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Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma with an aggressive clinical course. To investigate the potential of immune-checkpoint therapy, we retrospectively studied the tumor microenvironment (TME) using high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 "other" CNSL lymphomas with the presence of the Epstein-Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition and the functional spectrum of cytotoxic T cells were similar. But cytotoxic T cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T cells and geographic-type necrosis each predicted inferior outcome in PCNSL. Both M1-like (CD68 + CD163low) and M2-like (CD68 + CD163high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated with a better survival. PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0.4% of all CD8+ T cells. TIM-3, a marker for T cell exhaustion, was significantly more expressed in CD8posPD-1pos T cells compared to CD8posPD-1neg T cells, and a similar increased expression was observed in M2-like pro-tumoral phagocytes. In conclusion, the clinical impact of TME composition supports the use of immune-checkpoint therapies in PCNSL. Based on observed differences in immune-checkpoint expression, combinations that boost cytotoxic T cell activation (by blocking TIM-3 or TGFBR1) prior to the administration of PD-L1 inhibition could be of interest.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs., Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed. ispartof: ANNALS OF HEMATOLOGY vol:98 issue:6 pages:1421-1426 ispartof: location:Germany status: published

Fatigue is one of the most common and most distressing problems in lymphoma patients. A vicious circle is presumed between fatigue, physical activity and physical fitness. It is plausible that an exercise training program would be effective in reducing fatigue, by breaking this vicious circle. The purposes of this review are to provide an overview of the literature on physical activity and physical fitness in lymphoma patients before, during and after anticancer treatment, and to summarise the literature on exercise training interventions in lymphoma patients. We conducted a search for studies reporting on physical activity, physical fitness or the effect of exercise training in lymphoma patients. A total of 13 articles were selected. Due to a small number of articles and methodological issues, it was not possible to make final conclusions. The results indicated that 21 % to 29 % of lymphoma survivors meet the American College of Sports Medicine public health guidelines for physical activity. Maximal exercise capacity was decreased before treatment, especially in patients with advanced disease, and was close to normal during and/or after treatment. Lower levels of physical activity as well as lower physical fitness seemed to be associated with more symptoms of fatigue. Aerobic exercise training interventions seemed to be feasible and safe and had positive effects on cardiorespiratory fitness, fatigue and self-reported physical functioning. Further research is needed to examine physical activity and physical fitness in a longitudinal, objective way in large samples and to examine the effect of exercise training in lymphoma patients.

Contains fulltext : 79550.pdf (Publisher’s version ) (Closed access) Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array-based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34(+) progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.

Immune mechanisms have been shown to contribute to the process of myelodysplastic syndromes (MDS)-related bone marrow (BM) failure. The aim of this study was to evaluate the possible contribution of activated monocytes through CD40-CD40L(CD154) interactions with activated T helper cells. We demonstrated in 77 predominantly lower risk MDS patients that the CD40 receptor was expressed significantly higher on monocytes and that CD40L was expressed significantly higher on T helper cells in peripheral blood (PB) and BM. Increased levels of CD40 and CD40L were detected in the same patients. In addition, stimulation of the CD40 receptor on purified PB monocytes led to a significantly higher tumor necrosis factor alpha production in patients. Co-culture of BM mononuclear cells of 21 patients in the presence of a blocking CD40 monoclonal antibody (ch5D12) led to a significant increase in the number of colony-forming units. A correlation was seen between increased CD40 expression on monocytes with patients' age below 60 years and with the cytogenetic abnormality trisomy 8. These results demonstrate that CD40 expression on monocytes may identify a subgroup of MDS patients in whom immune-mediated hematopoietic failure is part of the disease process. As such, the CD40-CD40L-based activation of monocytes might be a target to counteract MDS-related BM failure. ispartof: Leukemia vol:21 issue:12 pages:2411-2419 ispartof: location:England status: published

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n = 4) and disease-related death (n = 4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B-12 was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.

Lymphomas are a heterogeneous group of diseases with differing histopathology, clinical behaviour, response to therapy and outcome. Lymphomas are highly sensitive to chemotherapy and radiotherapy, and the recent developments in treatment have considerably improved clinical outcome. However, there is increasing recognition that this has been at the cost of long-term treatment-related effects in a relatively young patient population. Thus, one of the most challenging aspects in the imaging of lymphoma patients is tailoring the intensity of the treatment to the individual patient. This paper reviews recently published data concerning the use of fluorine-18 fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for therapy monitoring in lymphoma patients and highlights the shortcomings and future directions. A temporary strategy for the implementation of [(18)F]FDG-PET in the management of lymphoma patients is proposed.

Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [(18)F]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [(18)F]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5 x 10(6) Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1-d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [(18)F]FDG uptake in the tumour and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [(18)F]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [(18)F]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable tumour cells was again observed and this was accurately predicted by an increase in [(18)F]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [(18)F]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells.

Item does not contain fulltext Comparisons of the effectiveness of chemotherapy and transplantation in AML in first complete remission (CR) have focused almost exclusively on patients with de novo disease. Here we used Cox modelling to compare these strategies in patients with MDS and s-AML treated by the Leukemia Group of the EORTC or at the MD Anderson Cancer Center. All patients were aged 15-60. The 184 EORTC patients received conventional dose ara-C + idarubicin + etoposide for remission induction, and after one consolidation course, were scheduled to receive an allograft, or an autograft if a sibling donor was unavailable. The 215 MDA patients received various high-dose ara-C containing induction regimens, and in CR, continued to receive these regimens at reduced dose for 6-12 months. CR rates were 54% EORTC and 63% MDA (P = 0.09). Sixty-five of the 100 EORTC patients who entered CR received a transplant in first CR. Disease-free survival in patients achieving CR was superior in the EORTC cohort, the 4-years DFS rates were 28.9% (s.e. = 4.8%) EORTC vs 17.3% (s.e. = 3.7%) MDA (P = 0.017). Survival from CR was not significantly different in the EORTC and MDA groups, as was survival from start of treatment. After accounting for prognostic factors the conclusions were unchanged. Despite various problems with the analysis discussed below, the data suggest that neither transplantation nor chemotherapy, as currently practised, can be unequivocally recommended for these patients in first CR and that questions as to the superior modality may be less important than the need to improve results with both.

The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex. Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene. Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro, the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.

We collected peripheral blood stem cells (PBSC) in 19 early chronic phase CML patients following each of two consecutive cycles of intensive chemotherapy (CT) to evaluate whether an additional cycle of CT would increase Philadelphia (Ph)-negativity of the PBSC harvest. Autologous SCT (autoSCT) was performed if a major cytogenetic response (MCR) of the PBSC harvest was obtained. CT consisted of cytarabine 200 mg/ m2/day (days 1–7)/idarubicin 12 mg/m2/day (days 1–2) (cycle one) and cytarabine 2000 mg/m2/day (days 1–6)/amsacrine 120 mg/m2/day (days 1–3) (cycle two). One patient died of fungal pneumonia after the first cycle. Stem cells were harvested in 18 patients after cycle one and in 16 patients after cycle two. After the first cycle, all patients showed a cytogenetic response of their graft (MCR in eight patients: three complete, five partial), after cycle two, seven patients obtained an MCR (one complete, six partial). Seven patients became eligible for autoSCT. All patients proceeded with IFNα maintenance. Currently, 16 patients are alive. At the latest cytogenetic examination of bone marrow, four patients showed an MCR and four a minor response. In conclusion, although a second cycle of CT may contribute to elimination of leukemia residing in the patient, it appeared to be ineffective in improving the Ph-negativity of the PBSC graft. Bone Marrow Transplantation (2000) 25, 1147–1155.

In order to gain insight into immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements in adult acute lymphoblastic leukemia (ALL), we studied 48 adult patients: 26 with precursor-B-ALL and 22 with T-ALL. Southern blotting (SB) with multiple DNA probes for the IGH, IGK, TCRB, TCRG, TCRD and TAL1 loci revealed rearrangement patterns largely comparable to pediatric ALL, but several differences were found for precursor-B-ALL patients. Firstly, adult patients showed a lower level of oligoclonality in the IGH gene locus (five out of 26 patients; 19%) despite a comparable incidence of IGH gene rearrangements (24 out of 26 patients; 92%). Secondly, all detected IGK gene deletions (n = 12) concerned rearrangements of the kappa deleting element (Kde) to Vkappa gene segments, which represent two-thirds of the Kde rearrangements in pediatric precursor-B-ALL and only half of the Kde rearrangements in mature B cell leukemias. Thirdly, a striking predominance of immature Ddelta2-Ddelta3 cross-lineage recombinations was observed (seven out of 16 TCRD rearrangements; 44%), whereas more mature Vdelta2-Ddelta3 gene rearrangements occurred less frequently (six out of 16 TCRD rearrangements; 38% vs >70% in pediatric precursor-B-ALL). Together these data suggest that the Ig/TCR genotype of precursor-B-ALL is more immature and more stable in adults than in children. We also evaluated whether heteroduplex analysis of polymerase chain reaction (PCR) products of rearranged Ig and TCR genes can be used for identification of molecular targets for minimal residual disease (MRD) detection. Using five of the major gene targets (IGH, IGK, TCRG, TCRD and TAL1 deletion), we compared the SB data and heteroduplex PCR results. High concordance between the two methods ranging from 96 to 100% was found for IGK, TCRG and TAL1 genes. The concordance was lower for IGH (70%) and TCRD genes (90%), which may be explained by incomplete or 'atypical' rearrangements or by translocations detectable only by SB. Finally, the heteroduplex PCR data indicate, that MRD monitoring is possible in almost 90% of adult precursor-B-ALL and >95% of adult T-ALL patients.

Nine patients with drug-induced agranulocytosis received recombinant human granulocyte colony-stimulating factor (rhG-CSF) to accelerate myeloid recovery because of life-threatening infections related to neutropenia. All patients showed a quick recovery of their granulocyte counts. Side effects were substantial, however. Three patients, two with a severe infection and one with preexisting pulmonary infiltrates, developed worsening of their respiratory status during neutrophil recovery, resulting in clinical manifestations of the adult respiratory distress syndrome (ARDS). In view of these major complications, the exact place of hematopoietic growth factors in the treatment of drug-induced agranulocytosis remains to be determined.

Imatinib mesylate induces durable complete remission of advanced CML persisting after allogeneic bone marrow transplantation

The clinical and ferrokinetic effects of escalating doses of subcutaneously administered recombinant human erythropoietin (rh-EPO) were studied in ten patients with myelodysplastic syndromes and severe transfusion-dependent anemia. Red blood cell transfusion requirements diminished in four patients, and one of the patients eventually became transfusion independent with an EPO-induced rise of Hb from 7.7 g/dl to 12.3 g/dl. Endogenous serum levels of EPO were significantly increased in all patients (100-5700 mU/ml), but three of four responders had a relatively low baseline level. The effective red cell iron turnover (RCIT) improved in two responding patients and even normalized in one patient. This increase in RCIT was accompanied with a decline in the ineffective red cell iron turnover (IIT). The other responding patients had a relatively preserved RCIT before EPO treatment. EPO therapy further increased the fraction of IIT in the latter patients. Red cell survival time did not increase during EPO therapy, even in the responding patients. One transient and one maintained increase in platelet count were observed. Disease progression with a sustained increase in blast cells in one patient and a transient elevation of blasts in another patient was seen. No other side effects of EPO therapy were observed. These results suggest that anemic MDS patients with low serum EPO levels and relatively spared effective erythropoiesis as measured by ferrokinetic studies may be the best candidates for treatment with recombinant human EPO.

We report on 22 patients with myelodysplastic syndrome (MDS), all of whom showed striking marrow fibrosis. Variable blood counts, often with teardrop poikilocytosis and a leukoerythroblastic picture, were present at diagnosis. Visceral enlargement was detected in 17 patients with a distinct splenomegaly in seven cases. All cases demonstrated dysplasia in at least two cell lineages. No specific cytogenetic abnormality seems to characterize this group of patients. Southern blot analysis showed no breakpoint cluster region rearrangement as observed in classical chronic myeloid leukemia. Ferrokinetic studies revealed quantitatively deficient erythropoiesis in all except two cases and an abnormally high fraction of ineffective erythropoiesis in all. Splenic erythropoiesis was present in eight patients. The median survival was 18 months. At the time of this report, 12 patients had died. The causes of death were disease progression (7 patients) and infection (5 patients). One might speculate that the present series of cases represents a transition between MDS and myeloproliferative disease, thereby displaying characteristics of both groups of diseases.

The influence of pentoxifylline on normal and diseased neutrophil function has been studied in vitro. In high concentrations pentoxifylline stimulated human neutrophil chemotaxis toward both bacterial oligopeptides and complement components. Pentoxifylline was also shown in vitro to restore the normal chemotactic capacity of neutrophils from patients with known functional defects, i.e. myelodysplastic syndromes, lazy leucocyte syndrome, juvenile parodontitis, hyper-IgE-syndrome and liver cirrhosis. Pentoxifylline was also shown to strongly inhibit the release of primary and secondary granule release of granulocytes. Moreover, pentoxifylline inhibits both basal and stimulated neutrophil adhesion to both aortic and pulmonary artery calf endothelium. The mechanism whereby pentoxifylline exerts this action is not adequately understood. While our results partially imply interference of pentoxifylline with neutrophil cyclic AMP and/or prostaglandin metabolism, down-regulation of neutrophil functional antigen (e.g. CD11, CD18) expression seems to play a key role in the observed drug effects. Finally, these results indicate that pentoxifylline may be useful in the treatment of granulocyte mediated diseases and symptoms.

Hopital de Jolimont, Haine -Saint -Paul and Cliniques Universitai res St Luc, Brussels, Belgium Corresponding author: Daan Dierickx , MD University Hospitals Leuven Department of hematology Herestraat 49 - 3000 Leuven - Belgium E -mail: Daan.dierickx@uzleuven.be Tel: ++32 16 346880 Fax: ++32 16 346881 Word count: 444 words Conflicts of interest: none peer-00615409, version 1 - 19 Aug 2011

We describe a patient with a long history of typical chronic lymphocytic leukemia (CLL) who developed hypercalcemia, osteolytic bone lesions, and a monoclonal protein, all features of a secretory plasma cell disorder. These features in CLL have been reported in only four previous cases. The hypercalcemia in our patient is felt to result from an increase in the osteoclastic process.