Search

Summary: Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. Objectives: To produce and evaluate the therapeutic performance of a new antibody–drug conjugate (Adcitmer®) targeting CD56 in preclinical models of MCC. Methods: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56‐targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56‐targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. Results: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56‐targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56‐mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. Conclusions: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors. What is already known about this topic? Merkel cell carcinoma (MCC) is an aggressive skin cancer.While immune checkpoint inhibitors constitute a major advance in treating patients with MCC with advanced disease, new therapeutic options are still urgently required.CD56, which is expressed by most MCC tumours, might constitute a therapeutic target for the development of antibody–drug conjugate therapies. What does this study add? We generated a CD56‐targeting monomethyl auristatin E (MMAE) bioconjugate antibody (Adcitmer®) and demonstrated its optimal biochemical properties, specific binding and cytotoxicity in vitro in MCC cell lines, and its capacity to reduce tumour growth in vivo in a MCC mouse model. What is the translational message? Adcitmer®, a new CD56‐targeting MMAE bioconjugate antibody, may represent a potential therapeutic option to be investigated as an alternative approach or in combination with immune checkpoint inhibitors in patients with inoperable MCC. Linked Comment: L. Leiendecker et al. Br J Dermatol 2022; 186:209–210. Plain language summary available online [ABSTRACT FROM AUTHOR]

Detection of increasing mixed chimerism (IMC) using standard PCR correlates with relapse after allo-SCT for acute leukemias (ALs). Quantitative real-time PCR of insertion/deletion polymorphism (indel qrtPCR) is a much more sensitive method, which can be performed on peripheral blood. We studied the significance of low increases of recipient cells (0.1%) detected by indel qrtPCR in a cohort of 89 transplants. We did not observe relapse among the 32 patients with no IMC. Fifty-seven patients presented a first IMC, which was followed by four different scenarios: a decreasing MC (26 cases, no relapse), a stable MC (1 case, 1 relapse), a second IMC (24 cases, 15 relapse) or no control of chimerism (6 cases, 5 relapses). In multivariate analysis, detection of two successive IMCs was strongly associated with relapse (hazard ratio (HR): 9.4, 95% confidence interval (CI): 3.8-23; P<0.0001). Among the 57 patients who presented at least one IMC, 27 underwent immunomodulation (tapering of immunosuppression or donor lymphocyte injection), leading to a 1-year relapse rate of 15.7% vs 57.6% in the 30 other patients (P=0.0007). Altogether, these results indicate that chimerism analysis using indel qrtPCR in peripheral blood is a useful tool for detection of relapse in patients transplanted for AL. [ABSTRACT FROM AUTHOR]

Since their introduction in the 2000s, echinocandin drugs have become widely used for the treatment and prophylaxis of invasive fungal infections and, notably, invasive candidiasis. Although cases of breakthrough candidiasis in patients receiving echinocandins have been reported, clinical failure during echinocandin treatment due to the acquisition of resistance by a normally susceptible Candida spp. isolate is considered rare. To date, no publications have been published correlating the use of echinocandins and the emergence of echinocandin resistance among Candida species. So, our goal is to report an initial analysis of echinocandin use in relation to the emergence of resistant Candida isolates. We report here a single-centre experience of the emergence of eight resistant isolates belonging to normally susceptible Candida species in six patients receiving echinocandins. We describe the context and analyse the use of echinocandins over the previous decade. For seven of these isolates, we identified FKS gene mutations involved in decreased susceptibility. Seven isolates were obtained in 2011, on the heels of a ten-fold increase in caspofungin use over the preceding decade. In contrast, in 2012, the use of echinocandins decreased in our institution by 19.5 % and, in that year, only one Candida-resistant isolate was detected, despite the stable global epidemiology of invasive candidaemia. This work underlines the necessity of improving the prescription of antifungal drugs. Improvement in the monitoring of strain susceptibility should also be considered in order to better detect the emergence of resistant or non-susceptible yeast strains. [ABSTRACT FROM AUTHOR]

Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53±17 years) receiving high-dose MTX (5.13±1.88 g m−2 in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 −24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the −24T allele as compared with noncarriers: 8.6±2.2 vs 6.7± 2.5 l h−1, P<0.01 and 30.7±7.7 vs 22.1±8.8 l, P<0.001, respectively. Consequently, −24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to baseline differential blood count and prognosis in lymphoproliferative disorders in the May 3, 2013 issue.

PurposeTo describe the clinical and imaging presentation, pitfalls in the diagnosis of choroidal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), as well as the therapeutic management and prognosis.MethodsA retrospective case review of nine choroidal MALT lymphomas was performed. Initial clinical presentation and imaging findings of these histologically confirmed cases of lymphoma were analyzed. Treatment methods, time to diagnosis, systemic work-up, and treatment prognosis were assessed.ResultsInitial presentation was essentially blurred vision. The features described on examination were: anterior and posterior scleritis, iridocyclitis, choroidal infiltration, and exudative retinal detachment. Fluorescein and indocyanine green angiography as well as ultrasonography and optic coherence tomography provided arguments in favor of the diagnosis. Biopsy sites included conjunctiva, Tenon's capsule, deep scleral tissue, episclera, lacrimal gland, and choroid. Treatment mostly consisted of a combination of chemotherapy and radiotherapy. The mean time to diagnosis was 12 months.ConclusionsOwing to the insidious onset of these tumors and their ability to simulate other conditions, the diagnosis is commonly delayed. The prognosis is generally good and treatment is effective in the case of localized lymphoma. [ABSTRACT FROM AUTHOR]

Waldenstrom's macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. These disease characteristics and the frequently advanced age of the WM patient pose a major challenge to the treating clinician even today. Recently, there has been not only substantial progress in our understanding of the biology of WM, but we have also significantly improved our tools to prognostify and to treat patients with this disease. This review summarizes our current knowledge about WM and aims at offering a guideline for the clinical management of patients with this lymphoma subtype, covering questions on how to manage diagnosis, prognostification and treatment based on the most recent data. [ABSTRACT FROM AUTHOR]

Waldenstrom's macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. These disease characteristics and the frequently advanced age of the WM patient pose a major challenge to the treating clinician even today. Recently, there has been not only substantial progress in our understanding of the biology of WM, but we have also significantly improved our tools to prognostify and to treat patients with this disease. This review summarizes our current knowledge about WM and aims at offering a guideline for the clinical management of patients with this lymphoma subtype, covering questions on how to manage diagnosis, prognostification and treatment based on the most recent data. [ABSTRACT FROM AUTHOR]

We investigated whether a young human leukocyte antigen (HLA)-matched unrelated donor (MUD) should be preferred as donor to an HLA-identical sibling (MRD) for older patients with myelodysplastic syndrome (MDS) (50 years) who underwent allogeneic stem cell transplantation (AHSCT). Outcomes of 719 MDS patients with a median age of 58 years (range, 50-73 years) who received AHSCT from related (n=555) or unrelated (n=164) donors between 1999 and 2008 and reported to the European Group for Blood and Marrow Transplantation were analyzed. The median donor age of the MRD was 56 years (range: 35-78), in contrast to 34 years (range: 19-64) for the MUDs. Influence of donor's age on survival was not observed for MRD (hazard ratio (HR): 1.01 (95% confidence interval (CI): 0.99-1.02), P=0.2), but there was a significant impact of MUD's age on outcome (HR: 1.03 (95% CI: 1.01-1.06); P=0.02). Transplantation from younger MUDs (<30 years) had a significant improved 5-year overall survival in comparison with MRD and older MUDs (>30 years): 40% vs 33% vs 24% (P=0.04). In a multivariate analysis, AHSCT from young MUD (<30 years) remained a significant factor for improved survival in comparison with MRD (HR: 0.65 (95% CI: 0.45-0.95), P=0.03), which should be considered in donor selection for older patients. [ABSTRACT FROM AUTHOR]

T-prolymphocytic leukemia (T-PLL) has a very poor prognosis with conventional immunochemotherapy. Incidental reports suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) might have a role in this disease. Therefore, the purpose of the present study was to analyze the outcome of transplants for T-PLL registered with the European Group for Blood and Marrow Transplantation database and the Royal Marsden Consortium. Eligible were 41 patients with a median age of 51 (24-71) years; median time from diagnosis to treatment was 12 months, and in complete remission (CR) (11), partial remission (PR) (12), stable or progressive disease (13) and unknown in 5 patients. A total of 13 patients (31%) received reduced-intensity conditioning. Donors were HLA-identical siblings in 21 patients, matched unrelated donors in 20 patients. With a median follow-up of surviving patients of 36 months, 3-year relapse-free survival (RFS) and OS was 19% (95% CI, 6-31%) and 21% (95% CI, 7-34%), respectively. Multivariate analysis identified TBI and a short interval between diagnosis and HSCT as factors associated with favorable RFS. Three-year non relapse mortality and relapse incidence were each 41% with the majority of relapses occurring within the first year. These data indicate that allo-HSCT may provide effective disease control in selected patients with T-PLL. [ABSTRACT FROM AUTHOR]

Background: Neuropathies associated with lymphoma (NAL) are rare and present a great clinical heterogeneity, making them difficult to diagnose and worsening their prognosis. Objectives: (1) To report the different patterns of NAL and discuss the mechanisms encountered; (2) to determine the relationship between a given type of lymphoma and a specific type of neuropathy; and (3) to assess the prognosis of NAL. Methods: Among 150 patients with lymphoma and neuropathy, we selected 26 in whom the neuropathy was not related to drug induced or IgM-antimyelin associated glycoprotein neuropathies. The pattern of neuropathy was defined in terms of its clinical and electrophysiological features. Neurological improvement, haematological remission and occurrence of death were taken into account to determine the prognosis. Results: 13 patients (50%) had a demyelinating polyneuropathy (PNP), seven (27%) had a radiculopathy linked to proximal root tumoral infiltration and six (23%) had an axonal multiple mononeuropathy (MM) related to distal lymphomatous infiltration or to paraneoplastic microvasculitis. Hodgkins lymphoma was only associated with demyelinating PNP. High grade B cell lymphoma was strongly associated with radiculopathy. Neurological improvement was observed in 69% of patients with demyelinating PNP, 29% with radiculopathy and 50% with MM. Haematological remission was observed in 46% of patients with demyelinating PNP, 29% with radiculopathy and 83% with MM. Conclusions: Demyelinating PNP, the most frequently observed neuropathy in this study, had the best neurological prognosis. Chemotherapy combined with immune mediated treatment was the most effective treatment in this group. Identifying the type and mechanism of NAL is crucial in order to define the therapeutic strategy and improve the prognosis. [ABSTRACT FROM AUTHOR]

Copyright of Oncologie (Tech Science Press) is the property of Tech Science Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.Leukemia (2007) 21, 2324–2331; doi:10.1038/sj.leu.2404850; published online 19 July 2007 [ABSTRACT FROM AUTHOR]

In an effort to better understand the structure and behaviour of bitumen in low temperature, we describe the first use of cryogenic atomic force microscopy and phase detection microscopy to characterize bitumen nano- and micro-structures. The results were interpreted in light of glass transition temperatures ( Tgs) for bitumen fractions. The domains visible by microscopy, the catana, peri and para phases, were attributed to domains rich in asphaltenes, naphthene and polar aromatics, and saturates, respectively. Between −10°C and −30°C, atomic force microscopy images revealed topographic features not visible in atomic force microscopy images acquired at room temperature. According to phase detection microscopy and Tgs, the features were assigned to viscous unfrozen saturates. Upon cooling to −72°C, unfrozen domains of 20–400 nm were observed. These domains were found in the paraphase rich in saturates and in the periphase rich in naphthene aromatics and polar aromatics. The findings indicate that new viscous domains form upon cooling to low temperatures owing to phase segregation, and that some bitumens are never entirely rigid in low temperatures. [ABSTRACT FROM AUTHOR]

Bitumen is a complex mixture of hydrocarbons for which microstructural knowledge is incomplete. In an effort to detail this microstructure, 13 bitumens were analysed by phase-detection atomic force microscopy. Based on morphology, the bitumens could be classified into three distinct groups. One group showed fine domains down to 0.1 µm, another showed domains of about 1 µm, and a third group showed up to four different domains or phases of different sizes and shapes. No correlation was found between the atomic force microscopy morphology and the composition based on asphaltenes, polar aromatics, naphthene aromatics and saturates. A high correlation was found between the area of the ‘bee-like’ structures and the vanadium and nickel content in bitumen, and between the atomic force microscopy groups and the average size of molecular planes made of fused aromatics. The morphology and the molecular arrangements in bitumen thus appear to be partly governed by the molecular planes and the polarity defined by metallic cations. [ABSTRACT FROM AUTHOR]

Fludarabine (FDR) therapy gives a response rate of about 30% in previously treated patients with Waldenström's macroglobulinemia (WM). The combination of FDR and cyclophosphamide (Cy) has been shown to be effective in chronic lymphoproliferative disorders. We administered the combination of FDR (30 mg/m2 i.v. D1–D3) and Cy (300 mg/m2 i.v. D1–D3) to 49 patients. Median age was 64 years. The median hemoglobin, albumin, beta 2 microglobulin and immunoglobulin M (IgM) levels were 9.9 g/100 ml, 39.6 g/l, 3 mg/l and 24.7 g/l, respectively. In all, 14 patients (29%) had not previously been treated. FDR/Cy was administered every 4 weeks for a median of four cycles. In all, 38 patients (77.6%) had partial responses, nine had stable disease and two had progressive disease. After a median of follow-up of 25 months, six patients relapsed and two patients developed large-cell lymphoma. The median time to treatment failure was 27 months. The main toxicity was hematological. In all, 12 patients died, four from progression, one from large-cell lymphoma, three from infection and four from a second malignancy. Two factors negatively influenced overall and event-free survival, age >65 years and IgM <40 g/l. The FDR/Cy combination, therefore, gives a high response rate in WM, even in previously treated patients with factors of poor prognosis.Leukemia (2005) 19, 1831–1834. doi:10.1038/sj.leu.2403885; published online 25 August 2005 [ABSTRACT FROM AUTHOR]

Objective: To study the prevalence and characteristics of arterial thromboembolic events (ATEE) in the course of AL amyloidosis. Methods: We report the case of a non‐anticoagulated patient with AL amyloidosis restrictive cardiomyopathy who developed acute lower limb ischaemia. We then prospectively determined the prevalence of ATEE in all patients with AL amyloidosis who were evaluated in our institution for autologous peripheral stem cell transplantation. Results: Nine out of 15 non‐anticoagulated patients (60%) developed ATEE: ischaemic stroke (3), transient cerebral ischaemic attack (2), multiple peripheral arterial emboli (1), bilateral iliac artery thrombosis (1), bilateral optic nerve ischaemia (1), and mesenteric ischaemia (1). Haemodynamic stasis seemed to play a leading role in the pathophysiology of ATEE, in that all patients were on sinus rhythm and only one had a thrombus on echocardiography. We identified possible contributing factors to ATEE occurrence: concomitant treatments with oestroprogestogen regimen, thalidomide, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and extracellular volume disturbances related to the cytapheresis procedure. Conclusion: We report on an unusual frequency of ATEE among patients with AL cardiac amyloidosis. Despite its theoretical risks, anticoagulation should be discussed for patients with amyloid cardiomyopathy. [ABSTRACT FROM AUTHOR]

Waldenström’s macroglobulinemia is a rare B cell malignancy. All prognostic studies have identified the adverse prognostic effect of advanced age and low hemoglobin level for survival, whereas the prognostic value of a high level of monoclonal component remains controversial. Response to treatment is probably a favorable prognostic factor for overall survival. Conventional treatment is based on alkylating agents, and especially chlorambucil. Purine analogues, used initially for salvage treatment, are increasingly employed as front-line therapy. Purine analogues have not been compared with alkylating agents as first-line therapy in randomized trials, and it is unclear whether purine analogues extend survival. An anti-CD20 monoclonal antibody has given a response rate in about 30% of patients. Autologous and allogeneic stem cell transplantation may be considered for patients with refractory or relapsing disease. [ABSTRACT FROM AUTHOR]

A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Coopératif Macroglobulinémie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWiST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWiST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWiST was 5.9 months longer in the FAMP group than in the CAP group (P = 0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P = 0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U(REL)), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical, angiographic, and cytopathologic features of ocular and central nervous system (CNS) lymphoma.Patients and Methods: Retrospective study of 44 patients over a 10-year period.Results: A total of 36 women and six men, mean age 54 years (range: 36-90 years), were included. The mean time interval between onset of ocular symptoms and diagnosis was 40 months (range: 1-144 months). Ocular involvement was bilateral in 84% of the cases. Laser flare photometry readings averaged 9.6 photons/ms (2.9-78.3 photons/ms). Vitritis was constant. Funduscopy revealed RPE abnormalities in 60.49% of the cases and punctuate retinal infiltrates in 33.5%. The most common findings with fluorescein angiography were window defects and hypofluorescent round lesions. Patients had CNS involvement in 66% of the cases. Cytologic examination of the vitreous samples showed high-grade B lymphoma in 86% of the cases. Interleukin-10 dosage, when performed, showed elevated levels averaging 2352 pg/ml in all vitreous samples. Molecular biology based on PCR confirmed the diagnosis in 12 patients. Treatment included systemic chemotherapy alone or associated with radiotherapy in various regimens. Fourteen patients died during follow-up. Only 12 patients were in complete remission.Conclusion: The prognosis of the disease remains poor. However, the new diagnostic tools and therapeutic strategies may improve the diagnostic delay and the survival outcome. [ABSTRACT FROM AUTHOR]

The cases of two patients with chronic myelomonocytic leukaemia associated with periarteritis nodosa-like, antineutrophil cytoplasmic antibody negative, systemic vasculitis, are reported. A 61 year old man was admitted with fever, diffuse myalgia, and abdominal pain. Blood and bone marrow examination showed chronic myelomonocytic leukaemia. Vasculitis of the gall bladder was responsible for acalculous cholecystitis. A massive spontaneous bilateral perirenal haemorrhage occurred. A 73 year old woman with chronic myelomonocytic leukaemia had been followed up for one year when unexplained fever occurred. Two months after the onset of fever, sudden abdominal pain was ascribed to spontaneous bilateral renal haematoma related to bilateral renal arterial aneurysms. Neuromuscular biopsy showed non-necrotising periarteriolar inflammation. To our knowledge, systemic vasculitis has never been reported in chronic myelomonocytic leukaemia. In our two cases a non-random association is suggested because (a) chronic myelomonocytic leukaemia is a rare myelodysplastic syndrome, (b) spontaneous bilateral perirenal haematoma is not a usual feature of periarteritis nodosa. [ABSTRACT FROM AUTHOR]

A article presents a case study of 56-year-old man who was presented with asthenia, fever, weight loss, polyadenopathy, and night sweats. Analyses revealed lactate dehydrogenase (LDH) elevation, polyclonal hypergammaglobulinemia, and morphologic and immunophenotypic characteristics of angioimmunoblastic T-cell lymphoma (AITL). The study indicates a graft-versus-lymphoma (GVL) effect on nodal relapse after allogeneic hematopoietic stem cell transplantation (HSCT for peripheral T-cell lymphoma.

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle. [ABSTRACT FROM AUTHOR]

Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3+ TCR alphabeta+ CD8+ CD57+ cells were compared with oligoclonally CD3+ CD8hi+ CD57- lymphocytes expanded after BMT. Leukemic CD3+ CD8hi+ CD57+ LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3+ CD8+ CD57+ LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhIL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity. However, culture of leukemic LGL with these stimuli allowed either a 2 week persistence (PMA or rhIL-2) of CD8+ CD57+ LGL or their disappearance after 3 days (PHA). Furthermore, leukemic CD8hi+ CD57+ T lymphocytes produced an inhibitor of cytotoxic functions as previously described for BMT recipients' CD8+ CD57+ cells. Thus, despite some phenotypic differences between both cell sources, leukemic CD57+ T-LGL display the same functional characteristics of cytotoxic effector and immunoregulatory T cells as CD8+ CD57+ T cells from BMT recipients which might represent their normal counterpart. [ABSTRACT FROM AUTHOR]

Since 1990 we have treated 60 patients with standard-dose fludarabine for chronic lymphocytic leukemia (B-CLL), on a compassionate basis. Three patients developed grade IV neurologic complications after treatment, with demyelination of white matter on magnetic resonance imaging (MRI) in patient # 1, diffuse demyelination, abnormal oligodendroglia and enlarged astrocytes at brain biopsy in patient n°2, and progressive multifocal leukoencephalitis (PML) with JC virus on brain biopsy in patient # 3. The neurotoxicity of fludarabine was often observed after administration of high doses (90-120 mg/m2). At standard doses (18-25 mg/m2) neurologic complications were observed in very few cases (0.2%). PML was observed in only 0.52% of patients with chronic lymphocytic leukemia (CLL), particularly those with advanced CLL. Our findings are consistent with the results of published studies and show an increase in neurologic complications in patients with advanced CLL treated with fludarabine. This increased vulnerability is probably multifactorial, but may be secondary to the immunodeficiency. [ABSTRACT FROM AUTHOR]

Posttransplant lymphoproliferative disorders (PTLD), developing after immunosuppressive therapy in human organ-graft recipients, are, for the most part, Epstein-Barr virus-induced. The earlier the diagnosis is made, the greater the potential for reversibility. The chest radiographs and CT scans of 10 patients with thoracic locations of PTLD were reviewed. Mediastinal ( n = 3) and hilar adenopathy ( n = 2), pulmonary nodules ( n = 8), and pleural thickening or effusion ( n = 4) were encountered. The incidence of partial resolution with clinical remission ( n = 4) appears to be noteworthy, and in all likelihood is related to the extensive necrosis ( n = 5) that is frequently seen. Slow regression, transitory deterioration in one case, and localization only on the graft side in two cases, were observed. These morphological and evolutionary peculiarities must be known in order to optimize the diagnosis, and thus the prognosis, of these very original disorders. [ABSTRACT FROM AUTHOR]

Given the generally poor outcome of advanced B cell chronic lymphocytic leukemia, experimental approaches are warranted, especially for younger patients in whom classical treatments have failed. We therefore conducted a prospective single-center study, using polychemotherapy (ESHAP) to prepare patients for hematopoietic stem cell collection and autologous stem cell transplantation as consolidation therapy. Twenty patients entered the study. An adequate response to ESHAP was obtained in 13 patients, and sufficient stem cells for grafting were obtained in eight of the 12 patients who underwent the collection procedure. Six of these grafted patients are alive in complete clinical remission a median of 30 months after transplantation. It should be noted that we were only able to graft 40% of the patients enrolled in this study, either because a new remission could not be obtained or because not enough hematopoietic stem cells could be collected. This argues for stem cell collection as soon as a first remission is obtained, even if the autograft is done later in the course of the disease. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Attempts to improve the efficacy of pretransplant conditioning regimens have been published, the potential of a better antileukemic effect being impaired by more frequent and severe toxicities. The efficacy of an intensified regimen, TAM (TBI, high-dose cytosine arabinoside and melphalan), is evaluated by analyzing long-term follow-up of a homogenous group of 42 high-risk ALL patients allografted in first CR. Age at time of BMT was 25.9 ± 10.4 years (3–41). Twenty-two patients had more than three adverse prognostic factors. Ten patients had a Ph chromosome. Probability of overall survival was 45 ± 9%, and for all surviving patients median follow-up time was 66 months. Event-free survival was 40 ± 8% at 7 years after transplantation and the expected relapse rate reached 31%. Twenty-two deaths occurred, six after a relapse but 16 appeared to be directly due to the BMT procedure. None of the pretransplant characteristics significantly affected outcome after BMT. TAM appeared to be an efficient antileukemic therapy for conditioning high-risk ALL patients before allogeneic transplantation, but was still very toxic. The use of TAM in adult ALL patients in first CR is not recommended and the real role of intensified conditioning regimens remains to be demonstrated. [ABSTRACT FROM AUTHOR]

Mice homozygous for a SCID mutation (SCID mice) are severely deficient in T and B lymphocytes. The absence of effector T and B cells has encouraged investigators to attempt engraftement of SCID mice with human fetal tissues, mature lymphocytes, hematopoietic progenitors and tumors. SCID mice can be reconstituted with human lymphocytes and are of interest for studying normal and abnormal lymphocyte development and function. SCID mice are also providing an in vivo model of infectious diseases. In addition, SCID mice readily support normal and pathologic human hematopoiesis differentiation and is useful for testing innovative hematological disease therapy. SCID mice with a fully functionnal human immune or hematopoietic system therefore seem to be extremely valuable for biomedical research. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) transplantation, whatever its conditions, is associated with an increased risk of infections and tumoral complications, because of a delayed immune reconstitution. T-cell regeneration has been mostly investigated and appears to come more from graft and/or host mature T-cells, rather than from the differentiation/maturation of reinfused progenitors. In allogeneic setting, the immune defect is enhanced by the immune host/donor conflict and the use of prophylactic or curative immunosuppressive therapy. The tools used for studying post-transplant immunity are the following: immunophenotyping (kinetics and alterations of lymphocyte subset reconstitution), functional studies of T cell proliferation, cytokine production, cytotoxicity and signal transduction, as well as studies of T cell repertoire diversity. The CD4/CD8 cell immunophenotyping might be enough for routine clinical evaluation, allowing an adapted prophylaxis of opportunistic infections in those immune-suppressed patients, while functional assays might be useful to evaluate the persistence overtime of defects in immune reconstitution. These overall assays are useful both for basic and clinical research and allow better understanding in the mechanisms for T cell regeneration in the diverse types of HSC transplants performed nowadays particularly after graft of purified HSC where immune reconstitution remains a key question. [ABSTRACT FROM AUTHOR]

Timed sequential chemotherapy (TSC) combining mitoxantrone on days 1–3, etoposide on days 8–10 and cytarabine on days 1–3 and 8–10, was administered to 240 patients with advanced acute myelogenous leukemia (AML). Sixty one percent of patients, with a 95% confidence interval (CI) ranging from 54 to 67%, achieved complete remission (CR), including 47% (CI: 38–55%) of refractory patients and 78% (CI: 70–86%) of late first relapse patients (p < 0.0001). Thirty percent of patients did not respond to therapy and 9% died from toxicity. Median duration of neutropenia was 32 days and of thrombocytopenia 29 days. Severe non hematologic toxicity included sepsis in 45% of patients and mucositis in 27%. Post-remission therapy varied but included maintenance chemotherapy in most patients, a second course of TSC in 27, autologous stem cell transplantation in 17 and allogeneic transplantation in 20. Median survival of patients who were not transplanted was 7 months with 13% (CI: 7–19%) survival at 5 years. Median disease-free survival (DFS) was 9 months with 13% (CI: 6–20%) DFS at 5 years. Previous refractoriness was the main factor associated with poor prognosis for achieving CR, DFS and survival in a multivariate analysis. There was no difference in DFS between patients receiving the different modalities of intensive post-remission therapy. These results confirm initial reports on TSC and show that some patients with first relapse off therapy can enjoy prolonged DFS using chemotherapy only. [ABSTRACT FROM AUTHOR]

Major expansions of CD8hi+CD57+ T lymphocytes frequently occur during human immunodeficiency virus (HIV) infection and after transplantation. To investigate mechanisms of such cell expansion, we compared the activation and functional status of CD8hi+CD57+ and CD57- peripheral blood lymphocytes (PBL) from normal, bone marrow transplantation (BMT) and HIV+ donor. The CD8hi+CD57+PBL from BMT and HIV+ donors preferentially displayed CD38 and HLA-DR activation markers without correlation between CD8hi+CD57+ percentages and HIV load, the CD45RA+ isoform in all ex vivo conditions but acquired CD45RO after in vitro expansion, CD11b and CD11c in BMT and HIV+ donors but decreased expression of CD62-L, VLA-2 and VLA-6. The CD8hi+CD57+ cells were positive for perforin and granzyme B and spontaneously mediated cytolytic activity in a CD3-redirected assay. In contrast the inhibitor of cytolytic functions (ICF) produced by CD8hi+CD57+ cells down-modulated the CD3-redirected cytolytic activity but only at low levels of CD3 cross-linking. While CD3-triggering induced a low, if any, short-term proliferation of CD8+CD57+ cells, this subset could be amplified after long-term stimulation either with mitogens or with HIV antigens, thereby enriched in HIV-specific T cells producing tumor necrosis factor-α. Altogether these data suggest that CD8hi+CD57+ cells represent a terminal differentiation state of activated effector cytotoxic T lymphocytes which are enriched in antigen-specific T cells and down-modulate their own cytolytic potential, thus participating in a negative control of effector cell functions during persistent viral infections or transplantations. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented on a case study of new chromosomal abnormality in Waldenstrom's macroglobulinemia.

Presents a letter to the editor on the relation between acute erythroleukaemia and RAEB-t.