Citations

An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome–negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P ≤ .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.

Abstract Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with, Her-2xDR3 and B6xDR3 mice expressing H2bxDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2b haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles. [Cancer Res 2007;67(14):7020–7]

Abstract Two common single nucleotide polymorphisms in immunoregulatory genes (TNF G308A, rs1800629 and IL10 T3575A, rs1800890) have been recently reported as risk factors for non–Hodgkin lymphoma (NHL) in a large pooled analysis. We systematically investigated the effects of other established NHL risk factors in relation to the tumor necrosis factor (TNF) G308A or interleukin 10 (IL10) T3575A genotypes. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) from 1,172 cases and 982 population-based controls in a U.S. multicenter study. We investigated NHL overall and two common subtypes [diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma]. NHL risks were increased among those with both an autoimmune condition and the TNF G308A GA/AA (ORNHL, 2.1; 95% CI, 1.0–4.2) or the IL10 T3575A TA/AA genotype (ORNHL, 1.6; 95% CI, 0.9–2.6) compared with individuals without an autoimmune condition and with the common TNF G308A GG or IL10 T3575A TT genotype, respectively; results were similar for DLBCL and follicular lymphoma. We found that elevated DLBCL risk associated with last-born status was more pronounced among those with TNF G308A GA/AA (ORDLBCL, 2.7; 95% CI, 1.1–6.4) or IL10 T3575A TA/AA (ORDLBCL, 2.9; 95% CI, 1.6–5.2). Similarly, elevated DLBCL risk associated with obesity (body mass index, ≥35 versus <25 kg/m2) was observed only among those with TNF G308A GA/AA (ORDLBCL, 2.5; 95% CI, 1.1–5.7) or IL10 T3575A TA/AA genotypes (ORDLBCL, 2.0; 95% CI, 1.1–3.5). These exploratory results require replication but provide evidence that autoimmune conditions, late birth order, and obesity act partly through a common inflammatory pathway, posing a greater risk to individuals with variant TNF and IL10 genotypes than those with wild-type alleles. [Cancer Res 2007;67(10):5042–54]

We compared the treatment-related mortality, relapse rate, disease-free survival (DFS), and overall survival (OS) by cytogenetic risk group of 261 patients with acute myeloid leukemia in first complete remission (CR1) and 299 patients in CR2 in undergoing matched unrelated donor hematopoietic stem cell transplantation (HSCT). For patients in first CR, the DFS and OS at 5 years were similar for the favorable, intermediate, and unfavorable risk groups at 29% (95% confidence interval [CI], 8%-56%) and 30% (22%-38%); 27% (19%-39%) and 29% (8%-56%); and 30% (95% CI, 22%-38%) and 30% (95% CI, 20%-41%), respectively. For patients in second CR, the DFS and OS at 5 years were 42% (95% CI, 33%-52%) and 35% (95% CI, 28%-43%); 38% (95% CI, 23%-54%) and 45% (95% CI, 35%-55%); and 37% (95% CI, 30%-45%) and 36% (95% CI, 21%-53%), respectively. Cytogenetics had little influence on the overall outcome for patients in first CR. In second CR, outcome was modestly, but not significantly, better for patients with favorable cytogenetics. The graft-versus-leukemia effect appeared effective, even in patients with unfavorable cytogenetics. However, treatment-related mortality was high. Matched unrelated donor HSCT should be considered for all patients with unfavorable cytogenetics who lack a suitable HLA-matched sibling donor.

AbstractRecent gene-expression data have suggested that host immune genetic signatures may predict outcomes in patients with follicular lymphoma. We evaluated the hypothesis that germ line common variation in candidate immune genes is associated with survival. Cox models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for individual SNPs after accounting for age, clinical, and other demographic factors. The median age at diagnosis of the 278 patients was 57 years, and 59 (21%) of the patients died during follow-up, with a median follow-up of 59 months (range, 27-78 months) for surviving patients. SNPs in IL8 (rs4073; HRTT = 2.14, 1.26-3.63), IL2 (rs2069762; HRGT/TT = 1.80, 1.06-3.05), IL12B (rs3212227; HRAC/CC = 1.83, 1.06-3.06), and IL1RN (rs454078; HRAA = 1.93, 1.11-3.34) were the most robust predictors of survival. A summary score of the number of deleterious genotypes from these genes was strongly associated with survival (P = .001). A risk score that combined the 4 SNPs with the clinical and demographic factors was even more strongly associated with survival (P < .001); the 5-year Kaplan-Meier survival estimates were 96% (93%-100%), 72% (62%-83%), and 58% (48%-72%) for groups at low, intermediate, and high risk, respectively. Common variation in host immune genes warrants further evaluation as a promising class of prognostic factors in follicular lymphoma.

Abstract Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

AbstractWe previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMT Ex8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

Abstract Most adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) will relapse. We examined the outcome of 609 adults with recurring ALL, all of whom were previously treated on the Medical Research Council (MRC) UKALL12/ECOG2993 study, where the overall survival (OS) of newly diagnosed patients is 38% (95% confidence interval [CI] = 36%-41%) at 5 years. By contrast, OS at 5 years after relapse was 7% (95% CI = 4%-9%). Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients younger than 20 years vs OS of 3% in patients older than 50 years; 2P < .001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2 years versus OS of 5% in those with a CR1 of less than 2 years; 2P < .001). Treatment received in CR1 did not influence outcome after relapse. In a very highly selected subgroup of patients who were able to receive HSCT after relapse, some were long-term survivors. We conclude from a large, unselected series with mature follow-up that most adults with recurring ALL, whatever their prior treatment, cannot be rescued using currently available therapies. Prevention of recurrence is the best strategy for long-term survival in this disease.

The quantities of immunoglobulin E (IgE) antibodies to grass or ragweed allergens were measured by an immunoabsorption in the serums of patients sensitive to one of these allergens. IgE antibodies to grass or ragweed allergens accounted for means of 30 and 29 percent of the total IgE protein. After the ragweed pollination season, the levels of serum IgE antibodies to ragweed allergens rose dramatically and in postpollination serums they accounted for 39 percent of the total IgE protein with a range from 13 to 50 percent.