704 Cold-Agglutinin Hemolytic Anemia: A Harbinger of Recurrent Lymphoma

S132 serum deprivation. Importantly, selective inhibition of IGF-IR by PPP decreased MCL cell viability and proliferation, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase 3 and PARP cleavages, upregulation of cyclin B1, and downregulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. These findings were consistent using IGF-IR siRNA. Our data show that IGF-IR is highly expressed and frequently activated in MCL, and suggest that IGF-IR can be used as a molecular target for the treatment of this lymphoma. 704 Cold-Agglutinin Hemolytic Anemia: A Harbinger of Recurrent Lymphoma Jonathan Brammer, Michael Siegelman Baylor College of Medicine Brief Abstract: Cold-agglutinin Hemolytic anemia (CAHA) is an uncommon cause of hemolysis that usually occurs in the setting of recent mycoplasma infection or lymphoma. We present the case of a patient who presented with CAHA and was subsequently found to have a recurrence of lymphoma, which had been previously missdiagnosed as a lesser-grade disease. Full Abstract: Introduction: Cold-agglutinin Hemolytic anemia is an uncommon cause of hemolysis that represents 13-15% of all autoimmune hemolytic anemias. Cold agglutinins are typically IgM auto-antibodies that bind to the surface of erythrocytes, causing complement activation and hemolytic anemia at an optimal temperature of 0-4oC. Clinical presentation is similar to other hemolytic anemias; with increasing dyspnea and fatigue-usually in the setting of recent mycoplasma infection or lymphoma. Case: The patient is a 72 year-old Cuban-American man with a past medical history of diffuse B-cell lymphoma (DLBCL) diagnosed one year prior and amyloidosis who presented from clinic with increasing dizziness, dyspnea, night sweats, and fatigue over one month. The lymphoma had been treated with 6 cycles of chemotherapy and was found to be in remission with no sign of residual disease on imaging. Laboratory values demonstrated hemolytic anemia with a hemoglobin of 5.6 g/dL, and direct Coombs test was positive. Blood smear demonstrated agglutination of the red blood cells at room temperature, and cold agglutinins titer demonstrated a level of 1:2048. The patient was transfused with packed red blood cells through a warmer throughout the hospital stay. Repeat biopsy of an inguinal lymph node demonstrated recurrent lymphoma, of the immunoblastic B-cell type-which was different from the previous diagnosis of DLBCL. Discussion: The patient in this report had a recurrence of lymphoma, which presented initially with cold agglutinin disease. This case is unique in several aspects. First, the patient had a positive direct Coombs test, indicating that at least some of the antibodies were of the IgG, and not the typical IgM type. Second, the patient was initially miss-diagnosed with DLBCL when he actually had a more aggressive immunoblastic lymphoma. This case illustrates the necessity to investigate the underlying cause of any autoimmune hemolytic anemia, including repeat biopsy in the setting of recurrent lymphoma. Clinical Lymphoma, Myeloma & Leukemia June 2011 Chronic Myeloid Leukemia 801 IL3R Directed Agents, SL-401 and SL-501, Inhibit the Growth of Leukemia Stem Cells in CML Olga Frolova, Arthur Frankel, Jorge Cortes, Hagop M. Kantarjian, Michael Andreeff, Marina Konopleva Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Scott & White Memorial Hospital, Temple, TX, Department of Leukemia, The University of Texas MD Anderson Cancer Center Brief Abstract: Expression of the IL3 receptor (IL3R) has been demonstrated on CD34 38leukemic stem cells in many hematological malignancies. The role of IL3R in CML stem cells has not been investigated. We demonstrated that IL3R is highly expressed on CML stem cells. In this study, we examined whether targeting IL3R with SL-401 and SL-501, IL3 conjugated to diphtheria toxin, could eradicate CML stem cells. Full Abstract: While imatinib and other tyrosine kinase inhibitors (TKIs) demonstrate high efficacy in the treatment of chronic myeloid leukemia (CML), patients can fail all of these therapies. TKIs have limited activity against CD34 CD38leukemic stem cells. Expression of the IL3 receptor (IL3R) has been demonstrated on CD34 38leukemic stem cells in many hematological malignancies. However, the role of IL3R in CML stem cells has not been fully investigated. Recently, we demonstrated that IL3R is highly expressed on CD34 38Bcr-Abl( ) CML stem cells and represents a feasible target for therapeutic intervention. In this study, we examined whether targeting IL3R with SL-401 and SL-501 could eradicate CML stem cells. SL-401, human IL3 conjugated to diphtheria toxin, has been shown to eradicate NOD/SCID-initiating AML stem cells. SL-501 is a second generation agent with high binding affinity to IL3R. Both agents direct the molecule to the leukemic cell surface, triggering endocytosis, cessation of protein synthesis, and apoptosis. In six primary CML samples, these agents reduced the absolute numbers of viable CD34 /CD38-/CD123 CML progenitor cells (p 0.03) by inducing apoptosis (SL-401, 52.2%; SL-501, 65.5%). To evaluate the effect of these agents on the growth of the most primitive stem cells, CML blasts were pretreated with IL3R targeted agents and grown in the Long-Term CultureInitiating Cell assay. These agents significantly reduced the formation of colonies in 4 primary samples in a dose-dependent manner (p 0.009). Similar results were obtained when growth of progenitor cells was assessed in the colony forming cell assay (p 0.0002, N 6). Notably, the majority of primary samples were obtained from patients resistant to TKIs and/or harboring an abl mutation. Moreover, the combination of imatinib with the IL3R targeted agents demonstrated synergistic effects (CI 1.0) against the KBM5 cell line and its TKI resistant KBM 5STI subline. In addition, combination of imatinib with these agents further enhanced the apoptotic rate in primary leukemic cells (N 5). Taken together, these data indicate that SL-401 and SL-501 represent a novel therapeutic modality for the