European Journal of Haematology

The physiology of B cells is intimately connected with the function of their B‐cell receptor (BCR). B‐cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre‐existing pathway for B‐cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR‐associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of ‘chronic’ or ‘tonic’ BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP‐1, SHP‐1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF‐κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the ‘BCR inhibitors’ target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

Abstract:  The permeability of red blood cells (RBCs) to thiol containing compounds, reduced glutathione (GSH) and N‐acetyl cysteine (NAC), has been studied in control adult and neonatal cells and after oxidative stress. NAC penetrates the cell membrane easily while GSH hardly permeates. We measured their capacity to enhance intracellular non‐protein thiols (NPSH), after inducing damage to the membrane by formation of defects. Diamide, phenazine methosulfate (PMS) and t‐butyl hydroperoxide (BHP) were chosen as exogenous oxidants, each inducing damage by a different mechanism. Our data indicate that although neonatal cells are more sensitive to oxidative stress, only membrane damage induced by diamide, renders adult and neonatal cells permeable to GSH. NAC treatment enhances thiol levels in cells exposed to oxidizing agents, as well as in control cells.

We examined the incidence and prognostic effect of IDH1 and IDH2 mutations in 233 Japanese adults with acute myeloid leukemia (AML). IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%, 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were associated with normal karyotype AML, cytogenetic intermediate‐risk group, and NPM1 mutations. Five‐year overall survival (OS) rates were significantly lower (15.6%) in patients harboring the IDH mutations than in patients lacking the IDH mutation (32.0%) in the entire cohort of AML (P = 0.005). Among patients aged 59 yr or younger with IDH mutations, 5‐yr OS in patients who underwent allogeneic stem cell transplantation (SCT) was significantly higher than that in those not receiving allogeneic SCT (50% vs. 10.6%, P = 0.020). Of 51 patients with NPM1 mutations, there was no significant difference in 5‐yr OS rates between patients with and those without the IDH mutations. In contrast, among 175 patients lacking the NPM1 mutations, 5‐yr OS rate in patients with IDH mutations was significantly lower than that in those without IDH mutations (0% vs. 34.7%, P = <0.001). These data suggest that IDH mutations have an unfavorable effect in AML, especially AML with the NPM1 wild type and younger AML patients with IDH mutations may benefit from allogeneic SCT.

Tóm tắt:  Mục tiêu: Đánh giá tình trạng tim mạch ở một nhóm lớn bệnh nhân thalassemia nặng đã được điều trị theo cách tiêu chuẩn từ khi còn nhỏ với liệu pháp truyền máu tích cực và chelat deferoxamine, những người có tuân thủ tốt phác đồ điều trị này. Phương pháp và Kết quả: Chúng tôi đã tiến hành đánh giá lâm sàng và siêu âm tim cho 202 bệnh nhân thalassemia nặng tuổi trung bình 27,3 ± 6,3 năm và 75 đối chứng khỏe mạnh cùng tuổi và giới tính. Bệnh tim mạch biểu hiện rõ đã được phát hiện ở 14 bệnh nhân (6,9%), trong đó có 5 bệnh nhân (2,5%) bị suy tim sung huyết, tuổi từ 26–37 năm, và 9 bệnh nhân bị rối loạn chức năng tâm thu thất trái (LV), tuổi từ 23–37 năm. Mười bệnh nhân (5,0%) có tiền sử viêm màng ngoài tim. Đường kính tâm nhĩ trái và LV, khối lượng LV và lưu lượng tim đều cao hơn đáng kể ở bệnh nhân so với các đối chứng, trong khi kháng lực ngoại vi và gánh nặng thất trái (afterload) thấp hơn đáng kể. Độ dày thành LV tương đối không khác nhau giữa bệnh nhân và đối chứng, nhưng giảm đáng kể ở các bệnh nhân có bệnh tim mạch biểu hiện rõ so với những người không có (P < 0,05). Sự lấp đầy LV có tính hạn chế được quan sát thấy ở 37,6% bệnh nhân và thường gặp hơn ở những trường hợp có bệnh tim mạch biểu hiện rõ (P < 0,01). Tăng huyết áp phổi hầu như không có. Các thông số huyết học và mức áp lực động mạch phổi không có liên quan độc lập với sự hiện diện của bệnh tim mạch biểu hiện rõ. Kết luận: Tuân thủ nghiêm ngặt phác đồ truyền máu và liệu pháp deferoxamine suốt đời đáng kể giúp giảm nguy cơ suy tim, rối loạn chức năng LV và viêm màng ngoài tim, ngăn ngừa suy tim sớm và tăng huyết áp phổi, nhưng không loại bỏ hoàn toàn bệnh tim mạch ở bệnh nhân thalassemia nặng.

Objectives:  To evaluate the prognostic value of absolute lymphocyte count (ALC) at diagnosis in patients with diffuse large B‐cell lymphoma (DLBCL).

Methods:  In a large cohort of patients with DLBCL treated with CHOP (n = 119) or RCHOP (n = 102) in our institution, we evaluated the prognostic value of ALC at diagnosis with regards to treatment response, overall (OS) and progression‐free survival (PFS). Use of rituximab, all International Prognostic Index (IPI) determinants, β2microglobulin level, presence of B symptoms or bulky disease, and ALC were evaluated.

Results:  Low ALC (<1.0 × 10⁹/L) was associated with advanced stage, performance status ≥2, elevated lactate dehydrogenase, number of extranodal involvement ≥2, B symptoms, elevated β2microglobulin and higher IPI risk group. Low ALC was associated with lower CR rate by univariate analysis (odds ratio = 3.29, P = 0.024) but not by multivariate analysis. By univariate analysis using Cox proportional hazard model, low ALC was associated with shorter OS [hazard ratio (HR) = 2.89, P < 0.001] and PFS (HR = 2.91, P < 0.001). Multivariate analysis revealed that low ALC was associated with shorter OS (HR = 2.51, P = 0.003) and PFS (HR = 2.72, P < 0.001), independent of above‐mentioned parameters. Subclass analyses revealed that the use of rituximab improves OS in patients with low ALC (HR = 0.42, P = 0.05) but not in those with high ALC (HR = 0.83, P = 0.71). This observation was most obvious in patients with higher IPI score.

Conclusion:  Low ALC is a poor prognostic marker in patients with DLBCL and suggests patients’ survival benefit from rituximab.

Abstract: A patient who developed myasthenia gravis (MG) 25 months after allogeneic bone marrow transplant was immunologically analyzed. OX40⁺CD4⁺ T cells in the peripheral blood prominently increased one month before the onset of MG. CD4/CD8 ratios, usually abnormally inverted in patients with chronic graft‐vs.‐host disease (cGVHD), showed pseudonormalization during the course of MG. We succeeded in uneventful rapid tapering of prednisolone (PSL) using mycophenolate mofetil (MMF). Monitoring of OX40⁺CD4⁺ T cells supported the tapering of PSL and MMF as a marker of cGVHD activity. This case suggested the utility of MMF and monitoring of OX40⁺CD4⁺ T cells in the management of cGVHD‐associated autoimmune diseases.

Background and objective:  The characteristic chromosomal translocation t(9;22)(q34;q11) in chronic myeloid leukaemia (CML) mainly results in the two different BCR/ABL fusion transcripts b2a2 or b3a2. Both transcript variants can occur simultaneously due to alternative splicing of the b3a2 transcript. Conflicting results have been reported on the influence of the transcripts on haematological findings at diagnosis and the course of the disease in adults while data concerning these topics on childhood CML are still missing. This paper reports on a correlation of BCR/ABL transcript variants with patients’ characteristics in childhood CML.

Design and methods:  Transcript types were determined in 146 paediatric patients with CML enrolled in trial CML‐paed‐I. Fifty‐five patients (38%) expressed b2a2, 53 patients (36%) b3a2 and 38 patients (26%) both transcripts, respectively. These findings were correlated with patients’ characteristics (sex, age, WBC, Hb, platelet count, hepatosplenomegaly, etc.) assessed at diagnosis.

Results:  While the co‐expression of both transcripts was evenly distributed among genders [b2a2 + b3a2: 22 females (28%), 16 males (24%)] a highly significant difference (P = 0.007) was found concerning the expression of the b2a2 transcript [34 male (51%) vs. 21 female (27%)] and vice versa of the b3a2 transcript [17 male (25%) vs. 36 female (45%)]. High platelet counts and the combination of high platelet counts in conjunction with pronounced leukocytosis were observed more often in patients expressing the b3a2 transcript.

Conclusions:  These findings demonstrate that in children like in adults specific BCR/ABL transcript types present at diagnosis are associated with distinct haematological alterations (e.g. a high platelet count with the transcript b3a2). However, the sex‐dependent skewed distribution of the BCR/ABL transcript types observed so far in this paediatric cohort only deserves further investigation.

Abstract: The purpose of the present study was to analyse the importance and prognostic value of renal failure in multiple myeloma patients. The frequency and reversibility of renal failure in 775 multiple myeloma patients diagnosed between 1984–86 and 1990–92 in the Nordic countries were studied. Renal failure, defined as plasma creatinine >130μmol/l, was observed in 29% of the cases at the time of diagnosis. During the first year after diagnosis 58% achieved normalisation of p‐creatinine, and this was achieved mainly during the first 3 months. Reversibility of renal failure was more frequently observed in patients with moderate renal failure, hypercalcaemia and low Bence‐Jones protein excretion. In a multivariate analysis renal failure, high age, stage III disease and hypercalcaemia were independent prognostic factors for survival. Patients who needed dialysis had a poor prognosis, with a median survival of 3.5 months. A 12‐months landmark analysis showed that reversibility of renal failure was a more important prognostic factor than response to chemotherapy. It is concluded that renal failure in multiple myeloma is reversible in about half the cases, and reversibility of renal failure improves long‐term survival.

Abstract:  Objective: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome‐positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). Methods: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty‐one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total‐body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose‐reduced conditioning with fludarabine‐based regimens. Results: The incidence of grades II–IV and III–IV graft‐versus‐host disease was 66% and 38% respectively. The probability of overall survival (OS), disease‐free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non‐relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine‐based conditioning therapy, age ≥40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. Conclusion: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant‐related mortality.