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Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.govas #NCT00319657 and #NCT01165762.

Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor–mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

Next-generation sequencing (NGS) of immune receptors has become a standard tool to assess minimal residual disease (MRD) in patients treated for lymphoid malignancy, and it is being used to study the T-cell repertoire in many clinical settings. To better understanding the potential clinical utility and limitations of this application outside of MRD, we developed a BIOMED-2 primer–based NGS method and characterized its performance in controls and patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic transplant. For controls and patients with GVHD, replicate sequencing of the same T-cell receptor β (TRB)libraries was highly reproducible. Higher variability was observed in sequencing of different TRBlibraries made from the same DNA stock. Variability was increased in patients with GVHD compared with controls; patients with GVHD also had lower diversity than controls. In the T-cell repertoire of a healthy person, approximately 99.6% of the CDR3 clones were in low abundance, with frequency <10−3. A single library could identify >93% of the clones with frequency ≥10−3in the repertoire. Sequencing in duplicate increased the average detection rate to >97%. This work demonstrates that NGS reliably and robustly characterizes TRBpopulations in healthy individuals and patients with GVHD with frequency ≥10−3and provides a methodologic framework for applying NGS immune repertoire methods to clinical testing applications beyond MRD.

Steroid refractory gastrointestinal (GI) acute graft-versus-host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T-cell receptor β (TCRβ) complementarity-determining region 3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T-cell alloreactivity in aGVHD. We identified T-cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRβ clonal structure between different biopsy sites in the GI tract than 8 primary therapy–responsive patients. Tracking GI clones identified longitudinally at endoscopy in the blood also revealed an increased clonal expansion in patients with steroid-refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T-cell activity is a major determinant.

Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional 2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel -AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether 2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)–matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

Integrated treatments for comorbid depression (often with anxiety) and obesity are lacking; mechanisms are poorly investigated.

In vivo analyses of thymopoiesis in mice defective in signaling through Kit and γc or Kit and IL-7Rα demonstrate synergy and partial complementation of γc or IL-7–mediated signaling by the Kit signaling pathway. Our molecular analysis in T-lymphoid cells as well as in nonhematopoietic cells shows that Kit and IL-7R signaling pathways directly interact. KL-mediated activation of Kit induced strong tyrosine phosphorylation of γc and IL-7Rα in the absence of IL-7. Activated Kit formed a complex with either IL-7Rα or γc, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that γc and IL-7Rα are each direct substrates of Kit. Kit activated Jak3 in an IL-7R–dependent manner. Moreover, deficient Stat5 activation of the Kit mutant YY567/569FF lacking intrinsic Src activation capacity was partially reconstituted in the presence of IL-7R and Jak3. Based on the molecular data, we propose a model of Kit-mediated functional activation of γc-containing receptors such as IL-7R, similar to the interaction between Kit and Epo-R. Such indirect activation of the Jak-Stat pathway induced by the interaction between an RTK and type I cytokine receptor could be the underlying mechanism for a context-specific signaling repertoire of a pleiotropic RTK-like Kit.

OBJECTIVES

The US Department of Veterans' Affairs (VA) conducted Cooperative Study #394 at nine sites to determine whether vitamin E was a safe and effective treatment for tardive dyskinesia (TD). The study used the Abnormal Involuntary Movement Scale (AIMS) to measure TD. To monitor inter‐rater reliability (IRR) on the AIMS, personnel at each site did initial AIMS assessments, on seven occasions, on a set of five unique subjects from videotapes. On four of these occasions raters re‐assessed sets of five subjects from seven to 13 months after their initial ratings. We analysed the initial ratings of 34 videotaped subjects and the second ratings of 19.

Objectives. The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non–Q wave myocardial infarction (NQMI) who were randomized prospectively to an early “invasive” strategy versus an early “conservative” strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up.

Introduction:Neural mechanisms underlying behavior therapy in obesity are poorly understood, particularly in patients with comorbid depression. Putative targets include neural circuits for conscious and nonconscious emotion regulation.Hypothesis:Changes in a priorineural circuits for emotion regulation from baseline (0) to 2 mo (mediators, M) mediate changes in BMI, physical activity, and eating behaviors from 0 to 6 or 12 mo (outcomes, Y).Methods:In a trial of integrated behavior therapy, adults with obesity and depression were randomized to intervention (n=59) or usual care (n=49). The yearlong intervention included 6 in-person problem solving therapy (PST) sessions for depression by 2 mo, 3 additional PST sessions for depression and 11 home videos on lifestyle changes for weight loss by 6 mo, and 6 maintenance calls by 12 mo. Participants completed validated conscious and nonconscious facial emotion viewing tasks in fMRI at 0 and 2 mo (time point corresponding to initial PST for depression in the intervention) and weight and height (baseline only) measurements, 7-day physical activity recalls, and 24-hour dietary recalls at 0, 6, and 12 mo. Analyses tested mediation as showing both a significant treatment effect (X) of the intervention vs. usual care on the mediator (X->M, path a) and a significant correlation of the mediator with the outcome either as a main effect or an interaction effect by treatment group (M->Y, path b).Results:Compared with usual care, the intervention led to significantly reduced nonconscious reactivity to threat-related facial emotions (fear, anger) at 2 mo for the left (-0.89, 95% CI -1.64 to -0.14; P=.02) and right amygdala (-0.84, 95% CI -1.54 to -0.13; P=.02) (path a). These reductions correlated significantly with increased leisure-time physical activity (MET minutes/wk) at 12 mo: main effect -686.0 (95% CI -1127.9 to -244.1; P=.003) and interaction effect 664.7 (95% CI 73.1 to 1256.4; P=.03) for the left amygdala and main effect -692.9 (95% CI -1365.3 to -20.6; P=.04) for the right amygdala. Similarly, the reductions correlated significantly with increased energy expenditure (kcal/kg/d) at 12 mo: main effect -1.72 (95% CI -2.49 to -0.95; P<.001) and interaction effect 1.89 (95% CI 0.84 to 2.95; P<.001) for the left amygdala; and main effect -1.82 (95% CI -3.08 to -0.56; P=.006) and interaction effect 1.94 (95% CI 0.50 to 3.38; P=.01) for the right amygdala (path b). Nonconscious reactivity to threat in bilateral amygdala did not correlate significantly with changes in BMI or eating behaviors.Conclusions:Reduced nonconscious reactivity to threat in bilateral amygdala in response to initial PST for depression significantly mediated improvements in leisure-time physical activity and energy expenditure. Results advance the understanding of neural mechanisms underlying behavior therapy in obesity and inform intervention optimization to enhance efficacy.

Miklos: Kite - Gilead: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Research Funding. Muffly:Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding.

The hypothesis that increasing iron burden (assessed by the serum ferritin level) with age contributes to the pathogenesis of cardiovascular (CVD) and other diseases of aging was tested in a 24-hospital, 6-year prospective randomized single blinded clinical trial of iron reduction by calibrated phlebotomy (JAMA 2007;297:603-9; JNCI 2008;100:996-1002). The primary outcome was all cause mortality and the secondary outcome death plus non-fatal MI and stroke (total n = 1,277 patients with PAD). Mean follow-up ferritin levels were significantly reduced in iron reduction patients (p<0.001). Although iron reduction had no significant effect on CVD outcomes overall, an association was observed for the secondary endpoint by age quartile (p for interaction = 0.004). The Cox proportional hazards regression model showed improved primary (p=0.02) and secondary (p<0.001) endpoints in the youngest age quartile patients (age 43 to 61) randomized to iron reduction versus control. Age analyzed as a continuous variable in the Cox proportional hazards regression model and the log relative hazards plots revealed that age interacted nonlinearly with iron reduction in both the primary (p=0.04) and secondary (p<0.001) endpoints. HYPOTHESIS: Iron reduction has beneficial effects on overall CVD outcomes that can be masked by interactions between age and ferritin level. METHODS: Computer randomization to iron reduction (n = 636) versus control (n = 641) groups was stratified by age, ferritin level and other prognostic variables at entry. Data tracked prospectively (including data on compliance with intervention) were subjected to pre-planned, intent-to-treat analysis. RESULTS: Mean follow-up ferritin levels declined with increasing age at entry in control patients. Older age (p = 0.027) and higher ferritin levels (p<0.001) at entry predicted poorer compliance with phlebotomy in iron reduction patients. Separation of mean follow-up ferritin levels between groups diminished with increasing age at entry. Plots of mean follow-up ferritin levels versus the log relative hazard for the primary and secondary endpoints for iron reduction patients showed significantly improved outcomes with lower mean follow-up ferritin levels (p = 0.028 and 0.044 respectively). Improvement in the primary outcome with lower ferritin levels was also found upon analysis of the entire cohort (p = 0.037). Kaplan-Meier analysis of mean follow-up ferritin levels for the entire cohort comparing patients having ferritin levels above versus below the mean showed improved primary and secondary outcomes with lower ferritin levels (p = 0.003 and 0.067 respectively). CONCLUSIONS: Lower body iron burden predicted improved clinical outcomes in patients with cardiovascular disease regardless of age or randomization status. Two factors seemed to account for the lack of an effect of intervention in the overall cohort. First, serum ferritin levels decreased with increasing age in control patients, apparently because patients with higher iron stores were more likely to die earlier. Second, younger iron reduction patients were more likely to comply with the phlebotomy intervention. Consequently, iron reduction therapy had less of a potential effect in older compared to younger patients because mean follow-up ferritin levels between groups converged with increasing age. An implication for future studies, and possibly for practice, is that adequate iron reduction targeted to patients with higher ferritin levels is more likely to be effective. These findings suggest cost – effective strategies for improving outcomes in diseases of aging.No relevant conflicts of interest to declare.

We investigated a novel graft-versus-host disease (GVHD) prophylactic regimen, sirolimus and mycophenolate mofetil (MMF), in patients with advanced hematologic malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from matched related donors (MRD). The sirolimus and MMF combination was chosen based on intriguing evidence of sirolimus, and less dramatically MMF, conserving the inhibition of T cell proliferation compared to cyclosporine (CSP) in an AGVHD murine model as well as multiple reports supporting sirolimus’ preservative or augmentative effects on the T regulatory cell population (CD4+CD25+, FoxP3+) in animals and humans in comparison to cyclosporine (CSP) and a theoretical reduction in the incidence and severity of AGVHD. In addition, this regimen may cause less severe toxicities compared with standard methotrexate and/or calcineurin inhibitor (CI)-containing GVHD prophylactic regimens. Sirolimus was begun as an oral medication on day -3 with a 12 mg loading dose followed by 4 mgs daily, dose adjusted to maintain serum trough levels of 3–12 ng/ml. MMF was begun on D0 at 15 mg/kg IV every 12 hours. Mycophenolic acid (MPA) pharmacokinetics were conducted on days 2 and 21 post-HCT. Sirolimus and MMF were scheduled to be tapered simultaneously beginning 100 days post-HCT. FoxP3+ cell populations in the peripheral blood (PB) were analyzed before and after HCT in the patients receiving sirolimus and MMF GVHD prophylaxis as well as in 15 control patients with similar disease categories and preparative regimens receiving CI-containing GVHD prophylaxis. Based on pre-study stopping rules of expected grade II–IV AGVHD incidence, the trial was closed to accrual after enrollment of 11 patients. The median age of the 11 patients was 51 years (26–59). The diagnoses of the study patients included myelodysplasia (5), acute myelogenous leukemia (3) and nonhodgkin lymphoma (3). Seven patients received busulfan, etoposide and cyclophosphamide (CY); three patients received carmustine, etoposide and CY and one patient received total body irradiation, etoposide and CY as the preparative regimens. Sirolimus was discontinued in 4 patients due to concern for toxicity-related events including severe sinusoidal obstructive syndrome (1), altered mental status (1), portal vein thrombosis (1) and risk of poor wound healing after abdominal exploratory surgery (1) 9 days, 9 days, 61 days and 39 days post-HCT, respectively. Six of 11 patients developed grade II-IV AGVHD a median of 15.5 days post-HCT (range 11–25 days), 3 of the 6 with grade IV AGVHD. Two of the 3 patients with grade IV AGVHD required discontinuation of sirolimus 9 days post-HCT due to toxicity. Five of the 6 AGVHD patients had skin-only and one had liver, gut and skin involvement. All patients responded to AGVHD therapy and there were no AGVHD-related deaths. One patient died 54 days post-HCT due to complications of colonic ulceration believed related to oral MMF therapy. Two patients died of relapsed disease at 103 and 304 days post-HCT. At a median follow-up of 416 days (328–652 days), 8 of 11 patients were alive without disease, 5 with active chronic GVHD. The median MPA area under the curve (AUC) on day 2 was 12.8 mcg*hr/mL (6.4–17.4) and day 21 was 17.9 mcg*hr/mL (8–26.6). We measured a statistically significant increase in the percentage of CD4+FoxP3+ cells per total CD4+ cells in the sirolimus/MMF study group compared to the CI historical control group with a mean of the individual patient means over the first 100 days post-HCT of 16% versus 6%, respectively (p.0005). Despite the increased percentage of CD4+FoxP3+ cells per total CD4+ cells identified in the PB of the sirolimus/MMF cohort, the incidence of grade II-IV AGVHD was similar to the CI cohort (6 of 11 versus 7 of 15, respectively). However, all but one patient had skin-only AGVHD and there were no GVHD-related deaths in the sirolimus/MMF group. All patients requiring early withdrawal of sirolimus had received the busulfan-containing preparative regimen with two of these patients developing severe AGVHD. In a subsequent GVHD prophylaxis trial including sirolimus and MMF, the busulfan-containing preparative regimen will be eliminated to optimize sirolimus and MMF administration with the continued goal of reducing the incidence and severity of AGVHD.

Background: High dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) is the most effective treatment for recurrent and refractory Hodgkin lymphoma (HL). Disease recurrence is still a major cause of treatment failure. Augmented BCNU-regimens are reported to have good outcomes but greater pulmonary toxicity. A novel transplant regimen incorporating gemcitabine and vinorelbine, active drugs in HL different from alkylating agents, was tested to establish the maximum tolerated dose (MTD) of gemcitabine and to assess safety and efficacy at the MTD. Methods: In this phase I/II study, dose escalation was performed with gemcitabine in combination with vinorelbine followed by BCNU at reduced dose, etoposide (VP-16), cyclophosphamide (CY) and AHCT. The first 7 patients had dose escalation of gemcitabine before determining the MTD at 1250 mg/m2 on the basis of elevated liver transaminases and a symptom complex of fever, headache, and skin toxicity. For phase II, a total of 92 patients with recurrent or refractory HL have been treated at the MTD to establish safety and efficacy. The regimen consists of gemcitabine 1250 mg/m2 IV at 10 mg/min and vinorelbine 30 mg/m2 on day-13 and day-8, BCNU 10 mg/kg on day-6, VP-16 60 mg/kg on day-4, CY 100 mg/kg on day-2. Regimen-related toxicity, freedom from progression (FFP) and overall survival (OS) were endpoints of the trial. Results: 70 patients were high risk (based on stage IV disease at relapse, failure to achieve minimal disease, or B symptoms at relapse) and 22 patients were low risk (having no risk features). Median age was 33 years. Median follow-up is 2 years (.26–6.8 years). Median time to neutrophil engraftment was 10 days. Regimen-related toxicities of grade 3 skin rash, fever, headache and liver transaminase elevations were transient. Remarkable was the reduction in incidence of systemic steroid-requiring pulmonary toxicity <100 days post-transplant to 15.2% (14 of 92 patients treated at the MTD), as compared to our standard regimen incidence of 35%. Also encouraging is the OS at 2 years for the entire group of 81% (+/−9%) and FFP at 2 years of 71%(+−11%). By risk factors, FFP at 2 years was 95%(+−10%), 75%(+−14%), 64%(+−22%), and 19%(+−31%) for patients with 0, 1, 2, or 3 risk factors. These results compare favorably to the historical FFP of 41% for patients with one or more of these same risk factors (Horning 1997). In the current study, having 1 or 2 risk factors resulted in similar FFP with the new regimen (p=.46) and significantly improved FFP as compared to patients with 3 risk factors (1 vs 3, p<.001; 2 vs 3, p=.004)- see figure. Conclusions: This novel transplant regimen for HL has decreased incidence of pulmonary toxicity compared with augmented BCNU-regimens and is associated with encouraging OS and FFP, even in the high risk groups. Figure Figure

Background: B cells are implicated in the pathophysiology of chronic GVHD. We hypothesize that prophylactic anti-B cell therapy delivered two months after reduced intensity conditioning (RIC) transplantation would prevent or reduce chronic GVHD incidence from the historical 50%. Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) were the target diseases as they are B cell malignancies with clear allogeneic GVL benefit. Methods: CLL and MCL patients were conditioned with total lymphoid irradiation (TLI) 80 cGy in 10 fractions, d-11 to d-1 and anti-thymocyte globulin (ATG) 1.5mg/kg/day, d-11 to d-7 (total 7.5mg/kg). PBPC were infused on day 0. Primary GVHD prophylaxis was cyclosporine (CSA) on d-3 with taper by 6 months, and MMF from day 0 until d28 for related donors, d100 for unrelated donors. Rituximab (375 mg/m2/week ×4) was infused on days 56, 63, 70, and 77 post-transplant. Results: 36 patients accrued to the study (median age 57, range 31–66 yrs), with 34 patients completing the 4 rituximab infusions. All 22 CLL patients were high risk (fludarabinerefractory, unmutated VH-IgG, or P53 deletion). The 14 MCL patients included 4 patients in PR and 10 patients in CR status at transplant. Median follow-up is 20 months. Twenty patients had sibling donors; 16, unrelated donors. Median CD34 cell dose was 7.5 CD34/kg. All patients had donor cell engraftment except for one patient who had graft failure with stable autologous recovery. Full donor chimerism (PB CD3>95%) was achieved in 14 out of 31 patients (45%) by day 90. However, all but 5 patients had achieved full donor chimerism at 1 year. The incidence of grade 2–4 acute GVHD was 6%. The incidence of chronic GVHD was 18%. Day 100 NRM was 0% and 1-year NRM was 3%. Ten relapses have occurred (5 CLL, 5 MCL). Estimated FFP and OS at 2 years for CLL patients is 82%(CI +/−16%) and 73% (CI +/−33%), respectively; for MCL patients, 64% and 68%, respectively Full donor chimerism was associated with persistent disease remission. Twelve of 19 VHIg mutated CLL patients have achieved minimal residual disease (MRD) by quantitative allele-specific oligonucleotide-IgH PCR (ASO-Q-PCR). DLI was given to 5 CLL patients and 1 MCL who had relapsed and had not achieved full donor chimerism.. There were no infusional toxicities with rituximab. Transient rituximab related neutropenia occurred in 10 patients d100–150. Post-transplant infections included influenza B, RSV, fungal sinusitis, pseudomonas, klebsiella infection, VZV reactivation, and one PTLD before day 56 rituximab. All recovered Of 22 patients at risk for CMV reactivation, 10 reactivated ( range 4 to 56 days post-HCT). Therefore, rituximab did not contribute to the CMV reactivation or increase infection incidence. Conclusion: Prophylactic rituximab infusion post RIC transplantation is well tolerated, provides safe donor B cell depletion without detrimental effect on engraftment or infection incidence, and is associated with a low incidence of chronic GVHD while maintaining GVL. A randomized trial of rituximab prophylaxis after allogeneic HCT is warranted.

Background: Iron accumulation in excess of requirements has been implicated in risk of malignancy through increased iron-catalyzed free radical-mediated oxidative stress. Reduction of body iron stores may lower risk of cancer.

Background: Recent data from retrospective and prospective studies indicate an improvement in the overall survival (OS) of follicular lymphoma (FL) patients (pt). We sought to evaluate survival data in FL pt managed at our institution and to analyze their presenting features, management and disease course. Methods: Previously untreated FL (grades 1 and 2) pt referred from 1960–2003 and followed at Stanford were identified from the Lymphoma Database for this retrospective study. Data were reviewed for quality and consistency of coding for histology (pathology reviewed at Stanford) and treatment courses. Four eras were defined by date of diagnosis 1 (1960–75, n=180); 2 (1976–86, n=426); 3 (1987–96, n=471); and 4 (1997–2003, n=257). Patient (age, gender) and disease (stage, histology) characteristics, management (time from diagnosis to referral, time to first treatment, courses/types of treatment), and outcomes (progression-free survival [PFS], OS, transformation) were evaluated, overall and with respect to era. Results: The OS for the 1334 FL pt in the dataset was 12.6 years (yr). Age (median = 49 yr), gender (54% male) and stage (83% III-IV) did not differ across the eras. Median OS improved from 11.2 yr [95% CI 10.2,12.1] in eras 1 and 2 (1960–86) to 18.4 yr [95% CI 14.5,22.4] in eras 3 and 4 (1986–2003), p<0.001. Greatest gains were observed in pt less than 60 yr old and in advanced stage disease. OS was not different in eras 3 and 4 (p=0.56) but median follow-up is just 5 yr in era 4. Although treatment varied over the eras, PFS was no longer for the later eras (3 and 4) compared to early eras (1 and 2), p=0.73. Initial therapy was more likely to be deferred in the later eras: 16%, 44%, 59%, 60% for eras 1, 2, 3 and 4, respectively. Rituximab use, as expected, varied over the eras: 1 (1% pt), 2 (8% pt), 3 (23% pt), 4 (42% pt). The incidence of transformation was similar over the eras and OS after transformation was significantly longer if patients were chemotherapy-naive at transformation (p<0.001). Conclusions: OS of patients with FL managed at Stanford University significantly improved in the 1986–2003 eras, particularly among younger and advanced stage patients. This improvement was not associated with longer PFS after the first course of treatment or differences in the incidence of histologic transformation. Application of a time-variant Cox regression model is in progress to better understand the contributions of treatment, particularly rituximab, as well as other factors in these patients.

Background: Age-related accumulation of excess Fe has been implicated in risk of disease, including cardiovascular disease and malignancy, through Fe-catalyzed free radical-mediated mechanisms. Methods: The effect of reducing body Fe stores through phlebotomy on disease risk and mortality was tested in a multi-center randomized, controlled, single-blinded clinical trial conducted between May 1, 1999 and April 30, 2005 in a cohort of 1,277 patients with symptomatic PAD. Patients with conditions likely to cause acute phase elevation of the ferritin level or with a diagnosis of visceral malignancy within the preceding five years were excluded. Patients were randomly assigned to control or reduction of Fe stores by graded phlebotomy (avoiding Fe deficiency) with stratification by hospital, age, baseline ferritin, diagnosis of diabetes mellitus, smoking status and HDL/LDL ratio. The primary outcome was all cause mortality; the secondary outcome was combined death plus non-fatal myocardial infarction and stroke. New non-fatal cardiovascular events and new disease diagnoses, including histologically confirmed visceral malignancy, were recorded during follow-up. Results: There were no significant differences between Fe reduction and control groups for the primary (p=0.172) or secondary (p=0.202) study outcomes. The mean age at entry was 67 years. Patients in the youngest age quartile randomized to Fe reduction had a 53.6% reduction in the primary endpoint (p = 0.019) and a 57% reduction in the secondary endpoint (p <0.001) compared to control patients. Kaplan - Meier analysis of the secondary endpoint revealed a significantly reduced hazard ratio with Fe reduction that was graded in patients within the youngest age quartile (p <0.001) and that persisted after excluding patients dying of cancer (p = 0.007). Patients randomized to Fe reduction had a 36.7% lower risk of cancer occurrence (p = 0.023) and a 68.6% lower cancer mortality (p = 0.003) compared to control patients. Reduced cancer risk was observed for most tumor types and occurred over the entire patient age range. Conclusions: Fe reduction in patients with symptomatic PAD did not confer an overall benefit in cardiovascular disease risk and mortality. Apparent improvement in cardiovascular outcomes with Fe reduction in the youngest age quartile suggests a role for Fe relatively early in the course of disease but confirmation in studies of specific patient subsets is needed. Fe reduction decreased cancer risk and mortality, an effect that was not age-related. Ferritin levels found commonly in adults are associated with disease risk while levels characteristic of childhood and pre-menopausal women (below about 80 ng/ml) are associated with reduced risk. These results suggest strategies for low-cost and non-toxic disease prevention and treatment through patient monitoring, selective and graded Fe reduction, and attention to optimal Fe nutrition.

The authors provide brief information about the Department of Veterans Affairs (VA) and the Veterans Health Administration, to establish an understanding of this large, multifaceted organization. They then offer an overview of the VA’s Office of Research and Development, with particular emphasis on recent and ongoing efforts to enhance protection of the rights of human participants in clinical research. The authors discuss various policies and regulations intended to protect human participants in any type of VA research. The protection of human research participants must be a major concern for all researchers. Patients should be well informed about the scope of the research and what their participation entails, and there should be no question as to the voluntariness of their consent. Making sure that these standards are met for each and every veteran who participates in VA research is of the utmost importance.