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.

Summary:In all, 30 patients with CLL proceeded to myeloablative allogeneic BMT using related (n ¼ 20, 67%) or unrelated (n ¼ 10) donors, at the Princess Margaret Hospital (Toronto) (n ¼ 20) or the Leukemia/BMT Program of BC (Vancouver) (n ¼ 10), from 1989 to 2001. Median (range) interval from diagnosis to BMT was 4.8 (0.3-13) years, median number of prior therapies was three and median age 48 years. The preparative regimen included total body irradiation in 15 (50%). In all, 14 of 30 patients (47%) are alive, with median (range) follow up of 4.3 (2.4-10.5) years. All are in complete remission, two following therapy for post-BMT progression. Actuarial overall (OS) and event-free survival (EFS) at 5 years is 39% (OS 48% for related donor and 20% for unrelated donor BMT); cumulative incidence of nonrelapse mortality (NRM) and relapse is 47 and 19%, respectively. Both acute (RR ¼ 0.008, P ¼ 0.01) and chronic (RR ¼ 0.006, P ¼ 0.02) Graft-versus-host disease (GVHD) were associated with markedly decreased risk of relapse. Patients receiving grafts from unrelated donors had increased NRM (RR ¼ 3.6, P ¼ 0.02) and decreased OS (RR of death ¼ 3.4, P ¼ 0.002). Allogeneic BMT has resulted in long-term EFS in approximately 40% of patients with CLL. There is evidence for a strong graft-versus-leukemia effect associated with acute and chronic GVHD, resulting in near complete protection from relapse. Bone Marrow Transplantation (2005) 36, 825-830.

The optimum intensity of conditioning therapy in patients aged 40-60 years with AML and myelodysplastic syndrome (MDS) undergoing allogeneic haematopoietic cell transplantation (alloHCT) remains uncertain. We compared outcomes of reduced intensity conditioning (RIC) and conventional intensity conditioning (CIC) in 101consecutive patients (CIC, 62; RIC, 39) with AML and MDS aged 40-60 years undergoing alloHCT from 2002 to 2008 at our centre. The median age, unrelated transplants and co-morbidity index were higher in the RIC group. Median OS and EFS were 31.0 months (95% confidence interval (CI): 12.8-59.3) and 20.7 months (95% CI: 11.0-30.4), respectively, with no significant difference between the two cohorts. The 3-year treatmentrelated mortality (TRM) and relapse were 28% (95% CI: 21-39) and 25% (95% CI: 17-36), respectively, with no significant difference between the two cohorts. No difference in OS, EFS, TRM or relapse was observed between the two cohorts in the multivariate model. Only disease risk was significantly associated with OS (Hazard ratio (HR): 1.85, CI: 1.01-3.45), EFS (HR: 1.73, 95% CI: 1.00-3.10) and cumulative relapse (HR: 3.24, 95% CI: 1.08-10.12). Disease biology rather than intensity of conditioning regimen seems to determine outcomes of alloHCT in patients aged 40-60 years with AML/MDS.

Early absolute lymphocyte count (ALC) has become an important end point for engraftment in patients undergoing autologous peripheral stem cell transplantation (APSCT). In this retrospective study, we evaluate the prognostic significance of early recovery of ALC ( > or = 0.5 cells x 10(9)/l on or before day 15) following APSCT in predicting transplant outcome in 72 patients with lymphoproliferative disorders, including non-Hodgkin's lymphoma (n = 30), Hodgkin's lymphoma (n = 8) and multiple myeloma (n = 34). The median quantities of CD34+ stem cells and lymphocytes infused were 4.97 x 10(6)/kg (range 0.64-11.7) and 11.3 x 10(7)/kg (range 1.11-110) respectively. After a median follow-up of 18 months (range 2-68), 28 patients had experienced a relapse and 16 had died. Of the 72 patients, 27 (37%) demonstrated early recovery of ALC. Early recovery of ALC was strongly associated with long-term overall and disease-free survival in patients aged less than 50 years (P < 0.001). In both univariate and multivariate survival analyses, a shorter time from diagnosis to APSCT was associated with early recovery of ALC (P = 0.03). These findings indicate that early recovery of ALC may contribute to longer survival in younger patients with lymphoproliferative disorders. A shorter time from diagnosis to APSCT may favor recovery of ALC independent of the infused stem cell or lymphocyte doses.

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BackgroundThe ongoing SURPASS trial (NCT04044859) evaluates safety and efficacy of next-generation ADP-A2M4CD8 SPEAR T-cells co-expressing the CD8α co-receptor with the engineered MAGE-A4c1032T cell receptor (TCR).MethodsFirst-in-human trial in HLA-A*02 positive patients (pts) with advanced cancers expressing MAGE-A4 antigen by immunohistochemistry. Eligible pts undergo apheresis, T-cells are isolated, transduced with a Lentiviral vector containing the MAGE-A4c1032 TCR and CD8α co receptor, and expanded. Expansion, transduction level, cellular composition and function of the manufactured product (MP) are assessed in vitro. Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days.ResultsAs of 16 July 2020, 5 pts (1 with MRCLS, 2 with esophagogastric junction [EGJ] cancers, 1 with ovarian cancer, and 1 with head and neck cancer) were treated with ADP-A2M4 CD8 (range ~1 to 5.7 billion transduced cells). No DLTs or SAEs have been reported. To date, 1 pt with EGJ cancer had a partial response (PR per RECIST) and has had progression-free survival >6 months. One pt with head and neck cancer also had a PR. All other pts have had best overall response of stable disease.MP expanded by an average of 15.3 fold during manufacturing (range 5.9 to 25.6-fold). On average, 43% of T-cells in the MP expressed the TCR (range 23 to 63%). The fraction of CD4+ cells in the final MP varied (range 45 to 84%). Co-expression of the MAGE-A4 TCR and CD8α in CD4+ T-cells in the patient MP enabled CD4+ T-cells to kill tumor target cells directly in vitro. MAGE-A4 expression in tumor biopsies varied (H-score range 55 to 300). Transduced T-cells were detected in peripheral blood of all pts. IFN-gamma increased transiently in the serum of 1 pt who responded.ConclusionsADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile and pts with EGJ cancer and head and neck cancer have demonstrated evidence of antitumor activity. Translational data and early clinical results indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated clinical and translational data will be presented.Trial RegistrationNCT04044859Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.