Median IgM Research Articles

Quantification of Serum IgMκ and IgMλ In Patients with Waldenstrom's Macroglobulinemia (WM) at Diagnosis and During Disease Course; Clinical Correlations

AbstractAbstract 3004Resolution of IgM monoclonal proteins (M-proteins) on serum protein electrophoresis (SPE) can make accurate quantification difficult. The same applies to the determination of total IgM by nephelometry which inherently includes monoclonal and polyclonal immunoglobulins. Specific polyclonal antibodies, which recognise epitopes spanning the junction of the heavy and light chains of the individual immunoglobulin isotypes, have been produced and used to develop nephelometric assays (Hevylite™). The purpose of the present study is to evaluate the prognostic value IgMκ/IgMλ ratios (HLCR) at diagnosis and the role of HLCR in disease monitoring. Retrospective sera from 31 WM patients, 4 IgM-MGUS, 2 IgM-like syndrome at diagnosis and for 9 of them during disease course, were included in the study. Analysis of IgMκ and IgMλ was performed on a Siemens Dade-Behring BN™II nephelometer and results were compared with disease parameters such as blood count, beta2-microglobulin (β2M), serum albumin, lactate dehydrogenase (LDH), and lymphoplasmacytic bone marrow infiltration. Abnormal HLCR were reported in 30/31 WM patients. There was a good correlation between summated IgMκ + IgMλ and total IgM (r=0.832 p<0.0001), although in 12 patients there was considerable disagreement between total IgM (range 12.9–80.4) and summated IgMκ + IgMλ (range 22.2–150.8, p>0.01). These 12 patients presented polyclonal hypogammaglobulinemia (with regard to their IgG and IgA levels). Median IgM HLCR (expressed as IgMκ/IgMλ or IgMλ/IgMκ with the involved Ig as numerator) were 90.88 (range 1.91–1000) in WM v 17.65 (range 1.08–34.57) in IgM-MGUS (p=0.06). Median IgM HLCR was significantly higher in WM patients requiring treatment (n=24) at presentation than in patients not (n=7) requiring treatment (185.7 v 13.45 p=0.023). IgM HLCR correlated with bone marrow infiltration (p=0.029) and time to first treatment (p=0.003). A simple risk stratification model utilising: IgM HLCR>median, β2M>5 and abnormal LDH, identified 3 prognostic groups with respect to survival (p<0.0001) in this series with a median follow-up of 59 months. In the 9 patients followed during treatment, involved HLC IgM and IgM HLCR mostly followed disease fluctuations and never normalized but patient entered only partial remissions. In 1 IgMκ WM patient who presented “flare” during treatment with rituximab the IgMκ and the IgM HLCR increased while the IgMλ remained constant, indicating that the flare involves only the monoclonal paraprotein. In 2 patients with polyclonal uninvolved hypergammaglobulinemia, response was accompanied with normalization of the uninvolved components. In conclusion, HL IgM and IgM FLCR seems to separate patients with a more aggressive disease. Further studies will be needed to evaluate their utility for monitoring WM patients. Disclosures:Mirbahai:Binding Site Group Ltd: Employment. Bradwell:Binding Site: Equity Ownership, Patents & Royalties. Harding:Binding Site Group Ltd: Employment.

A serosurvey of Orientia tsutsugamushi from patients with scrub typhus

AbstractMany countries where scrub typhus is endemic use their own cutoff values for antibody titres to differentiate between cured cases and current infections. To establish an antibody titre cutoff value, one needs to investigate the seroprevalence in endemic areas, and the duration of the increase in titre after complete cure. We conducted a follow-up study of anti-Orientia tsutsugamushi antibody titres using indirect immunofluorescence assays (IFA) and passive haemagglutination assays (PHA) in patients with scrub typhus. After the onset of symptoms, IgM antibody titres increased gradually over 2–3 weeks, peaked at about 4 weeks, and started to decrease rapidly between 4 and 5 weeks. At 1-year follow-up, the median IgM value was 1:10. Out of 77 patients who were tested at that time, 36 (47%) had IgM titres ≥1:20, and none had titres exceeding 1:80. Over the first 2 weeks, IgG antibody titres increased sharply, peaked at about 4 weeks and decreased rather gradually thereafter, with a median titre of 1:128 maintained up to the 18th month. At 1-year follow-up, five out of 77 patients (6.5%) had titres ≥1:1,024 and 57% had titres ≥1:128. Based on these results, a cutoff value of ≥1:160 for IgM antibody should differentiate between previous and current infections in endemic areas such as Korea and Japan, where scrub typhus occurs mainly in the autumn.

Abstract 2417: Preclinical evaluation of potential novel synthetic saponin adjuvants with conjugate cancer vaccines

Abstract We have tested a variety of naturally isolated and synthetic carbohydrate and peptide cancer antigens conjugated to keyhole limpet hemocyanin (KLH) plus an immunological adjuvant in pre clinical studies and clinical trials. The strength of the IgM and IgG antibody response was in each case determined by the potency of the immunological adjuvant, and the saponin fraction QS-21 was consistently the optimal adjuvant. However, there are draw backs to the use of QS-21 including local and systemic toxicity at immunologically relevant doses and poor stability at room temperature. Recent achievements in complex carbohydrate synthesis have enabled us to chemically synthesize a variety of saponin analogues. The effect of several of these synthetic saponin analogues were evaluated in mice in combination with GD3 ganglioside conjugated to KLH (GD3-KLH). Mice were immunized weekly for three weeks with GD3-KLH containing 10μg of GD3 alone, mixed with synthetic QS-21 (SQS-21) as positive control, or with 10, 20 or 50μg of synthetic QS-21 analogues SQS-101, SQS-102 or SQS-103 designed for improved stability as a consequence of amide modification. Toxicity (loss of weight) was monitored at 0h, 24h, 48h and 72h after each injection. Mice were bled 7 days after the third weekly vaccination and after the fourth (booster) vaccination on week 8. The sera were tested for the presence of antibody against GD3 or KLH by ELISA and against a tumor cell-line expressing GD3 antigen by FACS. We demonstrate that: 1) After vaccination with GD3-KLH alone, no IgM or IgG antibodies against GD3 were detected and the median titer of anti-KLH antibodies was 1/3200. 2) After vaccination with GD3-KLH plus 10 μg SQS-101, SQS-102 or SQS-103, or with positive control SQS-21, the boost antibody responses were similar with median anti-GD3 IgM titers of varies from 1/320 to 640, and anti-KLH IgG titers of 1/409,600 to 1,638,400. 3) SQS-21, SQS-101, SQS-102 and SQS-103, at the 50μg dose were each toxic with weight loss greater than 10% detected in most mice, but this was most extreme with SQS-102. The 10μg and 20μg dose of SQS-101 and 103, however, were well tolerated with no mice losing more than 10% weight. The 10μg and 20μg dose of SQS-102 mice lost more than 10% weight. 4) As expected anti-GD3 antibodies in each group were shown to react strongly with the cell surface of GD3 positive cancer cell lines by FACS. 5) These novel, amide-modified, non-natural synthetic saponin adjuvants selected for improved stability demonstrated adjuvant effects in vivo that equaled or exceeded that of SQS-21 and had comparable toxicity when mixed with a GD3-KLH conjugate vaccine. Supported by grants from the NIH (PO1 CA 52477) and Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research” and “The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center” and the Geoffrey Beene Cancer Research Center grant Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2417.

Murine typhus in children: clinical and laboratory features from 41 cases in Crete, Greece

Murine typhus, also known as endemic typhus, is a flea-borne infectious disease with a worldwide distribution, caused by an obligate intracellular, gram-negative microorganism, Rickettsia typhi [1]. The transmitting agent of R. typhi is the rat flea, Xenopsylla cheopis, although the cat flea, Ctenocephalides felis, has also been implicated [1–4]. Main reservoirs are rats, house mice, opossums, skunks and cats [1–3]. The actual incidence of murine typhus is unclear, as the common clinical manifestations of the disease are non-specific [1,2]. In children, only a small number of studies have focused on the occurrence and on clinical profiles of the disease [3–5]. The aim of this study was to confirm the presence and to assess the clinical and laboratory characteristics of R. typhi infection among children in the area of Chania, Crete, Greece. Forty-one children were hospitalised with acute R. typhi infection in the Pediatric Department of the General Hospital of Chania, from 2001 through to 2006. All other causes included in the differential diagnosis were ruled out. Diagnosis of acute R. typhi infection was considered positive by the combination of compatible clinical features and an indirect immunofluorescence test (Biomerieux, Lyon, France), when specific IgM and ⁄ or IgG titres on admission were >1 ⁄ 400 and >1 ⁄ 960, respectively. All cases were reviewed retrospectively for demographic, clinical and laboratory findings, treatment and outcome. Most admissions (87.8%) occurred between May and October. The mean age was 9.8 years old (range, 1–15 years old). Twenty children (48.8%) were males. History of recent contact with animals was positive in 13 children (31.7%); all 13 children reported contact with cats and 10 ⁄ 13 reported contact with dogs. On admission all patients had fever. Common clinical characteristics were fever, rash, hepatomegaly, splenomegaly and anorexia. Main laboratory features included elevated aspartate aminotransferase and alanine aminotransferase, abnormal chest radiography, thrombocytopenia and leucopenia. CSF analysis in one patient with confusion did not reveal any abnormalities. Clinical and laboratory manifestations found on admission are presented in Table 1. Serologic testing through IFA performed on admission was diagnosed for all 41 children, with a median IgM titre of 1 ⁄ 3200 (range, 1 ⁄ 400 to 1 ⁄ 31200) and a median IgG titre of 1 ⁄ 2880 (range, 1 ⁄ 480 to 1 ⁄ 30720). All children were treated upon admission. Combination therapy was administered to two of them. Antibiotics administered were doxycycline in 19 children (46.3%), chloramphenicol in 12 (29.3%), quinolones in five (12.2%), cephalosporins in three children (7.3%), and a combination of trimethoprim ⁄ sulfamethoxazole and b-lactams in two children (4.9%). The outcome was favourable for all 41 patients; apyrexia was recorded on a mean of 4.9 days after admission (range, 2–12 days). The mean total duration of fever was 9.1 days (range, 3–17 days). No complication or relapse was observed within 1 month of follow-up.

Cholesterol Regulation and Statin Therapy in Patients with Waldenstrom's Macroglobulinemia.

Abstract 4789Patients with WM commonly display low cholesterol levels, particularly LDL and VLDL levels. Given these observations, we examined their levels in 110 patients with WM, and observed decreased total cholesterol (<160 mg/dL), LDL (<100 mg/dL) and VLDL (<40 mg/dL) levels in 41 (37.3%), 68 (61.8%) and 90 (81.8%) patients, respectively. Importantly, median serum IgM levels which serve as a surrogate marker for WM disease burden were higher among patients with hypocholesterolemia (3440 vs. 1587 mg/dL; p=0.0004). Longitudinal follow-up of progressing as well as responding patients demonstrated an inverse correlation between serum IgM and cholesterol levels, which was not an artifact of laboratory testing. Importantly, significantly lower serum IgM levels (885 vs. 1960 mg/dL; p=0.004) were observed among those patients who were on a statin lipid-lowering agent. We therefore investigated the in vitro potential of statins to mediate anti-WM activity and showed that simvastatin acted a potent inducer of WM cell apoptosis through inhibition of geranylgeranylated proteins. Given these observations, we investigated the potential of simvastatin to suppress disease progression in WM patients with slowly progressing disease who would otherwise have been on watch and wait. Patients and MethodsEighteen patients, 8 of whom were previously untreated, and who were asymptomatic with slowly progressing disease were enrolled in this study. The median age for these patients was 67 (range 42-88 years), median IgM was 2,610 (571-5,880 mg/dL), and median hematocrit was 35.4 (range 30.2-41.4%). Patients received Simvastatin at 20 mg daily for the first week, then dose escalated weekly by 20 mg a day to a maximum of 80 mg daily by week 4. Patients were maintained on therapy until progression. ResultsWith a median follow-up of 6 months (range 3-18 months), 7 patients have demonstrated objective disease progression. No objective responses have been observed in any treated patients. Among non-progressing patients, serum IgM levels (2,610 vs. 2545 mg/dL) and hematocrit (35.4% vs. 34.5%) remain stable (p=NS). Grade 2 toxicities included elevation in CPK (n=1), and musculoskeletal pain (n=3). No grade 3 toxicities were observed. ConclusionsSimvastatin does not produce objective responses in patients with WM, though may have potential for suppression of disease progression in some patients with WM. Disclosures:No relevant conflicts of interest to declare.

Variables Influencing the the Protein C Pathway Response in Children with ALL.

Abstract 2986Poster Board II-962 Introduction:The protein C pathway is believed to be a crucial regulator of coagulation. Similar to the adult population, it is of utmost importance in pediatric patients to maintain the balance between pro- and anticoagulatory signals (Petaja and Manco-Johnson 2003). Cancer patients have been shown to have cancer and cancer-therapy associated pathologies of the protein C pathway. (Nijziel, van Oerle et al. 2003; Woodley-Cook, Shin et al. 2006).A test evaluating the response of the protein C pathway after activation of endogenous protein C has been shown to be a sensitive tool to screen for protein C deficiency and APC resistance whereas protein S deficiency is detected less reliably (Toulon, Halbmeyer et al. 2000). This is in line with findings suggesting that any pathology of this assay is related to an increased risk of VTE, independent of the pathology related to the abnormality of the test result (Toulon, Perez et al. 2007). Similarly, patients with idiopathic pregnancy loss were found to have a pathological response independent of the pathology related (Sarig, Lanir et al. 2002). Methods:We therefore evaluated the influence of different variables on the results of the global protein C assay (Pro C Global on a BCS analyzer, Siemens, Marburg, Germany) in 431 children enrolled into the Thrombotect study. The Thrombotect study is a prospective, randomized trial evaluating unfractionated heparin vs low molecular weight heparin vs antithrombin replacement for prevention of thromboembolism in children undergoing asparaginase containing chemotherapy for acute lymphoblasic leukaemia within the BFM protocol. A multivariate linear regression analysis on results obtained before treatment was performed (MedCalc 10.0.1). Results:To date (as of 8/09), 720 children have been randomized in the Thrombotect trial. At the time, we had complete data for laboratory evaluation available for 431 children on day 0 of the treatment protocol.Free protein S, IgG antibodies against cardiolipin or phosphatidlyserine, dRVVT, fibrinogen, the presence of F II G20210A, homocystein concentration, Lp(a) concentration and PAI-1 activity had no predictive value towards the protein C pathway assay result in this multivariate analysis.In contrast, the protein C pathway activity was expectedly shown to be dependent on the presence of the F V Leiden mutation (p<0.0001), protein C activity (p<0.0001) and F VIIIc (p=0.0001).Unexpectedly, the protein C pathway activity was also dependent on antithrombin activity (p=0.0166), F XIIc (p=0.0137) and IgM (but not IgG) antibodies against cardiolipin (p=0.0304) and phosphatidylserine (p=0.0006) in this multivariate analysis.Importantly, the association between protein C pathway activity and the “unexpected” predictors were independent of whether or not the results were in the reference range or not (median [95% CI] antithrombin activity 0.95 [0.93-0.97], median F XIIc 0.94 [0.90-0.98], median ACL IgM 2 [2-3] U/ml, median APS IgM 2 [2-3] U/ml). Conclusions:The protein C pathway is believed to be a crucial regulatory element of haemostasis. Our results from a large cohort (n = 431) of children with ALL and thus at risk for thromboembolism indicate that the protein C pathway is -expectedly (such as F V Leiden mutation, protein C activity, F VIIIc) and unexpectedly (such as antithrombin activity and the concentration of antiphospholipid IgM antibodies) - interdependent with many other variables of the coagulation system.These data provide evidence that the protein C pathway ex vivo in children with ALL is targeted by various elements of other haemostasis pathways in a significant manner in multivariate analysis. Disclosures:No relevant conflicts of interest to declare.

IgA and IgG Hypogammaglobulinemia Does Not Predict for Recurrent Infection Risk and Persists Despite Therapeutic Response in Patients with Waldentrom's Macroglobulinemia.

Abstract 1947Poster Board I-970Recurrent infections are commonly observed among patients with WM, and may be related to the presence of IgA and IgG hypogammaglobulinemia. The etiology for this finding remains unclear, and has been speculated to be on the basis of tumor-induced suppression. We therefore evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated WM patients and addressed the associated clinicopathological findings, and impact of therapy. The median age of these patients was 60, median IgM was 2,910, and median bone marrow (BM) infiltration was 40%. Of these patients, 131 (63.3%) and 120 (58.0%) patients demonstrated decreased serum IgA and IgG levels respectively, while 102 (49.3%) of these patients were abnormally low for both. BM infiltration, serum IgM levels, complete blood counts, absolute lymphocyte counts, b2-microglobulin, or the WM International Prognostic Scoring System score had no impact on the odds ratio of having IgA or IgG, or both IgA or IgG hypogammaglobulinemia by logistic regression analysis. The presence of adenopathy and/or splenomegaly was surprisingly associated with a lower incidence of hypogammaglobulinemia (p≤0.03). The presence of IgA, IgG or both IgA and IgG hypogammaglobulinemia did not predict for the occurrence of recurring infections, which were nearly all respiratory in nature and consisted of sinus (n=53; 25.85%), bronchial (n=16; 7.80%), unspecified upper respiratory tract (n=14; 6.83%), and pneumonic (n=7; 3.41%) infections. Lower IgA and IgG levels were however associated with disease progression in watch and wait patients. To understand the impact of WM directed therapeutic intervention on uninvolved immunoglobulin levels, we analyzed changes in IgA and IgG levels in a cohort of 93 patients who underwent treatment for WM. With a median follow-up of 12 months, no significant recovery in the median IgA and IgG levels was observed with any therapy during the course of follow-up, including in those patients who had follow-up in excess of 1 (n=46), 2 (n=25), and 3 (n=8) or more years post-therapy, and in those achieving a major remission including complete response. Lastly, we sequenced 8 genes (AICDA; BTK; CD40; CD154; NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 WM patients with IgA and/or IgG hypogammaglobulinemia. We observed an intronic variation at position c.1056-6T>C in 2 patients, and a hemizygous missense mutation at c.337G>A in another patient for NEMO, as well as a heterozygous missense mutation at c.425A>T in the highly conserved catalytic site of UNG for one patient. The results of these studies demonstrate that IgA and IgG hypogammaglobulinemia is common, and does not predict for recurrent infection risk in WM. Moreover, IgA and IgG hypogammaglobulinemia persists despite therapeutic intervention and response. These studies highlight the importance for further investigations into the IgA and IgG hypogammaglobulinemia of WM, as well as the signaling pathways involved in B-cell differentiation and immunoglobulin heavy chain class switching in the pathogenesis of WM. Disclosures:No relevant conflicts of interest to declare.

Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]

Diagnostic and prognostic use of FDG-PET scans in Waldenstrom's macroglobulinemia

e19518 Background: Waldenstrom's macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma. More sensitive tools of tumor burden and prognosis are needed in these patients (pts). The use of FDG-PET has not been previously studied in WM but has proved an effective diagnostic and prognostic tool effective in low-grade lymphomas. Therefore the objective of this study was to determine whether FDG-PET was an effective tool in evaluating pts with WM. Methods: We included all pts enrolled on a prospective phase II clinical trial of bortezomib and rituximab for pts with upfront or relapsed/refractory (RR) WM. All pts were CD20 positive with histologically confirmed disease and underwent staging evaluation by FDG-PET in combination with CT scan before and after therapy. Patients received 6 cycles of bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15q28 and rituximab at 375 mg/m2 on days 1, 8, 15 and 22 in cycles 1 and 4. Correlation was made with the international prognostic scoring system for WM and monoclonal protein response rate. Results: 53 pts were included, of which 35 were RR and 18 pts were upfront. Median age was 63 years (range 42–81), 64% were male. Before therapy, 34 pts (64.2%) had positive FDG-PET findings with a median IgM of 2825, Beta 2 microglobulin of 3.6, and Age of 61. 36 pts showed a minor response or greater with a correlation to negative PETs after therapy. Conclusions: Over 60% of WM pts demonstrated FDG-avid disease when using FDG-PET scans, with the majority showing negative disease after therapy. This correlates with the 67.9% response rate. Positive PET images were inversely correlated to IgM level and directly related to elevated Beta-2 microglobulin and age. Significantly PET positive individuals may demonstrate a poorer prognosis. FDG-PET scans may prove an effective tool in the diagnosis and prognosis in WM. [Table: see text]

Phase II Trial of the mTOR Inhibitor RAD001 in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: The Dana Farber Cancer Institute Experience.

INTRODUCTION: Previous studies have demonstrated the clinical activity of the mTOR inhibitor RAD001 in low- grade lymphomas. Our preclinical studies demonstrated activity of mTOR inhibitors in Waldenstrom Macroglobulinemia (WM) cell lines and patient samples. This phase II study aimed to determine safety and activity of the oral mTOR inhibitor RAD001 (Novartis Pharmaceutical, MA) in patients with relapsed or refractory WM.METHODS: Patients who had at least one previous therapy for WM, and who had symptomatic relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received daily RAD001 at 10 mg. A cycle was considered 28 days. Patients were allowed to stay on therapy until progression of disease or excessive toxicity. This study was conducted in a collaborative effort between Dana Farber Cancer Institute (DFCI) and Mayo Clinic College of Medicine. Here, we report the data on the patients accrued at DFCI.RESULTS: 19 pts (15 men and 4 women) have been treated to date. All patients had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including included rituximab, nucleoside analogues (fludarabine or 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3330 mg/dL (range 1010– 7410). The median follow on RAD001 was 8 months (range 3 – 22 months). Eighteen pts are currently evaluable for response. Best responses to RAD001 after 2 cycles using IgM monoclonal protein were as follows: partial remission in 8 (44%), minimal response in 5 (28%). Progressive disease occurred in 4 (22%) and stable disease occurred in 1 (6%). The overall response rate (PR+MR) was 72%. The median duration of response has not been reached (3–22+ months). Patients tolerated therapy well without significant toxicities. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 1 patient, grade 3 pneumonia in 1 patient, grade 3 hyperglycemia in 1 patient and grade 3 mucositis in 1 patient. Other adverse events of grade 2 or lower included nail cracking, mucositis, diarrhea, and fatigue. Attributable toxicities otherwise proved manageable with appropriate supportive care, and RAD001 was generally well tolerated. One patient enrolled on the study withdrew consent and changed to hospice care within 3 weeks of therapy, and passed away due to disease progression.CONCLUSIONS: The use of the oral RAD001 single agent RAD001 in patients with relapsed or refractory WM was welltolerated and demonstrated significant activity achieving an overall response rate in 72% of patients. Future studies of combination of this agent with rituximab and bortezomib are currently being planned.

Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia

INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines and patient samples. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM.METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. RESULTS: 37 pts (26 men and 11 women, median age 62 years, range 42 – 73) have been treated to date. All of them had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3540 mg/dL (range 700– 10,800). The median follow up is 10 months (range 1 – 24 months). Thirty pts are currently evaluable for response after completing at least 2 cycles of therapy using IgM monoclonal protein. Complete remission occurred in 1 (3%), partial remission in 16 (53%), and minimal response in 10 (33%). Progressive disease occurred in 1 (3%) and stable disease occurred in 2 (7%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). The median duration of response has not been reached (3–24+ months). Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6, and completely resolved within one month after stopping therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient, and thrombocytopenia in 1 patient. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and the family changed his status to comfort care, and the patient passed away within one week. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated.CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 90% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. Studies using this combination in newly diagnosed patients are ongoing.

ABO-Incompatible Kidney Transplantation Using Antigen-Specific Immunoadsorption and Rituximab: A 3-Year Follow-up

In 2001 a protocol for ABO-incompatible (ABOi) kidney transplantation based on antigen-specific immunoadsorption and rituximab was introduced at our center, short-term results being comparable with those of ABO-compatible (ABOc) living donor kidney transplantation. Of greater importance, however, is long-term graft function, thus far not evaluated. The aim of this study was therefore to assess long-term results of this protocol. Twenty ABOi kidney recipients with more than 12-month follow-up were included in the study: all adult crossmatch negative ABOi kidney recipients (n=15) were compared with an adult ABOc living donor recipient control group (n=30), and all pediatric ABOi kidney recipients (<16 years of age) (n=5) were compared with a group of pediatric ABOc kidney recipients (n=18). Mean follow-up was three years. There was no significant difference in patient survival, nor in graft survival or in the incidence of acute rejection in any of the groups. In the adult kidney recipients mean glomerular filtration rate was equivalent at all time points (79-83 mL/min), as was Deltas-creatinine. In the pediatric groups, Deltas-creatinine was similar but glomerular filtration rate lower among the ABOi kidney recipients. There was a significant reduction (P<0.0001) without rebound in A/B antibody titers after transplantation (median IgG 1:2 and median IgM 1:1>1 year posttransplant) compared with pretransplant levels (median IgG 1:32 and IgM 1:16). We conclude that ABOi kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to ABOc living donor kidney transplantation. ABOi transplantation after this protocol does not have a negative impact on long-term graft function.

Phase II trial of the novel oral Akt inhibitor perifosine in relapsed and/or refractory Waldenstrom macroglobulinemia (WM)

8546 Background: Perifosine is an oral, synthetic alkylphospholipid, with multiple effects including inhibition of Akt. We previously showed that perifosine induces significant growth inhibition in vitro and in vivo in WM models. This phase II study aimed to determine the activity and safety of orally-administered perifosine at a dose of 150 mg in patients (pts) with relapsed/refractory WM. Methods: Pts who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All pts received 150 mg perifosine daily for 28 days per cycle until progression; response was assessed after 2 cycles. Results: The trial accrued from 10/06 to 11/07, with 37 pts (27 men and 10 women, median age 65 years, range 51 - 80) treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). The median IgM at baseline was 3245 mg/dL (range 972- 8480). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. Thirty one pts are currently evaluable for response by IgM monoclonal protein after at least 2 cycles of therapy; best response was as follows: 1 (3%) partial response and 10 (32%) minimal response for an overall response rate (ORR) of 35%, with a median decrease of IgM of 44% (range, 26–51%). Only 2 pts (6%) progressed, and 18 (58%) pts achieved stable disease. The median duration of response has not been reached. With a median followup of 4 months (range, 1–13+) 16 (44%) pts remain on therapy and free of disease progression. Dose reduction (to 100 mg/d) was required in 5 pts due to toxicities, which included grade 3 nausea/vomiting in 3 pts and grade 3 arthritis/gout-like symptoms in 2 pts (which correlated with rapid response in these pts). Grade 3 corneal ulceration occurred in 1 pt which was possibly related to therapy. Attributable toxicities otherwise proved manageable with appropriate supportive care, and perifosine was generally well tolerated. Conclusions: Oral perifosine as monotherapy has been well tolerated and has encouraging activity with an ORR of 35% as a single agent in pts with relapsed and/or refractory WM. Future clinical trials in combination are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Keryx Keryx

Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results.

INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM.METHODS: Patients who had at least one previous therapy for WM, symptomatic, and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15 q 28 days x 6 cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4.RESULTS: 17 pts (10 men and 7 women, median age 62 years, range 43 – 81) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. The median IgM at baseline was 4070 mg/dL (range 1370– 10,800); median M-spike at baseline was 2.48 g/dL (range 1.5 – 4.87); and median hemoglobin was 11.0 g/dL (6.3–15.2). The median follow up was 5 months (range 1 – 11 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. 13 pts are currently evaluable for response, best response to bortezomib and rituximab after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with bortezomib and rituximab. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6 and improved to grade 1 within 2 weeks of holding therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient. One patient discontinued therapy on study after 1 cycle because of inability to travel to study site and completed similar treatment off study and was unevaluable on this study. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated.CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates exciting activity achieving CR+ PR + MR in 85%, and/or stabilization of disease in 15% of evaluable patients with relapsed WM. No significant peripheral neuropathy was observed with this regimen. Updated data will be presented at the meeting.ResponseN=13; ORR (CR+PR+MR)= 85%Median time to best response (months)Complete Response1 (8%)6Partial Response3 (23%)3.5 (3–4)Minimal Response7 (54%)4 (2–6)Stable Disease2 (15%)NAProgressive Disease0

Phase II Trial of Perifosine (KRX-0401) in Relapsed and/or Refractory Waldenström Macroglobulinemia: Preliminary Results.

INTRODUCTION: Perifosine is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt. We previously demonstrated that AKT is upregulated in samples of patients with WM and that the AKT inhibitor perifosine induces significant growth inhibition in vitro and in vivo in xenograft models in WM. Phase I trials with perifosine have demonstrated a favorable side effect profile. This phase II study aimed to determine safety and activity of the oral AKT inhibitor perifosine in patients with relapsed/refractory WM.METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 150 mg perifosine daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles.RESULTS: 28 pts (20 men and 8 women, median age 64.8 years, range 51 – 80) have been treated to date. The median number of lines of prior treatment was 2 (range 1 – 5). The median IgM at baseline was 3245 mg/dL (range 972– 8480); median M-spike at baseline was 1.9 g/dL (range 0.5 – 4.85); and median hemoglobin was 11.3 g.dL (7.0–14.0). The median follow up was 5 months (range 1 – 8 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. 21 pts are currently evaluable for response, best response to single agent perifosine after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with perifosine. The median M spike reduction was 20% (0 – 76). Patients tolerated perifosine well without significant toxicities: grade 3 nausea/vomiting in 1 patient resolved with dose reduction to 100 mg; grade 3 anemia in one patient was related to cold-agglutinin hemolytic anemia; and 2 patients had GI bleeding unrelated to therapy. Dose reduction (to 100 mg/d) was required in 4 patients; 2 for nausea and loss of weight, 1 for non-specific bone pain and 1 for an episode of fever and fatigue. Four patients discontinued therapy, one for cold-aggutinin related hemolytic anemia related to WM, one due to corneal ulceration that was possibly related to perifosine and corneal infection, and 2 for patient decision. Attributable toxicities otherwise proved manageable with appropriate supportive care and perifosine was generally well tolerated, with no peripheral neuropathy.CONCLUSIONS: Oral perifosine as monotherapy has been well tolerated and demonstrates encouraging activity achieving PR + MR in 34%, and/or stabilization of disease in 66% of evaluable patients with relapsed WM. Updated data will be presented at the meeting.Table 1ResponseN=21; ORR (CR+PR+MR)=34%Median time to best response (months)Partial response2(10%)5Minimal response5 (24%)4 (3–6)Stable Disease (SD)14 (66%)NAProgressive Disease0

Phase II Trial of the Oral mTOR Inhibitor RAD001 (Everolimus) in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results.

INTRODUCTION: mTOR inhibitors have been associated with responses in Mantle cell lymphoma and other lymphomas (J Clin Oncol 23; 5347, 2005). Phase I and II trials with the oral everolimus (RAD001, Novartis Pharmaceuticals) have demonstrated a favorable side effect profile. This phase II study tested everolimus in patients with relapsed/refractory Waldenstrom Macroglobulinemia (WM).METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. Other eligibility criteria included symptomatic disease, > 2 weeks from last therapeutic agent used, >10% involvement with lymphoplasmacytic cells in the bone marrow, IgM paraprotein > 2x upper limit of normal, absolute neutrophil count >1000/mm3 and platelet count >75,000/mm3, serum creatinine of < 2 x upper limit of normal. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 10mg RAD001 daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles.RESULTS: 10pts (8 men and 2 women, median age is 62 years, range 52–71) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5). The median IgM at baseline was 3970 mg/dL (range 3120– 7410); median M-spike at baseline was 2.07 gm/dL (range 1.41 – 4.02); and median hemoglobin was 11.3 g/dL (9.4–13.3). The median follow up was 4 months (range 1 – 7 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. Seven patients are currently evaluable for response. The best response to single agent RAD001 after 2 cycles is presented in Table 1. Median duration of response has not been reached. Patients tolerated RAD001 well without significant toxicities. The main toxicities observed were apthous ulcers in 4 patients. One patient required dose reduction due to mucositis. One patient stopped therapy within the first month of treatment and went on to hospice care before succumbing to his disease after one month. Attributable toxicities otherwise proved manageable with appropriate supportive care and RAD001 was generally well tolerated, with no peripheral neuropathy.CONCLUSIONS: Oral RAD001 as monotherapy has been well tolerated and demonstrates exciting activity achieving PR + MR in 57%, and/or stabilization of disease in 43% of evaluable patients with relapsed WM. Accrual of a total of 30 patients is rapidly ongoing. Updated data will be presented at the meeting.Table 1ResponseN=7; ORR (CR+PR+MR)= 57%Median time to best response (months)Partial Response1 (14%)5Minimal Response3 (43%)4 (3–6)Stable Disease (SD)3 (43%)NAProgressive Disease0

Expression of the Human Concentrative Nucleotide Transporter (hCNT1) Gene Correlates with Clinical Response in Patients Affected by Waldenstrom's Macroglobulinemia (WM), Undergoing a Combination Treatment with Cladribine (2-CdA) and Rituximab.

The aim of this prospective multicenter trial was to evaluate the efficacy of the nucleoside analogue 2-CdA in combination with Rituximab and to identify possible genetic factors that could influence the clinical response of the combination. From December 2003 to November 2006, 29 pretreated/newly diagnosed pts affected by WM were enrolled in the study. Pts characteristics included: sex (M/F) 9/19, median age 64 (range 36–75 yrs), a median IgM level before treatment of 2567mg/dL; 16 pts were newly diagnosed. The combination therapy was Rituximab at standard schedule (375 mg/mq) on day 1 followed by 2-CdA 0.1 mg/kg (sc injection) for 5 consecutive days. Each cycle was administered monthly for a total of 4 cycles. Clinical responses were evaluated two months after the end of treatment, according to Response Criteria from the 3rd International Workshop on WM. Expression analysis of the genes involved in the activity of 2-CdA (deoxycytidine kinase, deoxyguanosine kinase, 5′-nucleotidase, ribonucleotide reductase 1 and 2, human equilibrative nucleotide transporter and hCNT1) was performed on bone marrow cells, at baseline in 22 pts. The therapy was well tolerated, except in three patients who discontinued Rituximab due to cardiac toxicity during the first or second infusion. The treatment was delayed in 3 pts because of haematologic toxicity (G3 neutropenia) and in 2 of them the 2-CdA dose was reduced after 2 cycles. The only non-haematological complications observed were late respiratory infections which occurred in 3 pts. At a median follow-up of 21 (13–41) months we observed 17 (59%) CR/PR, 7 (24%) MR, 1 (3%) SD and 4 (14%) PD/NR. Pharmacogenomic analysis showed a statistically significant lower expression of the hCNT1 gene in pts who failed the treatment and who achieved a MR or SD than in those who achieved a CR or a PR (p=0.014) suggesting a possible relationship between reduced hCNT1 levels and a diminished clinical activity of 2-CdA. No significant difference was detected in the expression of the other genes analyzed. Our results suggest that the combination of 2-CDA and Rituximab is safe and active in WM pts; the use of pharmacogenomic analysis might contribute to a better selection of the patients who are more likely to respond to such a combination treatment.

Pilot Study of a Heptavalent Vaccine-Keyhole Limpet Hemocyanin Conjugate plus QS21 in Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission. Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 microg), Globo-H (10 microg), Lewis Y (10 microg), Tn(c) (3 microg), STn(c) (3 microg), TF(c) (3 microg), and Tn-MUC1 (3 microg) individually conjugated to KLH and mixed with adjuvant QS21(100 microg). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity). Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1, 1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against Lewis Y; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients. This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.

Antibody responses to pneumococcal and hemophilus vaccinations in splenectomized patients with hematological malignancies or trauma

In this study we addressed the question of whether an underlying hematological malignancy may affect the immune response to vaccination against bacterial polysaccharide antigens (e.g. Haemophilus influenzae type b, Streptococcus pneumoniae) in splenectomized patients. Between 1993 and 2003, 44 splenectomized adults from the outpatient clinic for infectious diseases were prospectively included in the study: 23 patients suffered from hematological malignancies (HM) and had undergone splenectomy; 21 were splenectomized following trauma (T) and served as the control group. Each patient received an intradeltoid injection with 0.5 ml of a single lot of a 23-valent pneumococcal polysaccharide vaccine, and 0.5 ml of a polyribosyl ribitol phosphate capsular polysaccharide vaccine of H. influenzae type b (Hib) into the opposite arm. Blood samples for determination of pneumococcal and Hib antibodies were taken prior to vaccination and again 6-8 weeks later. In assessing responses to the 23-valent pneumococcal polysaccharide vaccine, we found significant differences in antibody titer increase between the HM and T groups (median IgG increase 1.27 [0.7; 2.39] vs. 3.9 [2.1; 15.3], P < 0.001; and median IgM increase 1.33 [1.0;2.67] vs. 5.25 [2.3; 7.78], P < 0.001). In the HM group, only 8/23 and 6/23 showed a titer increase of twice or more the base value for IgG and IgM respectively, whereas in the trauma group an adequate response was shown by 16/21 and 16/20 respectively. Patients with splenectomy and hematological malignancies responded poorly to the 23-valent polysaccharide vaccine. Response to the conjugated Hib vaccine was slightly better, but still significantly lower than in individuals with posttraumatic splenectomy. Data suggest that vaccination response to the polysaccharide vaccines should be evaluated at least in the high-risk group.

IgA and IgG Hypogammaglobulinemia Are Associated with Mutations in the APRIL/BLYS Receptor TACI in Waldenstrom's Macroglobulinemia (WM).

IgA and IgG hypogammaglobulinemia are a common finding in patients with WM which may contribute to recurrent infections seen in up to half of WM patients. The etiology for this finding remains unclear. As part of these studies, we investigated the prevalence and genetic basis for IgA and IgG hypogammaglobulinemia among 89 previously untreated patients with the clinicopathological diagnosis of WM. Their median IgM was 2,980 (180–12,400) mg/dl, median BM involvement was 35% (5%–95%) and median B2M was 2.7 (1.4–13.7 mg/dL). Fifty-six (63%) and 66 (74%) of these patients demonstrated IgG (<700 mg/dL) and IgA (<70 mg/dL) hypogammaglobulinemia, respectively. Importantly, no correlation was seen between serum IgG and IgA levels and BM disease involvement, suggesting no direct impact of disease involvement on the production of uninvolved immunoglobulins. Given these findings, we undertook extensive germline and somatic sequence studies to determine if mutations existed within the APRIL/BLYS receptor TACI, which commonly is mutated in patients with Common Variable Immunodeficiency Disorder (CVID). Six of 29 (21%) sequenced patients displayed variants within TACI, which were present in both tumor cells (n=6) and germline (n=5). Importantly, patients displaying variants in TACI demonstrated significantly lower serum IgG (280 vs. 676 mg/dL; p=0.0009) and IgA (20 vs. 41 mg/dL; p=0.0006) levels versus patients without TACI variants. Lastly, sequence analysis of APRIL, BLYS as well as the TACI downstream TRAF proteins have led to detection of numerous variants which may further account for hypogammaglobulinemia among patients with normal TACI expression. These data suggest that aberrations in TACI signaling may account for IgG and IgA hypogammaglobulinemia in WM, akin to patients with CVID. Moreover, mutations within TACI signaling may have pathological implications for WM since a 300 fold increased incidence of lymphoma has been observed among CVID patients. The impact of TACI mutations on pathogenesis of WM is currently under investigation in our laboratory.