Árpád Szomor

The addition of rituximab to anthracycline‐based chemotherapy significantly improves outcome in ‘Western’ patients with intravascular large B‐cell lymphoma

Some case reports and a Japanese series suggest benefit from the use of rituximab in patients with intravascular large B‐cell lymphoma (IVL). Rituximab efficacy was evaluated in Western patients with IVL, comparing outcome of 10 patients treated with rituximab + chemotherapy (R‐CT) and of 20 patients treated with chemotherapy alone (CT). There were no significant differences in patients’ characteristics between the two subgroups. The addition of rituximab was associated with improved complete remission rate (90% vs. 50%; P = 0·04), event‐free survival (3‐year: 89% vs. 35%; P = 0·003) and overall survival (3‐year: 89% vs. 38%; P = 0·01). In conclusion, rituximab may substantially change the dismal prognosis of IVL.

In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient’s burden

This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ±s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 μg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient’s burden in MM transplant patients.

Penile chloroma in a patient with secondary acute myeloid leukemia

To the Editor: A 52-yr-old man was diagnosed as having secondary acute myeloblastic leukemia (AML), transformed from myelodysplastic syndrome. After achieving a partial remission with ‘3+7’ chemotherapy on the sulcus coronarius penis he developed a red, painful lesion. Initially it was treated as a superficial inflammation. As it did not improve, a biopsy was made and the histological result showed a chloroma (granulocytic sarcoma). There was a diffuse infiltration of variable pattern of blast cells, with a dispersed chromatin and smallto mediumsized nucleoli and more matured myeloid progenitor cells which were positive on chloroacetate esterase staining and showed very intense positivity with the Kp1 antibody reaction. Systemic antileukemic chemotherapy (mitoxantrone – cytosine arabinoside) and local irradiation was initiated. The lesion became smaller, but did not disappear. The patient died of septic shock. An autopsy revealed deep chloroma infiltration of the penis (Fig. 1). Most patients with AML have a short survival following the appearance of chloroma. The incidence of granulocytic sarcoma is 3–5% of patients with AML. It has been demonstrated on almost every part of the body. To our knowledge penile chloroma has not previously been described.

Intravascular lymphomatosis of the nervous system

Sirs: Intravascular lymphoma (IVL) is a rare and aggressive variant of diffuse large cell lymphoma [1–3]. Its rarity (one person per million), multiplicity of presentations, and absence of lymphoma cells in the reticuloendothelial system complicate early diagnosis [2– 5]. Most of IVL belong to systemic diffuse large B cell lymphomas (DLBCL), but aberrant expression of integrins prohibits extravasal migration [6]. Multifocal cortical and subcortical T2 hyperintense lesions were observed on the MRI of the brain (Fig. 1 A and Table 1). CSF showed albumino-cytological dissociation. Stereotactic brain biopsy revealed IVL. Cells displayed an activated B cell phenotype profile on immuno-staining (CD20+, MUM1+, Bcl-6+ and CD10–) (Fig. 1 B). In situ hybridiza-

Intravascular lymphoma presenting with neurological signs but diagnosed by prostate biopsy: suspicion as a key to early diagnosis

Dear Sir, Intravascular lymphoma (IVL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) characterized by neoplastic cells within the blood vessel lumina and occlusion of small vessels in different tissues [1,2]. The majority of the patients are presented with prominent or exclusive neurological symptoms [2–5]. Given its rarity (incidence: 1/1 million), the variety of clinical presentations and the absence of lymphoma cells in the rethiculo-endothelial system, early diagnosis is difficult, but critical for survival [2–7]. As diagnosis is provided by pathological examination of the affected tissues, particularly brain, a high index of suspicion is required. A 64-year-old man was admitted with a week history of subfebrility, dizziness and progressive confusional state. On physical examination, lymph nodes, liver and spleen were not palpated. There were no skin lesions. Body temperature was 37.8 C, blood pressure was 130/80 mmHg and pulse was 82/min with sinus rythm. Neurological examinations revealed acute confusional state, delirium with acustic and visual hallucinations and repeated, transient left-sided hemiparesis. Serum LDH (1393 U/l) and high-sensitive Creactive protein levels were elevated (hsCRP, 16.3 mg/l). Thrombocytopenia was found (82.7 · 10 platelets/l) but hemoglobin concentration was normal (135 g/l). Other blood sample tests were unremarkable including tumor, markers (PSA: 2.2 lg/l, CEA: 1.1 ng/ml; AFP: 1.1 lg/l; CA-125: 9 U/ml; CA-15-3: 15 U/ ml; CA-19-9: 3.8 U/ml) and systemic antibodies (ANA screen: 2.4 IU/ml; antidsDNA: 5.2 IU/ml; ANCA MPO3, PR3 IgG screen negative; anti-cardiolipin IgM, IgG screen negative; anti-B2-glycoprotein IgM, IgG screen negative; anti-phosphatidyl serine IgG: 4.0 U/ml, IgM: 0.7 U/ ml). Neuroimaging was performed twice. Following a negative cranial CT examination (slide thickness 4,5 mm, axial slice by slice mode with a Somatom Sensation 16 machine, Siemens, Germany), magnetic resonance imaging (MRI) of the brain did not indicate either signal alteration or enhancement (axial T2 turbo spin echo, TR: 6000 ms, TE: 93 ms, echo train: 18; coronal FLAIR, TR: 9000 ms, TE: 93 ms, echo train: 16; sagittal T1 gradient echo, TR: 440 ms, TE: 2.5 ms and diffusion-weighted ADC sequences, b = 0, b = 500, b = 1000 with 4 mm slide thickness performed by Siemens Trio Tim 3.0 T MRI machine, Erlangen, Germany) (Fig. 1a). Protein content of the cerebrospinal fluid was increased (1.2 g/l) but pathological cells and oligoclonal bands examined by isoelectric focusing were not found. Based on the clinical picture and laboratory abnormalities, IVL was suspected. As MRI was negative, abdominal and pelvic CT were performed to search for extracerebral manifestations. Enlarged adrenal glands and inhomogenously enhancing enlarged prostate gland suggested malignancy (Fig. 1b and c). Transrectal ultrasound guided prostate needle biopsy revealed large atypical lymphoid cells in the small venules and capillaries. After endogenous peroxidase blocking, slides were incubated with antibodies against CD3 (Dako, pre-diluted; Glostrup, Denmark), CD10 (Novocastra, 1:75; Newcastle, UK), CD20 (Novocastra, 1:400), Bcl-6 (Dako, 1:10), MUM1 (Dako, 1:30), GFAP (Bio-Genex, 1:750; San Ramon, CA, USA). The antibodies were visualized in an automated immunostainer (Ventana Medical System, Tucson, AZ, USA). Lymphoma cells were positive for CD20, MUM1, MIB-1 indicating an activated B-cell-like (ABC) phenotype (Fig. 1d). The first cycle of rituximabCHOP treatment (R-CHOP) resulted in resolution of neurological signs and normalization of laboratory parameters (LDH, CRP, platelet count). The patient has been in clinical remission for 5 months. The fever, mental state and transient neurological signs together with elevated LDH, hsCRP and thrombocytopenia were highly suggestive of IVL [2,4,6,7]. Increased protein in the CSF was also characteristic [4,6,7]. In the present case, MRI was negative despite of the clinical symptoms and signs. Brain MRI most often discloses signal alterations suggestive of small vessel ischemia or demyelination providing a site for stereotactic biopsy in IVL patients with neurological signs [6–8]. Cranial MRI may disclose non-specific hyperintense white matter lesions but are rarely normal in IVL [9–11]. Our recent case series indicated heterogeneous neuroimaging results in IVL, which may complicate diagnosis [7]. The negative MRI findings may be explained by incomplete and transitory obliteration of the small vessels. In the present case, the absence of signal alterations on MRI hindered brain biopsy. Therefore, search for extracerebral manifestations as potential biopsy sites was crucial to establish diagnosis. Abdominal CT was performed, which disclosed enlarged adrenal glands, a possible manifestation of IVL [7,8]. In addition, enhancement in the prostate, whilst PSA was normal, also suggested IVL rather than cancer, and provided a convenient site for biopsy. Rare case reports of IVL and large series of malignant lymphoma cases involving the prostate gland suggest that the diagnosis of solitary lymphoma or infiltration by a systemic lymphoma has to be taken into account if the PSA value is in the normal range [12– 17]. Prostate involvement has previously been described only in a few cases of intravascular B-cell lymphoma. In contrast to our case, the patients were referred to urology department due to lower urinary tract obstruction in those cases. Only a single patient presented neurological signs as well indicating lesions in the spinal cord [15–17]. In a review of 81 cases, prostate gland was not amongst diagnostic sites for in vivo diagnosis, indicating the rarity of prostate involvement [18]. In a recent review of eight neurological cases, no involvement of the prostate gland has been described [4]. In our recent case series, prostate gland was not affected [7]. Diffuse, CD20+ large B-cell lymphomas are known to be morphologically and immuno-phenotypically heterogeneous and can be divided into subtypes based on the expression of the late stage of B-cell

Changes in adhesion molecule expression and function in B-cell chronic lymphocytic leukaemia after in vitro interferon-α stimulation

Abstract:  Peripheral blood mononuclear cells (PBMCs) from 10 B‐CLL patients were investigated after 24 hours of in vitro interferon‐α (IFN‐α) stimulation. The constitutional expression of the L‐selectins (LECAM‐1), LFA‐1/CD11a, VLA α‐4/CDw49d and ICAM‐1/CD54 adhesion molecules was detected, and changes in their density after IFN‐α stimulation were compared to results obtained by the high endothelial venule (HEV)‐binding assay and a carbohydrate (phosphonomannan core polysaccharide: PPME and fucoidin) immobilization test. The LECAM‐1 and ICAM‐1 molecules were expressed on the great majority of CLL cells, while the LFA‐1 and VLA‐4 α‐chains were expressed by only a small number of cells. Statistically significant changes (p< 0.001) were observed in LECAM‐1 antigen density (changes in mean cell fluorescence), as well as in functional tests (HEV‐, PPME‐ and fucoidin‐binding; p<0.01) after in vitro IFN‐α stimulation. Based on a prior study (Jewell et al., Leukemia 1992: 6: 400–404) and on the present findings, not only an increased expression but also an enhanced function of the L‐selectins seem to be well substantiated after IFN‐α stimulation, which may explain the therapeutic effect of IFN‐α in reducing the accumulation of leukaemic B cells in the blood. The remarkably high expression of ICAM‐1 in this series necessitates further studies to clarify the exact expression rate and role of this molecule.

Primary bone marrow T-cell anaplastic large cell lymphoma with triple m gradient

We present a case of a 60-year-old male patient with primary bone marrow anaplastic large cell lymphoma. He was admitted to the hospital with the symptoms of anemia and fever. There was no evidence of lymphadenopathy or splenomegaly. Immunoelectrophoresis showed the presence of a triple M gradient (double IgM and an IgG), with the IgG and one of the IgM paraproteins functioning as a cryoglobulin. The patient had no hepatitis C virus infection. Bone marrow biopsy showed massive CD30-positive, ALK-negative large lymphoid cell infiltration of T-cell origin with anaplastic morphology. PCR analysis of lymphoid cells separated from the bone marrow demonstrated the presence of a B/T hybrid genotype disorder with no evidence of the t(2;5), nor t(1;2) translocations. The patient entered a period of remission following CHOP chemotherapy. The patient subsequently died of sepsis as a consequence of serious humoral immunodeficiency.

Genotypic analysis in primary systemic anaplastic large cell lymphoma

This report presents an experience of polymerase chain reaction (PCR) analysis of T-cell receptor γ- and β gene (TCR γ, TCR β), and immunoglobulin heavy chain (IgH) gene rearrangements in 9 cases of primary systemic anaplastic large cell lymphoma. We showed 2 clonal IgH, 2 TCR γ 1 TCR β rearrangements. The genotype was B/T-cell in 1, T-cell in 1, B-cell in 1 and null cell-type in 6 cases. We used reverse transcriptase PCR (RT-PCR) to detect t(2;5)(p23;q35) and t(l;2)(q25;p23) translocations. T(2;5) translocation was demonstrated in 2 cases, there was no t(l;2) translocation. In most cases the molecular genetic results were found to be in agreement with immunophenotypic data.

Factitious hyperkalemia in hematologic disorders

Hyperkalemia is a potentially lethal condition leading to fatal cardiac arrhythmias or asystole. After its urgent confirmation, immediate treatment is essential. Conversely, treatment of factitious hyperkalemia – where the measured potassium concentration does not reflect properly the actual potassium homeostasis of the patient – is unnecessary and may even have lethal consequences. Therefore, upon measuring elevated potassium concentration of a patient, distinction between true and factitious hyperkalemia is crucial. Hematologic disorders are often associated with distinct types of factitious hyperkalemia (pseudohyperkalemia or reverse pseudohyperkalemia). However, in spite of numerous reports, these conditions remain frequently unrecognized. In this letter, we present a case of thrombocytosis-associated pseudohyperkalemia to emphasize its clinical importance. Furthermore, we summarize distinct mechanisms behind factitious hyperkalemia in different hematologic conditions, overview their frequencies and propose a diagnostic algorithm to help their early recognition. Additionally, utility of ECG in recognizing factitious hyperkalemia is also discussed.

Autológ haemopoeticus őssejt-transzplantáció szerepe T-sejtes lymphomában. Magyar adatok

T-cell lymphoma is a poor prognostic hematological malignancy. The generally used - not sufficiently effective - induction chemotherapy should be improved with consolidative autologous hemopoetic stem cell transplantation. The authors describe the role, place and effectiveness of transplantation in this disorder. One hundred thirty three autologous stem cell transplantations were performed in the last 22 years in Hungary. Detailed results are available from the last 6 years. In this period 43 transplantations were carried out in 4 Hungarian centers. Carmustine-etoposide-cytosine arabinoside-melphalan (BEAM) conditioning regimen was used in 95%. The transplantation was done mainly in complete remission (84%), 1 year after transplantation 65% of patients were still in complete remission. Eleven patients died, 82% of them have progressive disease. Brentuximab vedotin has already proved the effectiveness, several other chemoterapeutics, monoclonal antibodies, kinase inhibitors are under investigation. In certain cases allogeneic stem cell transplantation has real indication among therapeutic options. Orv Hetil. 2017; 158(41): 1615-1619.Absztrakt: A T-sejtes lymphoma rossz prognozisu hematologiai malignitas. Az altalanossagban alkalmazott – nem kellően hatekony – indukcios kemoterapiat javitani lehet konszolidativ autolog haemopoeticus őssejt-transzplantacioval. A szerzők ismertetik az autolog atultetes szerepet, helyet, hatasossagat ebben a betegcsoportban. Az elmult 22 ev alatt Magyarorszagon 133 autolog atultetest vegeztek T-sejtes lymphomaban. Reszletesebb adatok hat ev transzplantacios eredmenyeiről allnak rendelkezesre. Ebben a periodusban 43 atultetes tortent a negy magyar centrumban kozel azonos esetszamokkal. Kondicionalo kezeleskent 95%-ban carmustin-etoposid-cytosin arabinosid-melphalan (BEAM) semat hasznaltak. Az esetek dontő tobbsegeben komplett remisszioban tortent az atultetes (84%), a beavatkozas utan egy evvel a betegek 65%-a volt komplett remisszioban. Tizenegy beteg halt meg a vizsgalt periodusban, 82%-uk alapbetegseg progressziojaban. Az uj szerek kozul a brentuximab vedotin mar bizonyitotta hatasossagat, szamos egyeb...