORT

Background and Aims The combined of cyclophosphamide, thalidomide and dexamethasone (CTD) haven’t reported in treatment of LCDD, and how the renal pathologic injury changes after treatment is still unknown. Method Here we descript a LCDD patients who undergone repeated renal biopsy after treatment. Results We report a 56-year-old woman presented with nephrotic syndrome, impaired renal function, and serum M-protein of IgG lambda. First renal biopsy showed severe nodular glomerulosclerosis with single lambda light chain linear deposit along GBM. The patient treated with 14 cycles CTD regimen, and reached the complete hematologic response and renal response. At the 29 months of follow up, the repeated biopsy showed the glomerular nodular sclerosis attenuated significantly, only trace granular electron-dense deposits along inner side of GBM.(Details in figure 1: The pathological findings of the first (A-D) and second (E-H) renal biopsy.) Conclusion This case highlights the hematologic response not only can improve the renal function, but also alleviate the renal nodular sclerosis. And the low-cost regimen, CTD, maybe a good choice.

Association between Hasford Scoring System and Hematologic Response in Chronic and Accelerated Phase of Chronic Myelocytic Leukemia Patient with Imatinib for Three Months

Background: Hasford score is a scoring system which was made in interferon treatment era to assess chronic myelocytic leukemia (CML) prognosis. Complete hematologic response (CHR) is the milestone of prognosis evaluation. CHR achievement will significantly increase survival. Imatinib is a revolutionized treatment that change the prognosis of CML. With the advent of Imatinib, lessened the prognostic impact of the Hasford score to predict prognosis.Materials and Methods: An observational analytic with prospective cohort study conducted in oncology outward division Dr. Soetomo hospital Surabaya, from July until October 2018. Hasford score determined in 32 patients at the beginning of the study, given imatinib and followed up regularly for 3 months to know the hematologic response. Data were analyzed using Fisher exact test which was considered significant if p<0.05.Results: Median age was 39 years old, male 37.5% and female 62.5%, the median spleen was 18 cm, median hemoglobin was 9.1 g/dL, median leukocyte was 180x109 /L, median thrombocyte was 645x109 /L, median eosinophil was 2.9%, median basophil was 4.6%, median myeloblast was 6%. Hasford score showed 3.1% in low risk, 25% in intermediate risk and 71.9% in high risk. As much as 78.1% complete hematologic response was found in patient, and 21.9% was incomplete.Conclusion: There was no association between Hasford scoring system and hematologic response in chronic and accelerated phase of chronic myelocytic leukemia patient with imatinib for three month. Hasford score had no impact in hematologic response with imatinib.Keywords: Hasford score, hematologic response, CML, imatinib

Therapeutic Responses of Imatinib and Nilotinib among CML Patients in Hasan Sadikin Hospital Bandung

Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative malignancy with an estimated incidence in the world of 1-2 cases per 100,000 adults. The use of Tyrosine Kinase Inhibitors (TKI) as a therapy for CML is still the first choice for treatment, but some cases show a high level of resistance or intolerance to TKI therapy. This study aims to identify the therapeutic responses of imatinib and nilotinib among CML patients in Bandung.Method: This study is an analytical descriptive study of CML patients at Hasan Sadikin Hospital’s Hematology and Medical Oncology Outpatient Clinic in 2017. The total number of samples in this study is 244 patients, consisting of 199 patients with Imatinib therapy and 45 patients with Nilotinib therapy. The data is processed using SPSS Statistics 22.0 software.Result: The results showed that CML patients had a median age of 42 years, sex ratio of 1: 1 and the highest prevalence was in Bandung City (21.3%). Hematologic response is dominated by complete hematologic response, as high as 72.86% with Imatinib and 66.67% with Nilotinib. Molecular response 3-6 months post therapy is dominated by suboptimal response in as many as 36,8% with Imatinib and failure in as many as 50% with Nilotinib. Molecular response 12-18 months post therapy is dominated by failure in as high as 69,4% with Imatinib and 52,4% with Nilotinib.Conclusion: Based on the molecular response, the rates of suboptimal response and resistance are quite high. Regular monitoring standards of therapy for CML patients are needed to identify TKI resistance so alternative therapies can be provided to improve the outcomes.

All Itching Is Not Benign; A Case of Refractory Hypereosinophilic Syndrome Treated with Off Label CD52 Inhibitor-Alemtuzumab

INTRODUCTION Usually attributed to allergies or parasites (Seifert et. al Medline 2008) eosinophila is often overlooked. However hypereosinophilia (absolute eosinophil count >1.5 X 109/L on two separate exams one month apart or with pathologic confirmation) can have serious manifestations. When hypereosinophilia is associated with eosinophil-mediated organ damage or dysfunction, a hypereosinophilic syndrome (HES) exists. With an unpredictable course, eosinophilic infiltration commonly affects the skin (eczema), lung (dyspnea), & GIT (gastritis). However life-threatening damage to the CVS (myocarditis) or the CNS may occur. Clinically HES is subdivided into: myeloid variants (M-HES), T lymphocytic variants (L-HES), Familial HES, Idiopathic HES, Organ-restricted, and specific/defined syndromes associated with hypereosinophilia (Roufosse et. al Respiration 2016). Treatment is based upon symptoms and the molecular presence of Fip1-like1-platelet-derived growth factor receptor alpha. If present, patients are initially treated with imatinib mesylate, while those with other types are given a trial of steroids (Cools et. al N Engl J Med 2003). Regrettably complete remissions are rare and long term corticosteroid uses are infamous. Corticosteroid-refractory HES can be fatal with a reported 10 year survival of <50% (Verstovsek, S et. al Clinical Cancer Res 2009). Options are limited for non-responders or recurrence. We present a patient that successfully reached clinical & pathological remission after treatment with alemtuzumab, an anti CD-52 monoclonal antibody. CASE A 71y/o M with a history of COPD complained of localized pruritus to his back that improved with antihistamines and topical steroids. After a few years he started to experience deterioration in his symptoms and was found to have eosinophilia. Any attempts to taper his oral steroids lead to a widespread manifestation of pruritus and lichenification. At the Mayo Clinic a comprehensive workup was performed including a bone marrow and skin biopsy that revealed perivascular and interstitial mixed dermal inflammation with eosinophils. He had an absolute eosinophil count of 6.92 X 109/L (N<0.5 x 109/L). FISH and 2,3-dinor 11B-Prostaglandin F2a, U levels were within normal limits. Serology was negative for multiple bacteria and parasites. A bronchoalveolar lavage revealed increased levels of eosinophils, concerning for lung involvement. Between mepolizumab, an anti IL-5 humanized monoclonal antibody used in severe eosinophilic asthmatics and alemtuzumab, insurance approved of the latter. After 12 treatments he reached complete remission and resolution of symptoms with a normal blood eosinophil level of 0.1 X 103/uL. A repeat bone marrow biopsy did not reveal any primary hematolymphoid neoplasm. DISCUSSION Alemtuzumab is a monoclonal antibody that targets CD 52, a cell surface glycoprotein present on T and B lymphocytes, monocytes and eosinophils. Approved for use on B-cell chronic lymphocytic leukemia and relapsing multiple sclerosis, the use of alemtuzumab on HES is justified by the evidence that CD52 is highly expressed on eosinophils but is notably absent on neutrophils and bone marrow precursors (Verstovsek, S et. al Clinical Cancer Res 2009). Prior studies have been promising regarding the efficacy of alemtuzumab and HES. Out of 12 patients that were followed for 3 years, 10 achieved complete hematologic response - defined as normalization of the absolute eosinophil count (Strati, P. et. al Clinical Lymphoma, Myeloma & Leukemia 2012). Adverse effects have been related to the infusion (fever), and lymphopenia. There is an increased risk of opportunistic infections, especially CMV. Late complications such as secondary lymphomas may also develop. Close follow up and appropriate prophylaxis can be used to mitigate these complications. CONCLUSION Our patient responded well to alemtuzumab, without any notable side effects. Therapy should be reserved due to early and late adverse affects but this agent has proved to be an effective treatment for HES in terms of both complete hematologic response and duration (Strati, P. et. al Clinical Lymphoma, Myeloma & Leukemia 2012). Moreover resistance is not seen, as patients with relapse were able to achieve a second remission. Data about efficacy and safety in the long-term remains lacking, but for treatment resistant and refractory HES, Alemtuzmab may be a suitable choice. Disclosures No relevant conflicts of interest to declare.