Citations

Abstract Profound disruption of immune function is an established risk factor for non-Hodgkin lymphoma. We report here a large-scale evaluation of common genetic variants in immune genes and their role in lymphoma. We genotyped 57 single nucleotide polymorphisms (SNP) from 36 candidate immune genes in 1,172 non-Hodgkin lymphoma cases and 982 population-based controls from a US multicenter study. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the association between individual SNP and haplotypes with non-Hodgkin lymphoma overall and five well-defined subtypes. A haplotype comprising SNPs in two proinflammatory cytokines, tumor necrosis factor-α and lymphotoxin-α (rs1800629, rs361525, rs1799724, rs909253, and rs2239704), increased non-Hodgkin lymphoma risk overall (OR, 1.31; 95% CI, 1.06-1.63; P = 0.01) and notably for diffuse large B cell (OR, 1.64; 95% CI, 1.23-2.19; P = 0.0007). A functional nonsynonymous SNP in the innate immune gene Fcγ receptor 2A (FCGR2A; rs1801274) was also associated with non-Hodgkin lymphoma; AG and AA genotypes were associated with a 1.26-fold (95% CI, 1.01-1.56) and 1.41-fold (95% CI, 1.10-1.81) increased risk, respectively (Ptrend = 0.006). Among non-Hodgkin lymphoma subtypes, the association with FCGR2A was pronounced for follicular and small lymphocytic lymphomas. In conclusion, common variants in genes influencing proinflammatory and innate immune responses were associated with non-Hodgkin lymphoma risk overall and their effects could vary by subtype. Our results require replication but potentially provide important clues for investigating common genetic variants as susceptibility factors and in disease outcomes, treatment responses, and immunotherapy targets. (Cancer Res 2006; 66(19): 9771-80)

AbstractPrimary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, is highly active in patients with multiple myeloma. We studied the toxicity and efficacy of lenalidomide in patients with AL. Patients with symptomatic AL, a measurable plasma cell disorder, and adequate hematologic and renal reserve were eligible. Patients received single-agent lenalidomide. If there was no evidence of progression after 3 months or of hematologic response after 3 cycles, dexamethasone was added. Twenty-three patients were enrolled. Thirteen were previously treated. Organ involvement was cardiac (64%), renal (73%), hepatic (23%), and nerve (14%). Within the first 3 cycles of therapy, 10 patients discontinued treatment: 4 early deaths, 3 adverse events, and 3 other causes. With a median follow-up of 17 months, 10 patients responded to treatment. In these patients, responses included 9 hematologic, 4 renal, 2 cardiac, and 2 hepatic. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3 or 4 adverse events at least possibly attributable to lenalidomide were neutropenia (45%), thrombocytopenia (27%), rash (18%), and fatigue (18%). In AL patients, we saw limited activity of single-agent lenalidomide, but significant activity of the combination with dexamethasone, which warrants further investigation.

Summary Serum and plasma are used interchangeably to measure anti-neutrophil cytoplasmic antibodies (ANCA), even though the release of ANCA target antigens during the preparation of serum could affect ANCA assays and cause discrepancies between the results obtained from serum and plasma. To what extent ANCA test results obtained from serum agree and correlate with results from plasma remains unknown. Therefore, a comprehensive comparison was performed using serum and plasma samples which were collected in 175 patients with active Wegener's granulomatosis at enrolment of a recent randomized trial. These paired serum and plasma samples were subjected to parallel ANCA testing by standard indirect immunofluoresence on ethanol-fixed neutrophils, a direct enzyme-linked immunoassay (ELISA) for proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, and two different capture ELISAs for PR3-ANCA. The concordance of categorical serum and plasma ANCA results was assessed using κ-coefficients. These were > 0·8 for all assays, indicating a very good concordance between positive and negative serum and plasma results. Spearman's correlation coefficients for serum and plasma PR3-ANCA values obtained by direct ELISA and both capture ELISAs were ≥ 0·95 (P < 0·0001). Our study shows that serum and plasma samples can be used interchangeably for measuring ANCA.

AbstractWe present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 × 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2V617F mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.

Background— The long-term prognosis of patients who develop carcinoid heart disease and the effect of cardiac surgery on outcome are not well established. Methods and Results— In this retrospective study, we identified 200 patients with carcinoid syndrome referred for echocardiography in whom the diagnosis of carcinoid heart disease was confirmed. Patients were divided into 3 groups of similar size according to the date from first diagnosis of carcinoid heart disease. Group A comprised patients diagnosed from 1981 through June 1989; group B, diagnosed July 1989 through May 1995; and group C, June 1995 through 2000. The end point was all-cause mortality. Median survival was significantly lower in group A (1.5 years, 95% CI 1.1 to 1.9 years) compared with groups B (3.2, 95% CI 1.3 to 5.1 years) and C (4.4, 95% CI 2.4 to 7.1 years; P =0.009). In a multivariate model adjusted for treatment and clinical characteristics, the risk of death in groups B (hazard ratio 0.67, 95% CI 0.46 to 0.99, P =0.04) and C (hazard ratio 0.61, 95% CI 0.39 to 0.92, P =0.006) was significantly reduced relative to group A. Cardiac surgery was performed in 87 patients. When cardiac surgery was included as a time-dependent covariate in a multivariate analysis, it was associated with a risk reduction of 0.48 (95% CI 0.31 to 0.73, P <0.001), whereas the time period of diagnosis was no longer significant. Conclusions— The prognosis of patients with recognized carcinoid heart disease has improved over the past 2 decades at our institution. This change in survival may be related to valve replacement surgery.

Clinical Pharmacology & Therapeutics (2003) 73, P81–P81; doi:

Abstract Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT+ ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT+ cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL. (Blood. 2004;104:558-560)

Purpose To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Patients and Methods A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n = 66) versus MEC (n = 63) to treat patients with relapsed or refractory AML and high-risk MDS. Results For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P = not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased—35% versus 15% for the remaining patients (P = .018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients’ overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR− patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P = .09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. Conclusion CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.