Thomas Relander

Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-01

PURPOSE Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. PATIENTS AND METHODS Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. RESULTS Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. CONCLUSION Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

Prognostic Factors in Follicular Lymphoma

Follicular lymphoma (FL) is one of the most common types of non-Hodgkins lymphoma. It is usually diagnosed at an advanced stage, for which many treatment options exist, however, no curative standard therapy has been identified. The outcome is highly variable with a median survival of approximately 10 years. The life expectancy of patients with FL has been extended with the use of rituximab, a monoclonal antibody targeting the CD20 antigen on FL cells, but there remains a group of patients who fail to respond to chemoimmunotherapy and die early of their disease. Transformation of FL to an aggressive histology is an important event with high morbidity and mortality. The Follicular Lymphoma International Prognostic Index has become the clinically useful prognostic tool, but gives only a rough estimate of expected outcome. There is a need for useful biomarkers for prediction of the disease course of single patients to individualize therapy, especially in the new era of chemoimmunotherapy.

Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis

Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P=0.011) and 3.19 (95% confidence interval, 1.06-9.57, P=0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes.

Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model-based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q-, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.

Gonadal and sexual function in men treated for childhood cancer.

BACKGROUND Insofar as a majority of children with malignant diseases are cured, the late effects of treatment are of major importance. PROCEDURE A retrospective study was conducted of gonadal and sexual function of 77 adult male survivors of childhood malignancies treated and cured at a single center from 1970 to 1989 and followed for a median of 13 years. The study included an interview, physical examination, sperm test, and hormonal analyses. RESULTS One-third of the patients were treated for hematological malignancies, one-third for CNS tumors, and one-third for other malignancies. Eleven patients required androgen substitution after treatment for tumors of the pituitary-hypothalamic region or acute lymphoblastic leukemia including testicular irradiation and/or orchiectomy. In three patients the testicles were removed. The other eight had small testicles, and those providing sperm samples had azoospermia, and sexual function was disturbed in most of them. Most of the remaining 66 patients had small testicles. Normozoospermia was found in 63%, oligozoospermia in 20%, and azoospermia in 17%. Although there was a highly significant correlation between testicular volume and sperm test, 25% of patients with testicles of <10 ml had normozoospermia. Sexual function was normal in 46 patients, and they were married at a frequency comparable to the normal population. Twenty-one patients had no signs of gonadal dysfunction. CONCLUSIONS Patients treated for tumors in the hypothalamic-pituitary region or treated with testicular irradiation or with high doses of alkylating agents had severe gonadal and sexual dysfunction. Most of the other patients had good prospects for preserved gonadal and sexual function.

Real world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry.

Peripheral T-cell lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. The addition of etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and upfront consolidation with autologous stem cell transplantation (auto-SCT) have shown promising results but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry, we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index factors, male gender was associated with an adverse overall survival (OS) (hazard ratio [HR], 1.28; P = .011) and progression-free survival (PFS) (HR, 1.26; P = .014). In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma), upfront auto-SCT was associated with a superior OS (HR, 0.58; P = .004) and PFS (HR, 0.56; P = .002) compared with patients treated without auto-SCT. The addition of etoposide to CHOP resulted in superior PFS in patients ≤60 years (HR, 0.49; P = .008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials.

Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma

The efficacy and safety of zanolimumab (HuMax‐CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty‐one adult patients with relapsed or refractory CD4+ PTCL of non‐cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL‐not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single‐arm multi‐centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26–85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III–IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL‐NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor‐prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

Hypogonadism Risk in Men Treated for Childhood Cancer.

CONTEXT Pediatric cancer treatment may imply an increased risk of hypogonadism, leading to metabolic disorders and osteoporosis. Such complications are potentially preventable. OBJECTIVE The aim of this study was to assess diagnosis- and treatment-dependent risk of hypogonadism in male childhood cancer survivors (CCS). DESIGN Male CCS who were treated during the period 1970-2002 and who in 2004 were 18-45 yr of age were eligible. SETTING The study was conducted in a university hospital clinic. PATIENTS A consecutive group of CCS treated at Lund University Hospital was selected for the study, of whom 151 (38%) agreed to participate. Furthermore, 141 healthy fertile men served as controls. INTERVENTIONS We measured serum levels of free and total testosterone, SHBG, and LH. MAIN OUTCOME MEASURES Odds ratios (OR) for biochemical hypogonadism, defined as total testosterone less than 10 nmol/liter and/or LH above 10 IU/liter, were calculated and related to type of cancer, treatment received, as well as testicular volume. RESULTS Hypogonadism was more commonly detected in CCS than in controls (OR, 6.7; 95% CI, 2.7, 17). The increased presence of hypogonadism was noted in the following treatment groups: brain surgery, chemotherapy (with and without radiotherapy), and testicular irradiation. Low total testicular volume (<or=24 ml) was associated with a high risk of hypogonadism (OR, 31; 95% CI, 11, 92). CONCLUSION Adult male survivors of childhood cancer are at risk of hypogonadism, which should be acknowledged in the long-term follow-up of these men.

Human Immunodeficiency Virus Type 1 Vectors with Alphavirus Envelope Glycoproteins Produced from Stable Packaging Cells

ABSTRACT Alphavirus glycoproteins have broad host ranges. Human immunodeficiency virus type 1 (HIV-1) vectors pseudotyped with their glycoproteins could extend the range of tissues that can be transduced in both humans and animal models. Here, we established stable producer cell lines for HIV vectors pseudotyped with alphavirus Ross River virus (RRV) and Semliki Forest virus (SFV) glycoproteins E2E1. RRV E2E1-stable clones could routinely produce high-titer pseudotyped vectors for at least 5 months. SFV E2E1-stable clones, however, produced relatively low titers. We examined the properties of RRV E2E1-pseudotyped vectors [HIV-1(RRV)] and compared them with amphotropic murine leukemia virus Env- and vesicular stomatitis virus glycoprotein G-pseudotyped vectors. HIV-1(RRV) displayed a number of characteristics which would be advantageous in ex vivo and in vivo experiments, including resistance to inactivation by heat-labile components in fresh human sera and thermostability at 37°C. Upon single-step concentration by ultracentrifugation of HIV-1(RRV), we could achieve vector stocks with titers up to 6 × 107 IU/ml. HIV-1(RRV) efficiently transduced cells from several different species, including murine primary dendritic cells, but failed to transduce human and murine T cells as well as human hematopoietic stem cells (HSC). These results indicate that HIV-1(RRV) could be used in a number of applications including animal model experiments and suggest that expression of RRV cellular receptors is limited or absent in certain cell types such as T cells and human HSC.

High risk of azoospermia in men treated for childhood cancer.

Childhood cancer survivors (CCS) have an increased risk of impaired spermatogenesis, but data regarding the disease- and treatment-related risk factors of azoospermia are scarce. Such information is crucial both for counselling CCS and for selecting patients for testicular tissue cryopreservation. The proportion of azoospermic men in CCS was 18% [95% confidence interval (CI): 12-26], specifically for leukaemias (19%; 95% CI: 5.5-42), Hodgkins disease (53%; 95% CI: 29-76), non-Hodgkins lymphoma (11%; 95% CI: 0.28-48) and testicular cancer (11%; 95% CI: 0.28-48). In CCS treated with high doses of alkylating agents, the proportion of azoospermic men was 80% (95% CI: 28-99) and if radiotherapy was used additionally, the proportion was 64% (95% CI: 35-87). In CCS with subnormal Inhibin B levels, the proportion of azoospermic men was 66% (95% CI: 47-81) and for those with elevated follicle-stimulating hormone (FSH) levels, the proportion was 50% (95% CI: 35-67). Among CCS with subnormal testicular volume (≤ 24 mL), azoospermia was found in 61% (95% CI: 39-80) of the cases. Most childhood cancer diagnoses are associated with an increased risk of azoospermia, especially in CCS receiving testicular irradiation, high doses of alkylating drugs and other types of cytotoxic treatment, if combined with irradiation. Inhibin B, FSH and testicular volume can be used as predictors for the risk of azoospermia.