A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520.

Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.

Functional outcomes of chemoradiation in patients with head and neck cancer.

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) has become the treatment of choice for oropharyngeal and hypopharyngolaryngeal cancers in many centers. Although it has increased the rates of organ preservation, there has also been an increase in treatment-related complications. We aimed to evaluate the functional outcomes of CCRT in head and neck cancer. STUDY DESIGN: Case series with chart review. SETTING: Tertiary cancer center. SUBJECTS AND METHODS: A retrospective study of patients treated with CCRT at the University of Arkansas for Medical Sciences was performed. Demographic data and treatment outcomes were extracted, specifically feeding tube and tracheotomy dependence and number of esophageal dilatations. RESULTS: Of the 243 patients treated with concurrent chemoradiotherapy (5-fluorouracil + cysplatin and radiotherapy), 152 patients received a feeding tube. The median percutaneous gastrostomy tube (PEG) use was 9 months (range, 1-96 months). More than 70% of the patients who had a PEG more than 6 months had a T3 or T4 tumor. Thirty-seven patients underwent esophageal dilatations, (median, 1; range, 1-7). The median use of a tracheotomy was 7 months, and 77% of these patients were treated for hypopharyngolaryngeal cancer. CONCLUSIONS: Despite major improvement in locoregional control rates, CCRT has a significant negative impact on the functional outcomes of head and neck cancer patients, with a high number of patients remaining PEG and tracheotomy dependent.

Cytopenia, dysplasia, and monocytosis: a precursor to chronic myelomonocytic leukemia or a distinct subgroup? Case reports and review of literature.

Chronic myelomonocytic leukemia (CMML) consists of disorders with overlapping dysplastic and proliferative features. The diagnosis of CMML requires absolute monocytosis (> 1000/µL) in addition to other criteria outlined by the World Health Organization (WHO) classification.(1) Monocytosis not reaching 1000/µL has been observed in myelodysplastic syndrome (MDS) and presents a diagnostic challenge in classification especially if increases in leukocyte count occurring during disease shifts the monocyte count into the absolute range. We discuss the laboratory and clinical features of 3 patients with myelodysplasia and associated monocytosis. Absolute neutropenia was the dominant feature at presentation, with mild anemia, thrombocytopenia, monocytosis (as a percentage), multilineage dysplasia, and increased myeloblasts, consistent with a diagnosis of refractory anemia with excess blasts (RAEB). Absolute monocytosis fulfilling the diagnostic criteria for CMML developed over 6-8 months, prompting a change in diagnosis. Two of 3 patients had normal cytogenetic examinations. JAK2 V617F mutation was detected after transformation to CMML in 1 of them; in the other, a novel translocation t(5;12)(p13;q24) was observed at the time of progression to acute leukemia. The use of different diagnostic terminologies--MDS, dysplasia with reactive monocytosis, myeloproliferative, and myeloproliferative/myelodysplastic syndromes by different and even the same pathologists at different times created confusion among the clinicians and patients. The disease course in these 3 patients was characterized by better survival and prolonged time to progression to acute leukemia, than predicted based on the original diagnosis of RAEB, suggesting that MDS with monocytosis may represent a subgroup distinct from MDS or CMML.

Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia.

BACKGROUND: Invasive fungal infections (IFI) in immunocompromised patients are associated with significant morbidity and mortality, despite appropriate antifungal treatment and recovery from neutropenia. The outcome of these infections depends significantly on the overall state of immunosuppression, including mainly the phagocytic system (neutrophils and macrophages). Interferon-gamma (IFN-gamma), granulocyte-colony--stimulating factor (G-CSF) and granulocyte-macrophage-colony--stimulating factor (GM-CSF) are cytokines that enhance the activity of neutrophils and macrophages. METHODS: The authors reported 4 patients with leukemia and refractory invasive candidiasis or trichosporonosis despite 1-13 months of appropriate antifungal treatment. RESULTS: Cytokines were administered for 1.5-5 months without significant toxicity. For each patient, initiation of interferon-gamma plus a colony-stimulating factor resulted in a clinical response. The contribution of cytokines to control the fungal infection in these 4 patients was suggested by the strong inflammatory reaction observed in the 2 patients who had an immediate response (within 7 days of initiation of cytokine therapy) and by the good outcome in the 2 other patients in whom antifungal agents were discontinued at the start of cytokine therapy. CONCLUSIONS: These data suggested a potential role for immunomodulation in patients with leukemia with refractory invasive fungal infections.

Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors.

PURPOSE: The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer. EXPERIMENTAL DESIGN: Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials. RESULTS: In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change. CONCLUSIONS: QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.

Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.

PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses >or= 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >or= 3 months, 22% >or= 6 months, and 7.2% >or= 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses