ALBERT

Description: A 58 year old male who developed paroxysmal nocturnal hemoglobinuria and acute granulocytic leukemia is described. This rare occurrence is pertinent in view of recent concepts suggesting common etiologic mechanisms for these diseases.

Description: Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20+ B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.

Description: Abstract 2838 Poster Board II-814 Background. Monoclonal gammopathy of undetermined significance (MGUS), the precursor of multiple myeloma (MM), is 2- to 3-fold more common in African-Americans (AA) than Caucasians (CA). Prior studies have reported clinical features of MGUS and MM to be different among AA compared to CA. Recent studies on CA MGUS cases have found serum free kappa and lambda light chain assays (sFLC) to be highly predictive of MM progression. We have conducted the first study designed to evaluate patterns of sFLC markers in AA. Methods. All AA MGUS patients seen at Walter Reed Army Medical Center (WR) and the Washington DC Veteran's Affairs Medical Center (VA) 2005-2009 were eligible. WR patients were enrolled through a retrospective chart review as sFLC has been performed routinely on MGUS patients. VA patients were enrolled in a prospective trial and sFLC was performed at WR. All patients were categorized for their risk of progression using the Mayo Clinic model (Rajkumar SV Blood 2005) and compared to the Caucasian Mayo Clinic population by the Fisher's exact test (2-tailed). Results. Eighty-six patients were enrolled, the median age was 73 yrs (42-92) and 74% were male. The MGUS isotype was 87% IgG, 10% IgA, 2% IgM and 1% biclonal. Kappa and lambda light chain disorders were present in 61% and 38%, respectively. The median monoclonal Ig concentration was 0.56 gm/dL (trace-2.33), 47% had a concentration '0.5 g/dL, 30% 0.51-1.0, 20% 1-2 g/dL, and 2% 2-3 g/dL. An abnormal sFLC ratio was present in 49% of patients. Based on the Mayo Clinic model, the risk of progression was: low 42% (95%CI 32-52), low-intermediate 49% (39-59), high-intermediate 8% (4-16) and high 1% (0-7). In comparing our data to the Mayo Clinic data, AA have significantly different distributions of MGUS isotype (p =0.001), lower monoclonal Ig concentration (p=0.0005), presence of an abnormal sFLC ratio (p=0.004) and distributions of Mayo Clinic risk groups (p=0.008) (see table). Conclusions. The clinical and laboratory features of AA patients with MGUS are distinctly different than in Caucasians, in particular a lower proportion of IgM MGUS, lower monoclonal Ig levels, a higher proportion of abnormal sFLC ratios, and fewer higher-risk patients. IgM MGUS is the precursor to Waldenstrom's macroglobulinemia (WM) and the lower proportion of IgM MGUS in AA is consistent with the very low rate of WM in AA. Non-IgM MGUS should be considered a separate entity and a direct comparison of AA and CA non-IgM MGUS patients using the Mayo Clinic data is planned. The significance of these differences on the risk of malignant progression will require prospective studies in racially diverse populations. Disclosures: Weiss: The Binding Site, Inc.: Research Funding.

Description: Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin Receptor Blockers (ARB) have long been considered standard therapy in the medical management of congestive heart failure and diabetes due to their beneficial effects in preventing progression of cardiac remodeling and diabetic nephropathy, respectively. The benefits of ACE-I, however, are tempered by their anti-erythropoietic effects and potential role in anemia. We conducted a retrospective study based on extraction of electronic medical records available through the Washington Veterans Affairs Medical Center. We compared hemoglobin levels of diabetic African-American and Caucasian patients on ACE-I or ARB, referred to the Hematology Section with a diagnosis of unexplained anemia within a 10-year span from January 1, 1998 to January 1, 2008. Additional sub-stratification analyses were performed on insulin dependence and renal function. Of the 102 African-Americans and 25 Caucasians evaluated, 60 African-Americans and 13 Caucasians were not anemic prior to initiation of ACE-I or ARB therapy. In this group, a greater decline from pretreatment hemoglobin levels were evident in African-Americans compared with Caucasians, with an average change in hemoglobin of −2.76 ± 1.34 g/dL compared with −2.04 ± 1.35 g/dL, respectively, though neither change was statistically significant. A greater decrease in hemoglobin levels was also evident depending on length of time on ACE-I therapy in African Americans. The average change in hemoglobin was −0.85 ± 1.87 g/dL at less than 5 years, −1.25 ± 1.55 g/dL at 5–10 years, and −3.15 ± 1.61 g/dL at 10–15 years after initiation of therapy. Limited data were available for Caucasians. Pearson correlation analyses also showed a weak positive correlation between decline in hemoglobin levels and decline in renal function. The average change in hemoglobin concentration after initiation of ACE-I or ARB therapy was greater in the subgroup of patients with estimated GFR less than 60cc/min in both African-Americans and Caucasians, with decrease of −1.85 ± 1.67g/dL and −1.60 ± 1.49g/dL, respectively. In African-Americans, decreases in hemoglobin were even greater for those patients with an estimated GFR less than 30cc/min, at 2.03 ± 2.19g/dL. Only one Caucasian patient had a GFR less than 30cc/min in our study. Greater decline in hemoglobin levels also correlated with insulin use even when renal function was accounted for, though this change was also not statistically significant. In diabetic African-Americans on ACE-I or ARB therapy, the change in hemoglobin was −2.03 ± 1.83 g/dL on insulin, compared with −1.64 ± 1.52 g/dL on no insulin. In diabetic Caucasians on ACE-I/ARB therapy, the change in hemoglobin was −1.38 ± 1.43 g/dL on insulin, compared with −1.11 ± 1.42 g/dL on no insulin. Our study is the first to include a large sub-population analysis of African-American diabetic patients to evaluate the effects of ACE-I and ARBs on the development or worsening of a hypoproliferative normocytic, normochromic anemia state. While results of this retrospective study were not statistically significant, due to small numbers, it does confirm ACE-I and ARB-mediated anemia may involve several downstream factors acting in concert and reinforces the need for additional large population studies.

Description: Efalizumab (Raptiva; Genentech Inc.) is a humanized, recombinant, T-cell targeted monoclonal antibody, which binds to CD11a which combined with CD18 forms lymphocyte function-associated antigen 1 (LFA-1) and is approved for use in adults with moderate to severe plaque psoriasis. Previous publications have described autoimmune thrombocytopenia, hemolytic anemia as well as neutropenia with use up to 8 months after initiating treatment. We now report two patients who developed refractory autoimmune hemolytic anemia nine and twenty-six months after successful treatment of their psoriasis with efalizumab. The first patient is a 56 year old African-American man who presented with severe Coombs positive (IgG+, C3d −}anemia, with a hemoglobin of 4.1 g/dL, reticulocyte count of 25% after 26 months of treatment with efalizumab. Over the next two weeks the anemia was refractory to high dose prednisone, a total dose of 100 gms of intravenous immune globulin (IVIG), mycophenolate, danazol and 2 doses of rituximab and 10 units of blood, hemoglobin remained at 5.9 g/dLand .splenectomy was performed two weeks after presentation. Hemoglobin 2 weeks post splenectomy improved to 10.4 g/dL with near normalization one month later. The second patient a 61 year old woman, presented to an outside hospital with severe anemia. Upon transfer 1 week later, she was found to be Coombs positive, with a hemoglobin of 6.1 g/dL, reticulocytes of 1 %., and underwent a bone marrow aspirate and biopsy with noted erythroid hyperplasia, this after nine months of treatment with efalizumab. The patient underwent splenectomy three weeks after high dose prednisone, intravenous cyclophosphamide, cyclosporine, danazol, IVIG, rituximab and plasmapheresis failed to induce a remission. After splenectomy, the patient remained refractory to treatment and eventually succumbed to a combination of arterial and venous thrombi, bowel ischemia and bacterial sepsis six weeks after presentation. Little is known regarding the mechanism behind the immune mediated cytopenias following efalizumab therapy. In addition to lymphocytes, CD11a is expressed on several other cell lines, however, CD11a is not expressed on mature erythrocytes making a direct antibody mediated response against an efalizumab/LFA-1 complex less likely. The development of anti-efalizumab antibody occurs in 5% of patients but is not associated with autoimmune phenomena. More likely mechanisms may include dysregulation of autoreactive T cells from either defective T-cell function, loss of regulatory T cells or aberrant antigen presentation. These two cases highlight the difficulty and relative resistance to treatment in patients who develop autoimmune hemolytic anemia secondary to efalizumab and stress the importance of continued close monitoring of complete blood counts throughout the duration of active treatment.

Description: Abstract 4869 The information regarding monoclonal gammopathy of unknown significance (MGUS) derives mainly from studies of Caucasian individuals. In contrast, this study describes the characteristics of 492 African American (AA) male patients identified with MGUS from the electronic database at the Washington VAMC. Review of their individual electronic records showed that none of the patients initially had evidence of myeloma or other symptomatic plasma cell or lymphoproliferative disorder. The median age at diagnosis of MGUS was 68 years old (range 28.5 to 95.6 years). The distribution of monoclonal immunoglobulin (M Ig) subtypes were IgG 78.1%, IgA 14.8%, IgM 6.9%; light chain only in the urine 2.9% or in the serum 1.0%, The light chain distribution of the M Igs was 60% kappa, 40% lambda. Fifty-nine patients (12%) had diclonal and 4 (0.8%) had triclonal M Igs. The median amount of M Ig was 0.26 g/dL; 47.8% were too small to quantitate. Ninety-four (25.5%) of 368 tested had Bence-Jones proteinuria, with a similar kappa:lambda distribution and 4 patients showed both light chains. Clinical characteristics were as follows: hepatitis C 15.5%, HIV 5.1%, other significant infections 26.8%, and chronic autoimmune or inflammatory disorders 10.3%. The patients were followed clinically for a median of 4.1 years (range 0.35 to 21.02 years), and the median interval between the first and last electrophoresis was 1.41 years (range 0 to 19.97 years). During this period 21 patients (4.3%) progressed to a malignant plasma cell disorder (myeloma 20, solitary plasmacytoma 1). 133 patients (27.0%) died of other causes, and in 26 (5.3%) the M protein had resolved. The actuarial risk determined by a Kaplan Meier plot of progression to a symptomatic plasma cell disorder was 13.5 % at 11 years. The initial M Ig in the patients who progressed was IgG in 15, IgA in 4, and isolated BJ proteinuria in 2. The only recognized predicting characteristic for progression was the detection of Bence-Jones proteinuria at diagnosis of MGUS: Thirteen of 20 (65%) progressing patients tested were positive as compared to 81 of 348 (23.0%) of the non-progressors (p = .0003) A number of features distinguish this AA MGUS cohort from previous series of Caucasian patients. MGUS was detected at an earlier age: 8.9% (5.2% excluding HCV and HIV patients) were under the age of 50. The percentage of AA patients with very low level M proteins was more than threefold that previously reported. The percentage of patients with IgM M Ig was less than one-half noted in previous studies. The actuarial risk of progression to a symptomatic plasma cell disorder as calculated from a Kaplan Meier plot appears to be comparable to previous reports in predominantly Caucasian series. Dr. Desai worked on this project following completion of her internal medicine residency. She is now a Hematology Oncology fellow at Montefiore Medical Center, New York NY. Disclosures No relevant conflicts of interest to declare.