BACKGROUND The prognosis of patients with relapsed Hodgkin lymphoma, especially those who relapsed after stem cell transplant, remains poor, and the development of new agents for this relatively young patient population represents an unmet medical need. In this study, we examined the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin lymphoma METHODS Patients with relapsed or refractory classical Hodgkin lymphoma aged 18 years or older were treated with mocetinostat administered as an oral dose three-times weekly, in 28-day cycles. Two dose cohorts were evaluated (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary objective was to estimate the disease control rate induced by mocetinostat, defined as CR, PR or SD (for at least 6 cycles) analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982 FINDINGS A total of 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, 28 additional patients were treated with a reduced dose of 85 mg to improve treatment tolerance. Based on intent to treat analysis, the overall disease control rate was 34.8% and 25% for the 110 mg and 85 mg groups, respectively. Thirty-four out of 42 (81%) patients who completed at least 2 cycles of therapy had a decrease in their tumor measurements. Forty-seven percent (24/51) discontinued therapy due to disease progression, 57% (16/28) in the 85 mg cohort and 34% in the 110 mg cohort. Twenty-four percent (12/51) discontinued due to adverse events, 32% (9/28) in the 85 mg cohort and 13% (3/23) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events included neutropenia, which was observed in 4 (17.4%) patients in the 110 mg group and in 3 (10.7%) patients in the 85 mg group; fatigue (in 5 (21.7%) of the 110 mg group vs 3 (10.7%) of the 85 mg group); and pneumonia (4 (17.4%) of the 110 mg group vs 2 (7.1% of the 85 mg group). Four patients, all in the 110 mg cohort, died during study, of whom two were considered possibly related to treatment. INTERPRETATION Mocetinostat 85 mg three-times weekly has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin lymphoma. FUNDING MethylGene Inc., Montreal, Canada; Celgene Corporation, Summit, New Jersey; Tufts Medical Center, Boston, MA

The authors measured brain atrophy in nine patients undergoing immunoablation and autologous hematopoietic stem cell transplantation for multiple sclerosis. From baseline to 1 month after treatment, atrophy was 10 times faster than before treatment. A patient with non-CNS lymphoma showed comparable acute brain atrophy after analogous therapy. These observations suggest that brain atrophy after immunoablation may not be due entirely to the resolution of edema but may be related to chemotoxicity. the Canadian MS BMT Study Group Brain atrophy occurs at a faster rate than normal in patients with multiple sclerosis (MS) and may be accelerated in the year after initiation of immuno-modulatory therapy 1-a phenomenon that is often attributed to the resolution of edema. To explore the nature of the changes in brain volume after anti-inflammatory therapy, we measured global brain volume changes on MRI scans of patients with aggressive MS being treated with immu-noablation and autologous hematopoietic stem cell transplantation (AHSCT). We also measured brain volume changes on MRI scans of a patient with lym-phoma that did not involve the CNS and who was undergoing a similar treatment. Methods. We studied nine secondary progressive (SP) MS patients with active disease who were participating in a tricenter phase II trial of immunoablation followed by AHSCT. 2 Stem cell mobilization was achieved with IV cyclophosphamide (4.5 g/m 2) and 10 days of granulocyte colony-stimulating factor (10 g/kg/day). Immunoablation was accomplished using IV cyclo-phosphamide (200 mg/kg), dose-adjusted oral busulfan (maximum 16 mg/kg) and rabbit antithymocyte globulin (5 mg/kg). 2 Solu-Medrol was administered for 4 days during the conditioning regimen. A 54-year-old man with non-Hodgkin lymphoma and no CNS involvement was followed up after chemotherapy (IV busulfan: 12.8 mg/kg [total 845 mg]; IV cyclophosphamide: 120 mg/kg [total 7,920 mg]; dose-adjusted IV methotrexate: 45 mg/m 2 [to-tal 76 mg]; cyclosporine: 1.5 mg/kg every 12 hours from day 1) and allogeneic bone marrow transplantation (BMT). MRI scans included T1-weighted and dual spin-echo (PD/T2-weighted) sequences acquired at baseline and serially after treatment as previously described. 3 In two cases, the earliest baseline scans were performed more than 12 months before the last base-line scan because of delays in the study. The rate of brain atrophy was calculated using SIENA 4 (http:// www.fmrib.ox.ac.uk/fsl). Gadolinium-enhancing lesions were segmented manually, and T2-weighted lesion volume (T2LV) was quantified automatically using a Bayesian classifier followed by manual correction. A simplified estimation of T2-relaxation maps were calculated based on a single-exponential fit of the image intensities of the dual spin-echo sequence. Results. The patient demographics and rates of atrophy at baseline and 1 month after AHSCT are shown in the table. Atrophy (brain volume loss) is reported as a positive percentage change. The entire therapy (stem cell mobilization , immunoablation, and ...

Summary:The purpose of this study was to evaluate the estimated incidence of secondary malignancies post-allogeneic bone marrow transplantation (BMT) in a cohort of adult patients previously reported now with an additional 8.5 years of follow-up. A cohort of 557 patients older than age 16 years underwent allogeneic BMT between June 1970 and November 1993. Histologic reports confirmed the diagnosis of a secondary malignancy. Multivariate Cox proportional hazards method was utilized to investigate predictors for the development of secondary malignancies. In all, 31 patients in this cohort developed a secondary malignancy a median of 6.79 years after their transplant. The estimated cumulative incidence rate of secondary malignancy was 4.2% at 10 years post transplant. When compared to the general population, the estimated observed/expected ratio of new cancer diagnoses was 5.13. On multivariate analysis, older age at the time of transplant was the only significant predictor for development of secondary cancer (P ¼ 0.01). The most common malignancies observed were nonmelanomatous skin cancers and squamous cell cancers of the buccal cavity. The risk of developing a secondary malignancy after allogeneic BMT is significant, particularly in older patients. Long-term survivors of transplant require regular monitoring for early signs of cancer, particularly of the skin and oral cavity. Bone Marrow Transplantation (2005) 35, 51-55.