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Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma., Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m² on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m² with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle., Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m². DLTs at 340 mg/m² were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria., Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity., (Copyright © 2011 S. Karger AG, Basel.)

Objectives/hypothesis: Document survival, prognostic variables, and functional outcomes of patients with AJCC stage III or IV oropharyngeal cancer, treated with transoral laser microsurgery (TLM) +/- adjuvant therapy., Study Design: Analysis of prospectively assembled data pertaining to the above-described patient cohort., Methods: Patients treated with TLM for AJCC stage III or IV oropharyngeal cancer at Washington University School of Medicine from 1996 to 2006 were followed for a minimum of 2 years. Recurrence, survival, functional, and human papilloma virus data were analyzed., Results: Eighty-four patients met inclusion criteria. Mean follow-up was 52.6 months. Overall AJCC stages were: III 15% and IV 85%. T stages were T1-2, 74%; T3-4, 26%. Eighty-three patients underwent neck dissection, 50 received adjuvant radiotherapy, and 28 received adjuvant chemoradiotherapy. Overall survival at 2 and 5 years was 94% and 88%, respectively. Disease-specific survival at 2 and 5 years was 96% and 92%, respectively. Six patients recurred (7%): locally (one), regionally (four), and distant (five). T stage, positive margins, and p16 status significantly impacted survival. The addition of adjuvant chemotherapy in high-risk patients did not significantly impact survival. Five patients (6%) had major surgical complications, but without mortality. Eighty-one percent of patients had acceptable swallowing function at last follow-up. Immediately postoperatively, 17% required G-tubes, which dropped to 3.4% of living patients at 3 years., Conclusions: In this population, our findings validate TLM +/- adjuvant therapy as a highly effective strategy for survival, locoregional control, and swallowing recovery in AJCC stage III and IV oropharyngeal cancer. Our finding also show that p16 positivity improves survival.

Background: Acute graft-versus-host disease (GVHD) is a major complication of both bone marrow and hematologic stem cell allografts. T cells and natural killer (NK) cells have been linked to the development of GVHD. Modulation of these cells via the CD2 receptor may be a potentially important approach to the management of this disease., Methods: The safety profile and tolerability of siplizumab (MEDI-507), a humanized anti-CD2 IgG-1kappa monoclonal antibody, in the treatment of GVHD were evaluated in a phase I, double-blind, multiple-dose, placebo-controlled study. Thirty-four subjects with at least grade II acute GVHD were randomized to receive four doses of 0.012, 0.04, 0.12, or 0.4 mg/kg siplizumab or placebo intravenously every 3 days. Subjects received concurrent 2 mg/kg per day methylprednisolone for more than or equal to 10 days., Results: No meaningful difference occurred between siplizumab and placebo groups in the incidence or severity of adverse events or laboratory test results. No increase in incidence of infection secondary to siplizumab treatment was observed. During 100 days postinitial infusion, a modest increase in resolution of GVHD, grade 0 (67% vs. 54%, P=0.0629), was reported for the siplizumab-treated group., Conclusion: Siplizumab administered with corticosteroid therapy for grade II or higher acute GVHD treatment exhibited an acceptable safety profile that would support further clinical development.

Purpose of Review: To review the outcomes of allogeneic transplantation with regimens of varying total body irradiation (TBI) doses (0-1575 cGy), with an emphasis on reduced-intensity conditioning (RIC) regimens., Recent Findings: RIC regimens with a broad range of TBI doses (0, 200, 400, 550, and 800 cGy) have been studied. Durable donor stem cell engraftment occurred in most patients, with a low rate of toxicity and nonrelapse mortality. Patients excluded from myeloablative regimens were able to tolerate RIC regimens. Retrospective comparisons of patients treated with RIC and myeloablative regimens showed lower nonrelapse mortality but higher relapse risk with RIC; however, overall survivals were similar though a larger fraction of RIC patients had high-risk pretransplant features. Study design weaknesses limit the ability to generalize and apply these results. RIC and myeloablative TBI-based regimens result in durable engraftment of donor stem cells, tolerable toxicity, and acceptable rates of relapse risk and overall survival. Determination of the optimal dose of TBI for allogeneic transplantation is complex and depends on several variables and may vary based on a specific permutation of these variables., Summary: A broad range of TBI doses for RIC regimens are effective; however, all conclusions are limited by the lack of prospective, randomized trials comparing RIC and myeloablative regimens.

Tumor necrosis factor (TNF)-alpha inhibitors have been used effectively to treat rheumatoid arthritis and inflammatory bowel disease. Although the role of TNF-alpha in tumor development is not well understood, an increased risk of malignancies with anti-TNF-alpha therapy has been suggested. We report an instructive case of a patient, treated for Crohn's disease with infliximab, who presented with a neck abscess diagnosed to be head and neck squamous cell carcinoma. The patient's clinical course illustrates a temporal relationship between reappearance of his cancer after a complete response to therapy and the resumption of infliximab for worsening Crohn's disease.

Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). In a single-institution phase III trial, 95 recipients of allogeneic peripheral blood stem cell (PBSC) transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ, or placebo starting 21 days pretransplant and continued until day +365. HCQ was very well tolerated and not associated with side effects. Overall, the incidence of acute GVHD (aGVHD) was 59% in both arms, and severe aGVHD occurred in 11% (HCQ) and 14% (placebo) (P = .76). Sixty percent and 78% of patients developed chronic GVHD (cGVHD) in the HCQ and the placebo arms, respectively (P = .15). With a median follow-up of 18 months, relapse-free and overall survivals (OS) were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single-agent CSA had no effects on aGVHD or cGVHD or survival.

We analyzed outcomes of patients with myelodysplastic syndrome (MDS) or secondary acute myelogenous leukemia (sAML) that were treated at our institution with a reduced intensity conditioning (RIC) regimen of 550-cGy total body irradiation and cyclophosphamide followed by related donor (RD) or unrelated donor (URD) transplantation. Fifty-one consecutive patients with MDS or sAML received this RIC regimen and URD (n = 30) or RD (n = 21) stem cells. Graft-versus-host disease prophylaxis consisted of cyclosporine alone (RD) or with corticosteroids and methotrexate (URD). Median patient age was 44 years. With a median follow-up of 3.7 years after transplantation in the 19 surviving patients (37%), Kaplan-Meier estimates of overall survival were 88%, 46%, 33%, and 11% for patients transplanted with sAML in remission, refractory anemia, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or sAML refractory/untreated, respectively. Kaplan-Meier estimates of relapse-free survival were 75%, 46%, 33%, and 11%, respectively. Overall, the cumulative incidences of relapse and transplant-related mortality were 27% and 37%, respectively. In patients with MDS, this is an effective RIC regimen for allogeneic transplantation that can be used as an alternative to other RIC or conventional conditioning regimens.

Background: It was hypothesized that transfusion of two granulocyte-colony-stimulating factor (G-CSF)-mobilized prophylactic granulocyte components into allogeneic peripheral blood progenitor cell (PBPC) transplant patients during the regimen-related neutropenic interval would result in clinical benefit., Study Design and Methods: HLA-matched sibling PBPC donors (n=151) were biologically randomized based on ABO mismatch to donate granulocyte components (Cohort G) or not donate granulocytes (control group, Cohort C). ABO-matched donors who did not meet other study-specific criteria were reassigned to Cohort C., Results: Feasibility, defined as the proportion of ABO-matched donors who underwent granulocyte collections, was 42 percent (53 of 125). The percentage of patients who developed fever during the initial hospitalization was greater in Cohort C versus Cohort G (82.7% vs. 64.2%; p=0.03). In the interval from when granulocyte transfusions were initially given in Cohort G (Day +3 or Day +5) until neutrophil engraftment, the number of febrile days was less in Cohort G versus Cohort C (median, 0 vs. 1; Mann-Whitney p=0.003). The median number of days of intravenous antibiotics given during the initial hospitalization was less in Cohort G versus Cohort C (9 vs. 11; Mann-Whitney p=0.03), a difference accounted for in the interval from Day +3 or Day +5 to neutrophil recovery. There was no significant difference in length of the initial hospital stay, acute graft-versus-host disease rates, or 100-day survival between the two cohorts., Conclusion: This prospective study demonstrates a modest, but significant, benefit of G-CSF-mobilized HLA-matched prophylactic granulocyte transfusions in neutropenic allogeneic PBPC recipients.

Purpose: To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL)., Patients and Methods: A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients., Results: Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively., Conclusion: These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

We hypothesized that low-dose (550-cGy), single-exposure, high dose rate (30 cGy/min) total body irradiation (TBI) with cyclophosphamide as conditioning for HLA-compatible unrelated donor (URD) bone marrow transplantation (BMT) would result in donor chimerism (DC) with a low risk for serious organ toxicity and treatment-related mortality (TRM). Twenty-six patients with good risk diagnoses (acute leukemia in first complete remission [CR] and chronic-phase chronic myelogenous leukemia [CML]) and 84 with poor risk diagnoses underwent this regimen and URD BMT. Unsorted marrow nucleated cells were assessed for chimerism using VNTR probes. All DC occurred in 78 (86%) of 91 evaluable patients at 1 or more follow-up points. Graft failure occurred in 7 (7.7%) patients. Fatal organ toxicity occurred in only 2% of patients. TRM rates through 2 years of follow-up were 19% and 42% in those with good and poor risk diagnoses, respectively. Overall and disease-free survival rates in the good risk group were 47% and 40%, respectively, and in the poor risk group they were 25% and 21%, respectively, at a median follow-up for living patients of 850 days (range, 354-1588 days). This regimen resulted in 100% DC in most patients undergoing URD BMT with a relatively low risk for fatal organ toxicity and TRM.

Purpose: To analyze the effects of preautografting treatment with rituximab (R) on stem-cell mobilization, post-transplantation complications, engraftment, disease-free survival, and overall survival in patients with non-Hodgkin's lymphoma (NHL)., Patients and Methods: Single-institution retrospective comparative outcome analysis in a cohort of 273 relapsed chemosensitive NHL patients of whom 127 (47%) received R pretransplantation., Results: R was administered a median of 3 months before autologous transplantation. When compared to the nonrituximab group, R patients were older (56 v 50 years; P < .001), and had delays in post-transplantation platelets recovery (39 v 27 days; P = .001). Pretransplantation R did not affect stem-cell mobilization, post-transplantation early complications, duration of hospitalization, or mortality rates at days 30 and 100. In contrast to patients with low-grade NHL, both disease-free and overall survival rates were significantly better when R was included in the pretransplantation salvage therapy for patients with intermediate-grade NHL., Conclusion: In this large, single-center retrospective analysis, pretransplantation treatment with R was associated with improved survival in patients with intermediate-grade NHL, at the price, however, of a delay in platelet engraftment.

Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long-term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor-induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft-versus-host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1-70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2-594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor-induced neurotoxicity is frequently reversible but associated with a poor prognosis.

High-dose melphalan has been commonly used as conditioning for amyloidosis with considerable toxicity. We hypothesized that the novel conditioning regimen of 550 cGy total body irradiation (TBI) alone for autologous peripheral blood stem cell transplantation would have reduced organ toxicity and thus permit safer transplantation of primary amyloidosis patients, even those with poor risk disease. The comprehensive regimen included pretransplantation chemotherapy, single-dose TBI alone (550 cGy at 30 cGy/min) conditioning, and post-transplantation interferon-alpha maintenance. Thirteen patients were enrolled in this feasibility study. Patients with multiorgan involvement were included; 10 patients had poor or intermediate risk disease. Cardiac toxicity was significant. Treatment-related mortality through 100 days post-transplantation was 15% and was caused by cardiac mortality. One patient died from arrhythmia after receiving TBI; 2 patients had grade IV cardiac toxicity (with subsequent complete recovery). One patient died 1 month after mobilization from progressive cardiomyopathy and never received conditioning. However, noncardiac organ toxicity was mild. No patient required parenteral nutrition support; no patient developed mucositis; and no patient experienced gastrointestinal bleeding following transplantation. The complete hematologic remission rate was 45%, with pretransplantation chemotherapy being the most active part of the regimen. Survival estimates from enrollment to 1 and 2 years post-transplantation were 66% and 47%, respectively. Causes of death were disease progression (6), myelodysplasia (1), arrhythmia following TBI (1), and congestive heart failure after mobilization (1). In this cohort of primary amyloidosis patients, the transplantation regimen of 550 cGy TBI was feasible and associated with modest treatment-related mortality. Efficacy with TBI conditioning may be reduced compared with high-dose melphalan, but this should be explored in a future trial with a larger cohort of patients.

We studied the impact of donor cytomegalovirus (CMV) serologic status on CMV viremia and disease when prophylactic granulocyte colony-stimulating factor (G-CSF)-mobilized granulocyte transfusions (GTs) were given following allogeneic peripheral blood stem cell (AlloPBSC) transplantation. A cohort of 83 patients who received 2 prophylactic GTs from ABO-compatible stem cell donors following AlloPBSC transplantation was compared with a cohort of 142 patients who did not. AlloPBSC donors were eligible for granulocyte donation irrespective of their CMV serostatus. Recipients received no prophylactic therapy for CMV. Donor CMV serostatus had no impact on CMV viremia and disease in the 2 cohorts. Our data show that in an era of effective surveillance and preemptive therapy for CMV, AlloPBSC recipients can safely receive 2 transfusions of prophylactic G-CSF-mobilized granulocyte components from CMV-seropositive AlloPBSC donors. This knowledge may help expand the donor pool in areas with a high prevalence of CMV in the general population.