Clinical Characteristics of Brazilian Patients with Paroxysmal Nocturnal Hemoglobinuria and Changing Prognosis with Eculizumab

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic cells due to acquired mutations in the phosphatidylinositol glycan class A (PIG-A) gene, which is required for glycosylphosphatidylinositol (GPI) anchor biosynthesis. This leads to partial or complete absence of all GPI-linked proteins, who are complement regulatory proteins, resulting in an increased sensitivity of the red blood cells to the action of complement. PNH is characterized by signs and symptoms related to intravascular hemolysis, hypercoagulability state, and varying degrees of medullary insufficiency. The anti-complement therapy radically changed the PNH patients outcomes. However, there are little data on the clinical characteristics of PNH in Latin American countries. Methods: We performed a retrospective analysis of 109 patients with PNH clone followed from January 1987 until July 2019 in two Brazilian centers: Universidade Federal de Sao Paulo and Hospital Sirio Libanes (Sao Paulo-Brazil). Most patients (88%) were evaluated while the others had lost follow up or died and data was obtained from their medical reports. Patients were separated into 3 groups: classical PNH (n=44) PNH associated with other bone marrow disorder(n=12), and subclinical PNH, defined as PNH clone (at least 0.01% of cells with PNH clone) associated with another bone marrow disorder (n=53, aplastic anemia in 95% of cases). Median follow up was 60 months (range: 3-394). Results: Median age at diagnosis was 41 years (range: 18-81), and 51% were male. Among the 56 patients with hemolytic PNH, 86% had fatigue, 66% hemoglobinuria, 45% abdominal pain and 16% dysphagia. Venous thromboembolism was observed in 14 cases (25%), with abdominal thrombosis in 7 cases (50%). Seven patients (13%) had arterial thrombosis (stroke or transient ischemic attack). Only 5 patients (10%) in the hemolytic group had acute renal failure and needed dialysis therapy due to a hemolytic crisis, but progressed to recovery of renal function after the event. No patient in this series had moderate or severe chronic kidney disease. Most hemolytic patients (73%) were treated with eculizumab, with a median time from diagnosis to the start of eculizumab of 25 months (range: 2-275). All eculizumab-treated patients had significant reduction in intravascular hemolysis with lactate dehydrogenase (LDH) normalization. Most had significant improvement in anemia, with increase in the median hemoglobin from 9.1 g/dL before treatment to 11.7 g/dL after eculizumab. The vast majority (94%) became transfusion-independent. Overall survival (OS) at 5 years was 100% at 5 years for classical PNH (n=44), 89% for subclinical PNH (n=53) and 71% for PNH associated with another bone marrow disease (n=12). Conclusion: The clinical data and the distribution of the three subtypes of PNH in this study in this large series of Brazilian PNH patients were similar to other published series, except for a lower frequency of venous or arterial thrombosis in hemolytic patients before eculizumab treatment and a lower frequency of chronic kidney disease in our series. We also confirmed in our series the efficacy of eculizumab in controlling hemolysis and PNH-related complications and death risk. Disclosures No relevant conflicts of interest to declare.

Plasma cell myeloma lytic lesions mimicking vanishing bone syndrome in a young patient

Plasma cell myeloma is a bone marrow disorder characterized by neoplastic proliferation of plasma cells within the bone marrow replacing normal cells. We present a case report of a 25-year-old female with bilateral lower and upper limb pains. She had been seen in various health facilities for the past 2 years with progressively worsening disability. Skeletal survey revealed multiple osteolytic lesions in the appendicular skeleton resembling vanishing bone syndrome. Ultrasound-guided biopsy was done with histological diagnosis of plasma cell myeloma. This case is unique because of the young age at presentation, HIV seropositive status and atypical appearance of the lesions.

An Unusual Case of Vomiting Caused by Myeloid Sarcoma

Myeloid sarcoma is an extramedullary mass consisting of myeloblasts that may present simultaneously or precede a bone marrow disorder. It has been reported to occur without a known preexisting diagnosis of acute leukemia, myelodysplastic syndrome or a myeloproliferative neoplasm and this is known as primary myeloid sarcoma. Here, we report a case of an 80-year-old male who presented with intermittent vomiting and significant weight loss for 3 months. The imaging and histological findings were consistent with a mesenteric myeloid sarcoma encasing the coeliac trunk and superior mesenteric artery, abutting and obstructing the proximal small bowel, causing subacute bowel obstruction. Systemic chemotherapy with low dose cytarabine achieved a reduction in the size of myeloid sarcoma and improved patient’s symptomatology but unfortunately our patient succumbed to progression 11 months later.

Cold agglutinin disease

Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.

Clinical Features of Chinese Patients with Paroxysmal Nocturnal Hemoglobinuria Diagnosed By FLAER

Objective: To summary the clinical features of Chinese patients with paroxysmal nocturnal hemoglobinuria (PNH) diagnosed by FLAER. Methods: The clinical data of 98 cases diagnosed by FLAER from September 2011 to March 2014 were analyzed retrospectively, including clinical features, laboratory examination results and complications. Patients were divided into three clinical groups according to the standard proposed by the International PNH Interest Group. This classification has been applied to each patient considering the clinical characteristics of the disease, bone marrow failure and PNH clone size. Statistical analysis: We presented continuous data as mean and standard deviation or median and interquartile range (IQR), with extreme values. The distributions of the presentation characteristics were compared among the three subcategories and between classic PNH and PNH-sc/AA by chi-square test or Fisher exact test when necessary for qualitative characteristics, and by Kruskal-Wallis (three subcategories) or Mann-Whitney (two groups) test for continuous characteristics. Spearman's rank correlation coefficient was used to measure correlations. Overall survival (OS) estimated by the Kaplan-Meier method was compared using the log-rank test. The Cox proportional hazards model was used to assess the risk factors for survival in both univariate and multivariate analyses. All of the analyses were performedusing statistical package SPSS 17.0. P<0.05 was considered as statistically significant. Results: There were 43 cases of classic PNH, 45 of PNH combined with other specific bone marrow disorders, 10 cases of subclinical PNH. 11 patients with PNH less than 18 years of age belong to adolescents, and other 87 PNH were adults. 70 patients were with fatigue, 41 patients with PNH manifested hemoglobinuria. Thrombosis in 6 cases, mostly formed in rare sites. 17 cases and 19 cases concurrented with renal and liver impairment respective. Only 2 cases of PNH were suffered with pulmonary hypertension simultaneously. Classic PNH was more susceptible to hemolysis, the bone marrow failure features of PNH combined with other specific bone marrow disorder was markedly obvious. The value of lactate dehydrogenase (LDH) level over normal range was related with the size of clone PNH-the GPI negative granulocyte, linearly (R=0.710, P<0.001). Patients with high PNH clone were specially prone to thrombosis. The incidence of hemoglobinuria in adolescent group was significantly lower than the adult group, but the rate of bleeding was higher than that of adult group. Conclusion: In Chinese patients with PNH, bone marrow failure, renal and liver impairment and thrombosis in rare sites was relatively common. But pulmonary arterial hypertension happened seldomly. Adult patients were more susceptible to hemolysis, but the megakaryocyte hematopoietic failure of adolescent patients combined with other specific bone marrow disorder was more obvious. Disclosures No relevant conflicts of interest to declare.

GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia

Key Points GATA2 deficiency-associated bone marrow disorder can present with features that overlap with idiopathic aplastic anemia. GATA2 marrows have severely decreased hematogones, monocytes, NK cells, and B cells; variable dysplasia; and clonal cytogenetic abnormalities.

Durable Hematological and Major Cytogenetic Response in a Patient with Isolated 20q Deletion Myelodysplastic Syndrome Treated with Lenalidomide

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective hematopoiesis. It is characterized by peripheral blood cytopenia and significant risk of progression to acute myeloid leukemia result. Deletion of the long arm of chromosome 20 (20q deletion) is present in 3–7% of patients with MDS. Lenalidomide is an immunomodulatory agent with antiangiogenic activity. It is FDA approved for the treatment of anemia in patients with low or int-1 risk MDS with chromosome 5q deletion with or without additional cytogenetic abnormalities. Study of lenalidomide in patients with MDS without 5q deletion but other karyotypic abnormalities demonstrated meaningful activity in transfusion dependent patients; however, response of patients with isolated 20q deletion to lenalidomide is not known. We are reporting a patient with 20q deletion MDS treated with lenalidomide after he failed to respond to azacytidine; to our knowledge this is the first report of a patient with isolated 20q deletion treated with lenalidomide.

The Significance of Unexplained Macrocytosis

Background: Macrocytosis is a relatively common finding in adult patients undergoing automated complete blood cell (CBC) counting with an incidence varying from 1.7 % to 3.6 %. Approximately 60% will not have associated anemia. Causes of macrocytosis include alcohol intake, vitamin B12 and folate deficiency, chemotherapy and other drugs, hemolysis or bleeding, liver dysfunction, myelodysplastic syndrome (MDS), and hypothyroidism. Approximately 10% of patients will have unexplained macrocytosis after laboratory evaluation. Data on the diagnostic approach and management of patients with unexplained macrocytosis are limited. Methods: To investigate this topic, the records of 9,779 patients diagnosed with macrocytosis in our institution between 1995 and 2005 were reviewed. Macrocytosis was defined as a mean corpuscular volume (MCV) greater than 100 in two consecutive occasions. Patients with evidence of liver disease, alcohol abuse, hypothyroidism, folate or vitamin B12 deficiency, hemolysis, or use of any drugs known to cause macrocytosis were excluded. Patients found to have MDS or any other bone marrow disorder documented by bone marrow biopsy within 3 months of the diagnosis of macrocytosis were also excluded. Data collection included CBC and MCV at the time of diagnosis, time of first cytopenia, and last follow-up; bone marrow biopsies and monoclonal protein evaluation (MPEV) results were also collected. Patient outcomes were divided in 4 categories which included: Resolved macrocytosis, defined as MCV less than 96 at the last follow-up. Worsening cytopenias, defined as development of new-onset anemia, thrombocytopenia, or leukopenia; or hemoglobin drop greater than 2 g/dl, or transfusion requirements. Bone marrow disorder, defined as morphologic, flow cytometric, and/or cytogenetic evidence of a primary bone marrow disorder. Stable disease, if none of the above conditions were met. Results: Forty three patients were found to have unexplained macrocytosis. Twelve (28%) had associated anemia at the time of diagnosis. The median follow-up was 4 years. Five (11.6%) patients developed a primary bone marrow disorder (two B-cell lymphomas, two MDS, one plasma cell disorder), 7 (16.3%) developed worsening cytopenias, 30 (69.7%) had stable disease, and 1 (2.3%) resolved. The median time to first cytopenia was 18 months. Monoclonal paraproteinemia was found in 5 out of 22 patients tested (22.7%). The outcomes were not significantly different when comparing patients with or without anemia upon diagnosis of macrocytosis. The probability of a bone marrow biopsy establishing a diagnosis of a primary disorder was two out of six (33.3%) in patients with macrocytosis without anemia, compared to three out of four (75%) in patients with macrocytosis with anemia. Conclusions: Unexplained macrocytosis may not be a benign condition and requires close follow-up as up to 27.9% of patients will develop worsening cytopenias (16.3%) or will be ultimately diagnosed with a primary bone marrow disorder (11.6%). We suggest a strategy of follow-up with CBCs every 6 months. Bone marrow biopsy should be performed at the time when cytopenias are present, since this approach might give a higher yield of diagnosis, and also provide information when the clinicians are more likely to take therapeutic decisions. Given the high incidence of monoclonal paraproteinemia in these patients, we propose that MPEV should be considered as part of the initial work-up for macrocytosis.