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The guideline group was selected to be representative of UK-based medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2013 under the heading: ‘tumour lysis syndrome’. The writing group produced the draft guideline. Review of the manuscript was performed by the British Committee for Standards in Haematology, BCSH Haemato-oncology Task Force, BCSH Executive Committee and by the haemato-oncology sounding board of the British Society for Haematology (BSH). This comprises over 50 members of the BSH who have reviewed the guidance and commented on its content and applicability in the UK setting. It has also been reviewed by representatives from Leukaemia and Lymphoma Research but they do not necessarily approve or endorse the contents. The ‘GRADE’ system was used to quote levels and grades of evidence (www.bcshguidelines.com). The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with tumour lysis syndrome (TLS). The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. First described by Bedrna and Polcák (1929) in patients with chronic leukaemia treated with radiotherapy, tumour lysis syndrome (TLS) is a metabolic syndrome caused by the breakdown of malignant cells. It is characterized by hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. The consequences are potentially severe and include acute kidney injury, cardiac arrhythmias, seizures and even death (Will & Tholouli, 2011). TLS can affect patients of all ages, typically in the first few days after the start of chemotherapy. TLS has also been observed in patients with haematological malignancies given radiotherapy (Yamazaki et al, 2004), steroids (Sparano et al, 1990; Coutinho et al, 1997), immunotherapy (Yang et al, 1999) and as spontaneous TLS secondary to the high turnover of the tumour itself (Jasek & Day, 1994). TLS is caused by the excessive release of nucleic acids, proteins and intracellular metabolites from tumour cells, which overwhelms the normal homeostatic control mechanisms and leads directly to increases in plasma uric acid, phosphate, potassium and a reduction in plasma calcium (Locatelli & Rossi, 2005). TLS is particularly likely to occur during induction chemotherapy when there is high tumour burden and tumour cells have a particularly high rate of cell turnover and an increased sensitivity to antimitotic agents. Other factors may also increase the risk of developing TLS, including an elevated serum lactate dehydrogenase (LDH) level, extensive bone marrow involvement, pre-existing renal disease or reduced urinary output (Ribiero & Pui, 2003; Davidson et al, 2004). There is some evidence that elderly patients may be at increased risk (Locatelli & Rossi, 2005). In a minority of patients the metabolic derangements are already present before the start of treatment, most often in patients with B-cell non-Hodgkin lymphoma (B-cell NHL), particularly Burkitt leukaemia and lymphoma and acute lymphoblastic leukaemia (ALL) (Jasek & Day, 1994; Alkhuja & Ulrick, 2002; Hsu et al, 2004). In some cases TLS develops unexpectedly in patients presenting with apparently low TLS-risk malignancies. Definitions of TLS have evolved for both adults and children over the last two decades. Patients may have metabolic abnormalities alone (laboratory TLS) or both laboratory and clinical problems (clinical TLS). In many cases laboratory TLS will herald clinical TLS, though clinical TLS can be prevented in many patients with appropriate therapy. The Cairo-Bishop definition of TLS (Cairo & Bishop, 2004) is shown in Table 1. It can be seen from the table that the laboratory syndrome is defined by specific electrolyte abnormalities immediately before, during or just after treatment for malignancy. The clinical syndrome is manifest by the development of organ failure or other symptoms caused by the electrolyte imbalance. There has been some debate with regard to the importance or otherwise of the criteria for definition based on 25% changes from baseline. It is, in our opinion, fair to say that these individual calculations are not usually performed by clinicians. Nonetheless, the importance of monitoring and responding to the trajectory of any change in electrolyte balance is absolutely fundamental to good management and dictates the frequency of monitoring as well as therapeutic interventions. The metabolic effects of TLS are caused by the release of intracellular potassium, phosphate and nucleic acids, the catabolism of which produces large amounts of excess uric acid. In patients with a high tumour burden, the normal homeostatic mechanisms for dealing with the release of cellular contents from dying cells are often overwhelmed, causing laboratory and then clinical TLS. The first observed effect of TLS is often hyperkalaemia. This can occur as quickly as 6 h after the start of chemotherapy and may be severe enough to be immediately life threatening (Flombaum, 2000; Locatelli & Rossi, 2005). Simultaneously, as a direct consequence of hyperuricaemia, uric acid crystals precipitate out in the renal tubules, particularly in the acid environment of the distal renal tubules, causing a reduction in the ability of the kidneys to excrete the products of cellular disruption (Will & Tholouli, 2011). Renal function becomes further compromised when the released phosphates increase the plasma phosphate concentration and calcium phosphate begins to crystallize out in the soft tissues, including in the renal tract. The development of acute kidney injury causes further increases in plasma potassium levels and the consequent acidosis accelerates the crystallization of uric acid in the renal tubules (Jones et al, 1995); at this point the situation spirals out of control, causing a cascade to clinical TLS. Whilst clinical TLS is a relatively rare event, affecting around 3-6% of patients with high-grade tumours, the consequences are significant, with one-third of affected patients requiring dialysis and an overall mortality rate in excess of 15% being reported (Annemans et al, 2003; Candrilli et al, 2008). The key to the management of TLS is recognizing those patients at risk of developing the syndrome and using prophylactic measures to prevent its occurrence. It will be difficult, however, to completely eradicate TLS, as a small proportion of patients with very aggressive tumours develop spontaneous TLS prior to receiving any therapy (Galardy et al, 2013). In the UK, two drugs are licensed for the prevention and management of clinical TLS: the oral xanthine oxidase inhibitor, allopurinol; and the exogenous recombinant urate oxidase, rasburicase. Allopurinol is a xanthine oxidase inhibitor. It reduces the production of uric acid by decreasing the rate of the conversion of hypoxanthine to xanthine and xanthine to uric acid (Fig 1). Because both hypoxanthine and xanthine are relatively more soluble than uric acid, this reduces the formation of uric acid crystals in the renal tubules, particularly in the distal tubules where the more acid environment encourages uric acid to precipitate as insoluble urate salts (Hande et al, 1981; Pui et al, 2001). Importantly, it does not increase the rate of breakdown of any uric acid that has already been formed and so its therapeutic effect is delayed by 24–72 h (de Bont & Pieters, 2004; Rampello et al, 2006). Rasburicase is a recombinant form of the enzyme urate oxidase (UO). Urate oxidase is an endogenous enzyme commonly found in most mammalian species, but not humans as a consequence of the acquisition of a nonsense mutation in the coding region during hominoid evolution (Yelandi et al, 1991). Rasburicase metabolizes urate to allantoin (Fig 1), a substance that is approximately five to ten times more soluble than uric acid (Brogard et al, 1972; Pui, 2002). Rasburicase acts immediately, even on already formed urate. It is extremely effective and will reduce the plasma levels of uric acid within 4 h of its intravenous administration, allowing chemotherapy to be started earlier than might be safe with allopurinol (Pui et al, 2001). Given these respective mechanisms of action, where rasburicase is being used in the treatment or prophylaxis of TLS, the addition of allopurinol is unnecessary and has the potential to reduce the effectiveness of rasburicase. The international expert consensus panel (Cairo et al, 2010) have produced an excellent model to allow stratification of patients into 3 main categories: those at low, intermediate or high risk of TLS development. Cairo et al (2010) recommended that those at low risk of TLS development be actively monitored and offered hydration +/- allopurinol prophylaxis. Those at intermediate risk of TLS development were recommended to be offered active monitoring, hydration and allopurinol prophylaxis. Those at high risk of TLS development were recommended to be offered active monitoring, hydration and rasburicase prophylaxis. To our knowledge, there have been no additional publications that fundamentally impact the model proposed by Cairo et al (2010). The issue that seems, to our group, most important to address in these current guidelines is which patients are at high enough risk of TLS to warrant administration of rasburicase. We would therefore propose that high-risk patients are identified early as distinct from those requiring hydration +/- allopurinol only. Patients fulfilling the criteria for high-risk disease should generally be offered a schedule of monitoring and prophylaxis that includes the use of rasburicase. Patients who do not fulfil these criteria should be offered a schedule of monitoring, hydration and possibly allopurinol. There is little evidence available to inform decisions regarding omission of allopurinol and whether specific patient groups can be determined. What is clear though, is that any form of prophylaxis is only likely to be useful during the first course of treatment and at future time points where re-induction or salvage chemotherapy is used. There is no rationale for using prophylaxis in the setting of consolidation therapy including bone marrow transplant if the patient is in or near to a remission. Special attention should be paid when patients, even those with low-grade disease, are being treated with potent novel agents. TLS may be seen in the context of lower risk disease in this instance. The exact fluid volume required is not known but it seems reasonable to aim for 3 l/24 h in adults. In patients at high risk of TLS, the use of allopurinol in association with a forced alkaline diuresis was the traditional method to manage these patients. Uric acid has an increased solubility in an alkaline pH, so giving sodium bicarbonate intravenously might theoretically aid its excretion. However both xanthine and hypoxanthine, that precede uric acid in the biochemical pathway, become less soluble in alkaline conditions and so precipitate before any uric acid can be formed thus negating any potential advantage of the increased solubility of uric acid at high urinary pH. Alkaline diuresis is therefore not recommended (Ten Harkel et al, 1998; Coiffier et al, 2008). The standard recommended dosing schedule for allopurinol in prevention of TLS is 200–400 mg/m2/day in 1–3 divided doses for adults, up to a maximum of 800 mg daily. In children, the recommended dose is 300–450 mg/m2/day in three divided doses up to 400 mg daily. In infants weighing <10 kg the dose is 3·3 mg/kg every 8 h. In practice, most adult haematologists simply use 300 mg/day and, for the most part, this is effective but it may be prudent to increase the dose of allopurinol or, preferably, switch to rasburicase in the presence of deteriorating biochemical or clinical markers., Allopurinol doses may need to be adjusted in renal failure. Allopurinol should be given for up to 7 days after chemotherapy is started. In patients with an allergy to allopurinol it is generally safe to use prophylactic hydration only along with careful monitoring as patients at very high risk of TLS would be given rasburicase. Rasburicase prophylaxis along with appropriate hydration and monitoring is recommended for patients with the very high-risk characteristics detailed in the criteria above. The drug is licensed for the treatment and prophylaxis of TLS but is contra-indicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Rasburicase is highly effective in the treatment of TLS and has been used in prophylaxis but, with the exception of one small underpowered study (Goldman et al, 2001), no other formal randomized trial against allopurinol has been performed. The licensed dose is 0·2 mg/kg and the licensed duration of therapy for prophylaxis is 5–7 days. Rasburicase is undoubtedly a highly effective agent in TLS prophylaxis in both adults and children (Coiffier et al, 2003; Pieters & Uyttebroeck, 2003; Yim et al, 2003; Jeha et al, 2005). Although the licensed dose of rasburicase is 0·2 mg/kg/day, a number of publications have explored lower doses and shorter courses of therapy. Previous guidelines have reflected these observations; Cairo et al (2010) recommended a dose of 0·1–0·2 mg/kg on the first day, repeated for up to 7 days. all of these dosing have been of There has been one randomized trial a dose of rasburicase five doses in patients at risk of TLS et al, In the dose patients rasburicase which be repeated on a if required at the of the patients were in the of which were in the dose and only of those required more than one The that a dose of rasburicase was as effective as therapy for the of patients. Other groups have dosing of patient et al a dose of 3 mg a in a used this dose in a of patients with uric acid levels receiving a cell transplant or chemotherapy for a haematological malignancy. patients required a dose and there were no renal in any this group have in a of adult patients et al, 2011). patients were treated with a dose of rasburicase. failure was defined as failure to uric acid levels h after In patients with a uric acid of the failure rate was as to in those with uric acid The of this lower dose has been in a study of patients at high risk of TLS et al, dose was in patients from a of haematological including patients with and ten patients with but 8 of the patients required a including patients with a cell over There were no no for and no seen in this et al, has at the effectiveness of a dose of rasburicase in adult patients at high risk of developing TLS. was with from patients treated with rasburicase given at the licensed dose for days or patients treated with allopurinol. The dose from mg/kg to The for the dose of rasburicase that a dose was as effective as the rasburicase treatment with to the control of uric acid levels but to allopurinol. In a standard dose of defined clinical with the licensed In the first trial the use of rasburicase for the prevention of TLS has been (Galardy et al, 2013). patients, with aggressive B-cell malignancies were treated with rasburicase at the licensed dose with a treatment, which was repeated if prior to or to chemotherapy The number of doses was with patients being given a In this high-risk only of patients renal after rasburicase administration and of those patients patients in required in five of these it was prior to chemotherapy and the other patient required dialysis for It is to the use of rasburicase. these into and available in the of clinical or laboratory TLS, TLS can be prevented in the of adult patients using a dose of 3 mg rasburicase. It is to for biochemical and clinical of TLS and if there is evidence of any then the dose should be repeated of TLS have to to TLS will management as described Whilst there is evidence to the use of a dose for prophylaxis in an adult this is in It would very reasonable to this into children based on the that for a dose they will a dose kg than adults for this is In the of however, this a We however, further in this for adult patients, if a rasburicase dose is it is to for biochemical and clinical of TLS. there is evidence of any then the dose should be repeated of TLS have to clinical TLS develops prophylaxis then patients should be with a standard 0·2 dose of rasburicase as It be that the presence of rasburicase in the will lower urate levels in are to the laboratory on be that low urate levels are not used to therapy. of this a including and The clinical of the patient can change very quickly and monitoring is are not available for management then should be given to the patient to an or to a a of as defined by BCSH criteria et al, It is to have a high of for TLS. The first in TLS is to a high output with hydration and careful monitoring of fluid The aim is to prevent uric acid crystallization and calcium phosphate in the renal The of these products in the renal tubules a of deteriorating renal function to hyperuricaemia, and hypocalcaemia. biochemical abnormalities in further of uric acid and calcium There are no that a rate of fluid to be than but 3 every h would be reasonable in adults et al, Cairo et al, & Tholouli, with the aim of a output of for infants and for patients. or are and it is that no potassium is to the hydration output should be at and a formal of fluid balance should be at 6 should be to all fluid as or the elderly and those with pre-existing cardiac and renal disease are at risk of fluid can be useful in fluid balance and infants may need to be to fluid reduction in output should of fluid balance and laboratory the disease, it may be appropriate to whether there is a to by which may a reduction in output may herald renal failure and fluid may should be in using in this Whilst mg/kg intravenously can be a useful treatment, the drug may uric acid (Jones et al, and is likely to be less in the presence of renal The presence of fluid of the is not recommended to only evidence of and increased risk of calcium phosphate along with reduced xanthine solubility at increased (Coiffier et al, Harkel et al, 1998; & 2004; et al, Allopurinol is a xanthine oxidase that acts by the development of uric acid crystals in the renal tubules but it does not the breakdown of uric acid that has already been this useful in the prophylactic is not the drug of in TLS. In to a recombinant urate oxidase, metabolizes urate directly to the more soluble Rasburicase of uric acid and reduce urate levels more quickly than allopurinol (Goldman et al, Pui et al, et al, 2003; Jeha et al, 2005). patient who has been on allopurinol as a prophylactic should be to rasburicase if they develop clinical TLS, the being patients who have to rasburicase and those in it is to deficiency. In those patients allopurinol should be but renal dialysis is more likely to be The standard recommended dose of rasburicase is 0·2 given as a The duration of treatment should be by the clinical The current and and include dosing for up to days. Whilst there are some to duration of rasburicase or reduced dose therapy in the context of prophylaxis there are no those of the to dosing in the setting of TLS. It seems reasonable to rasburicase 0·2 be given for days with careful monitoring of hydration and administration of rasburicase do not prevent hyperphosphataemia, it can be to control phosphate levels other than by The use of has been described Coiffier et al, but is to and thus is not recommended in this setting. should not be treated as treatment can precipitate further calcium phosphate in the calcium levels or there has been a 25% from (Cairo & Bishop, 2004) then cardiac monitoring is cardiac or should be treated with calcium in the standard doses for adults and The aim is to the symptoms but not to the biochemical The effects of including are well It is recommended that patients with potassium levels or a 25% increase in potassium from should be offered cardiac potassium a medical and dialysis is likely to be required measures can be to reduce potassium levels but the effects are and dialysis is often should be treated with a of calcium with cardiac or intravenous can be as can intravenous of and increase of potassium from the to the intracellular The use of urate oxidase therapy to have reduced the need for dialysis in patients at risk of TLS. The group patients with Burkitt and monitored and over an et al, the first time of the study no patients urate In the some were given the drug and in the it was recommended that all patients were treated with a urate the course of the study the of TLS was in one and The of were a study reported a of TLS when a of adults at high risk of TLS was of patients TLS and TLS was an risk for acute kidney injury and increased even in the rasburicase et al, 2013). Nonetheless, when the measures described have to prevent renal and fluid hyperuricaemia, or have renal dialysis is dialysis is not recommended for this clinical is than with other of dialysis & In patients may have which would this approach. There are no with or other and all to be Given the release of metabolites into the in the setting of TLS, some groups have that dialysis may be the et al, 2008). In patients who are renal therapy can be should there is of renal function and the and in these guidelines is to be and at the time of to the the British Society for Haematology the any for the content of these The British Committee for Standards in Haematology will review this guideline on an to it the at to if the guideline has been or The will also the the guideline was last reviewed the the draft of the manuscript and the the group, reviewed the literature and the and reviewed the literature and the The to for in the literature and for as a medical The would to the BCSH haemato-oncology BSH sounding BCSH and Leukaemia Lymphoma Research for in these The BCSH paid the during the writing of this medical for was by the have of to the BCSH and Task has for and of the other to of the writing group will inform the writing group if any evidence becomes available that would the of the in this or it The will be and from the BCSH current guidelines if it becomes are an will be on the BCSH guidelines (www.bcshguidelines.com). changes are required to changes in of evidence or additional evidence becomes available to current a of the guidance will be on the BCSH

The disease currently recognized as angioimmunoblastic T-cell lymphoma (AITL) was first described in the 1970s as a clinical syndrome characterized by generalized lymphadenopathy, hepatosplenomegaly, anaemia and hypergammaglobulinaemia (Frizzera et al, 1974; Lukes & Tindle, 1975; Lennert, 1979). The lymph node histology was observed to show a number of distinctive features such as the partial effacement of normal architecture by a polymorphic inflammatory infiltrate, including large blasts and marked vascular proliferation. Based on these histological appearances, the disease was initially referred to by a variety of terms, including immunoblastic lymphadenopathy (Lukes & Tindle, 1975), lymphogranulomatosis X (Lennert, 1979) and angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) (Frizzera et al, 1974). The latter term was accepted by most investigators and has come to define this clinical syndrome. AILD was initially thought to be an atypical lymphoid hyperplasia, a premalignant lesion, with a tendency to develop into a lymphoma rather than a frank neoplasm at onset. With the advent of immunophenotyping and molecular techniques, it became apparent that most cases of AILD contained monoclonal T-cell populations as well as clonal cytogenetic abnormalities, strongly suggesting that the majority of the patients were neoplastic from the onset. AITL was included in the Updated Kiel Classification for Lymphomas (Stansfeld et al, 1988) and is accepted as a distinct clinicopathological entity in the current WHO classification (Jaffe et al, 2001). It is likely that earlier series, published before the availability of immunophenotyping and molecular tests, are diluted by a number of reactive proliferations. In this review, as far as possible, we have used the data from relatively recent reports published after the neoplastic nature of AITL was established. No consistent risk factors for the development of the disease have been reported and to date no aetiological agent has been identified. A significant proportion of patients have a history of drug use (Tobinai et al, 1988; Sasaki & Sumida, 2000), in particular, antibiotics. These are more likely to represent drugs prescribed to the patients because of systemic illness clinically mimicking an infectious process, rather than the primary cause of the disease. A number of infectious diseases and agents have been reported to be associated with AITL, including bacterial infections such as tuberculosis (Rho et al, 1996) and fungal infections such as cryptococcus (Konig et al, 1991). Perhaps most intriguing is the relationship of AITL with a number lymphotropic viruses. The most significant of these is the Epstein–Barr virus (EBV), which is discussed separately below. The presence of other viruses, including human herpes virus (HHV)-6 (Luppi et al, 1993), HHV-8 (Luppi et al, 1996), human immunodeficiency virus (HIV) (Helm et al, 1990) and hepatitis C virus (Luppi & Torelli, 1996), have been reported in AITL. Other than EBV, the evidence for the role of a viral infection in the pathogenesis of AITL remains tenuous. HHV-6 was reported in seven out of 12 AITL patients identified by the polymerase chain reaction (PCR) (Luppi et al, 1993), but immunohistochemistry (Luppi et al, 1998) and in situ hybridization studies (Khan et al, 1993) showed that the expression of HHV-6 antigens was absent in the T cells, which is suggestive of a lack of a direct role for HHV-6. Occasional cases of AITL have also been described to have HHV-8 infection by PCR, but we (unpublished data) and others (Chadburn et al, 1997) failed to observe any evidence of HHV8 infection by PCR or immunohistochemistry in AITL, which, once again, argues against a causal relationship. Associations with other viruses are limited to a few case reports and are likely to be coincidences. The lymph node biopsy of AITL is characterized by the partial effacement of the lymph node architecture by a polymorphic infiltrate, predominantly occupying the paracortical (interfollicular) areas. Usually the lymph node sinuses are preserved but the infiltrate leaks into the perinodal tissue. In the original descriptions of AITL, the absence of reactive hyperplastic B-cell follicles was considered to be a characteristic feature; it is now recognized that the architectural changes in AITL fall into three overlapping patterns (Ree et al, 1998, 1999; Attygalle et al, 2002a). In pattern I (20% of the patients), there is a preservation of the lymph node architecture. Hyperplastic B-cell follicles with poorly developed mantle zones and ill-defined borders are easily identifiable in the cortex of the lymph node. These merge into the expanded paracortex containing a polymorphic infiltrate of lymphocytes, transformed large lymphoid blasts, occasional multinucleate cells that are reminiscent of Reed–Sternberg cells (RS), plasma cells, macrophages and eosinophils within a prominent vascular network (Fig 1). Histological appearances of AITL (H + E). (A) A pattern I–II patient in whom the architecture is partly preserved. Despite paracortical expansion, the follicles can be identified in low-power view. (B) A pattern II patient in whom architecture is effaced by a polymorphic infiltrate with marked vascular proliferation. (C) A pattern II patient with a depleted follicle surrounded by characteristic clear cells. (D) A high-power view of polymorphic infiltrate and prominent vessels in the paracortical area. (E) Aggregates of large clear cells, which are a typical feature of AITL. (F) A pattern II patient with marked FDC proliferation. Pattern II (30% of the patients) is characterized by the loss of the normal architecture, except for the presence of occasional depleted follicles with concentrically arranged follicular dendritic cells (FDC). In some patients, FDC proliferation extending beyond the follicles can be seen. The remainder of the node shows a polymorphic infiltrate with increased numbers of transformed lymphoid blasts and vascular proliferation similar to that described for pattern I (Fig 1). In pattern III (50% of the patients), the normal architecture is completely effaced and no B-cell follicles are present. Prominent irregular proliferation of FDCs can be seen in haematoxylin and eosin (H&E)-stained sections in most patients, and this is accompanied by extensive vascular proliferation and a polymorphic infiltrate similar to that seen in patterns I and II (Fig 1). Approximately half of the patients contain perivascular collections of atypical, medium–large-sized lymphoid cells with either clear or pale cytoplasm, whereas in other patients cytological features of malignancy may not be apparent. In a few cases, where consecutive biopsies from the same patient have been reviewed, an apparent transition from pattern 1 to pattern III as the tumour progresses has been noted, suggesting that pattern III patients represent advanced disease (Ree et al, 1998; Attygalle et al, 2002a). The reproducibility of the diagnosis based on histological appearances appears to be high, at least amongst expert haematopathologists (Rudiger et al, 2002). In most patients, histological examination has to be supplemented by additional ancillary tests. The histological diagnosis may be problematic in a small number of patients as the morphology and phenotypic features can overlap with a variety of reactive and neoplastic conditions, such as reactive lymphadenopathies, multicentric Castleman's disease, diffuse large B-cell lymphoma and classical Hodgkin's lymphoma (Attygalle et al, 2002a). Although generalized lymphadenopathy is the main presenting sign and the diagnosis of AITL rests on histological examination of the lymph node, many patients have evidence of extranodal involvement at the time of diagnosis. The most frequently involved extranodal sites include the bone marrow, spleen, skin and lungs. The histological appearances in these sites are usually non-specific but mimic some of the features described in the lymph node, including increased vascularity and a polymorphic inflammatory infiltrate with or without clear cells (Seehafer et al, 1980; Ghani & Krause, 1985; Brown et al, 2001). Cytological features of malignancy can rarely be identified, and tumour involvement can only be shown by immunohistochemistry and molecular clonality analysis (Martel et al, 2000; Murakami et al, 2001). Immunohistochemistry shows the expansion of the interfollicular areas by a diffuse infiltrate of CD3+ T cells. In most patients, CD4+ T cells dominate but there is usually an intermixed population of CD8+ T cells. The B-cell markers CD20 and CD79a highlight the residual follicle centre and mantle zone B cells as well as many of the large transformed blasts and RS-like cells in the interfollicular areas. In some instances, these can be numerous, mimicking a large B-cell lymphoma or classical Hodgkin's lymphoma, though they are typically polytypic for light chain expression. As described by histology, one of the most distinctive features of AITL is the proliferation of FDC which is best appreciated with immunostaining for the FDC markers CD21, CD23 or CD35 (Leung et al, 1993; Raymond et al, 1997; Jones et al, 1998; Bagdi et al, 2001). In early cases (pattern 1), the FDC proliferation can be minimal and limited to a few follicles. In more advanced cases (Pattern II and III), the FDC are seen to extend into the interfollicular area and wrap around the arborizing vessels (Attygalle et al, 2002a) (Fig 2). Immunophenotype of AITL (immunohistochemistry). (A) A low-power view of CD21 staining, highlighting marked FDC proliferation. (B) A high-power view of CD21 staining showing the FDC wrapping around small vessels, which is a characteristic feature of AITL. (C) CD3 staining, most cells are positive, including large lymphoid cells. (D) CD4 staining in the same area as (C): most CD3-positive cells also express CD4. (E) A pattern II case stained for CD10. Numerous small to medium cells expressing CD10 are seen surrounding the follicle, and spilling into the paracortex is shown. Note the weaker reactivity of follicle centre B cells. (F) The same area as (E) double-stained for CD20 in brown and CD10 in blue. CD20 cells are limited to the follicle centre whereas CD10-positive T cells surround the follicle. (G) A low-power view of a pattern II patient's sample stained for CD10. There are numerous aggregates of CD10-positive cells. (H) A high-power view of one of the aggregates shown in (G). The CD10-positive T cells correspond to the clear cells seen in H&E-stained sections. Until recently, the assessment of the immunophenotype of AITL tumour cells was difficult, as in many patients the neoplastic cells were not readily identifiable and no specific markers were available to recognize the tumour cells. However, studies using immunohistochemistry, single-cell microdissection and molecular analysis have now shown that the neoplastic tumour cells of AITL can be recognized by the aberrant expression of CD10 (Attygalle et al, 2002a). CD10, also known as neutral endopeptidase (NEP), is a cell surface metallopeptidase normally expressed by a subset of lymphocytes, and epithelial and stromal cells. It belongs to a family of membrane peptidases that includes, among others, the structurally related leucocyte-associated molecules CD26 and CD13. Physiologically CD10/NEP reduces the peptide concentration available for receptor binding and regulates a number of cell functions (Antczak et al, 2001a, b; Turner et al, 2001). In haematopathology, CD10 has been extensively used for the diagnosis of lymphomas because of its restricted expression by the precursor B-cell and follicle centre B-cell compartments (Chu et al, 2000; Dogan et al, 2000). In both lung (Shipp et al, 1991) and prostate cancer (Papandreou et al, 1998), CD10 has been shown to regulate tumour survival in vivo by decreasing extracellular neuropeptide concentrations and inhibiting certain signal transduction pathways (Sumitomo et al, 2000, 2001). In lymphocytes, its expression is largely restricted to B-cell compartments with a typically high rate of apoptosis (Chu et al, 2000). CD10 is not expressed by normal peripheral T cells or nodal peripheral T-cell lymphomas, but is induced in T cells undergoing apoptosis during HIV infection in both in vivo and in vitro experiments (Cutrona et al, 1999). This close association with CD10 expression and apoptosis suggests that CD10 plays a role in the regulation of lymphocyte survival. In AITL, it appears that most, if not all, tumour cells express CD10, and CD10-positive T cells account for only a fraction of the infiltrate, varying from around 5% of all cells in pattern II patients to up to 30% of all cells in pattern III patients (Fig 2). Interestingly in early cases, the CD10-positive cells have low-grade cytology and a relatively low proliferation fraction. CD10-positive T cells are intimately related to the residual reactive B-cell follicles and the expanded FDC meshwork, some being located within the follicle centres and others in the area surrounding the follicles. As the tumour progresses (patterns II and III), the tumour cells spill into the interfollicular area but retain the intimate association with the FDC meshwork. This suggests that the FDC microenvironment may be important for tumour growth. Moreover, in many patients, the neoplastic cells stain for CD4, CD57 and B-cell lymphoma-6 (Bcl-6), markers expressed by normal follicle centre T cells, suggesting that the tumour may have derived from this cell population (Ree et al, 1999; de Leval et al, 2001; Yuan et al, 2002). The neoplastic T cells in extranodal dissemination may retain the expression of CD10 and this may aid diagnosis (Attygalle et al, 2002b). There appears to be a substantial immune activation in the peripheral blood and lymph nodes of AITL patients compared with the reactive lymph nodes or other peripheral T-cell lymphomas. The evidence for this includes increased levels of serum soluble interleukin 2 (IL-2) receptor, CD30 and CD8 molecules (Pizzolo et al, 1990), and also the expression of an array of cytokines such as tumour necrosis factor alpha, and et al, 1993; et al, et al, 2000). studies the expression of T-cell activation markers have shown an increased expression of the receptor family et al, receptor et al, 2000), and which is a of early T-cell activation & 2002). These molecules are associated with the in normal T cells, suggesting that characterized by and is a feature of AITL. In to this marked immune the studies on T cells from lymph nodes and peripheral blood of AITL patients have shown T-cell an The reported include a of the number of T cells, of the high of T cells T-cell in vitro to the and minimal and in vitro functions (Pizzolo et al, factor one of the main cytokines in human is expressed at high levels by the stromal cells in AITL et al, It has been that it may be for the vascular proliferation observed in AITL. the increased signal appears to with the number of cells the suggesting that cell activation may also a role in the pathogenesis et al, 2001). A characteristic feature of AITL, seen in of all patients, is the presence of increased numbers of cells compared with both normal lymph nodes and peripheral T-cell lymphomas. studies the cells be within both the T-cell and B-cell population et al, In studies using immunohistochemistry, in situ hybridization and microdissection have shown that all cells by are B cells, and that infection is to a primary role the of AITL et al, et al, et al, 2001). The cells have a with some an and others an RS-like account for most of the large B cells in the interfollicular zone of the AITL lymph The expression pattern in AITL B cells is usually consistent with et al, et al, 2002). The for the expansion of cells are not It is likely that an immunodeficiency with and the presence of factors the of cells the availability of molecular that can the presence of expanded of T and B cells, the neoplastic nature of AITL was not appreciated and the disease was considered to be a premalignant from which large cell lymphomas became and were the first to the clonality of in AITL et al, the presence of clonal T-cell not only in patients with apparent lymphoma, but also in patients as AILD the cytological features of This was by a number of similar the presence of a monoclonal T-cell population in all patients with et al, et al, 1988; et al, 1988; et al, 1998; et al, 2000; et al, 2001; Attygalle et al, 2002a). The of clonality from the large are in of the to be during these studies was the presence of an expanded monoclonal B-cell population in a significant of This has to the that AITL is a of T-cell lymphomas and B-cell lymphomas, but not a clinicopathological However, the current evidence suggests that these patients also fall within the of AITL. These patients typically increased numbers of cells, and it is thought that the B-cell by molecular analysis of lymph node within this It is likely that this is an that to the immunodeficiency associated with the AITL, to other that are associated with et al, 2002). a subset of AITL patients on to develop diffuse large B-cell lymphomas et al, et al, 1993; et al, or lymphoma et al, 1979). The studies on the changes in AITL have been by a number of including the of the tumour and of tumour cells by a large number of reactive cells. of on changes from These are in Approximately of AITL patients have cytogenetic observed by the use of and et al, 1988; et al, et al, et al, et al, are seen in of the and of an X are the most seen in AITL, but these are also in other peripheral T-cell lymphomas. and showed that half the patients which is a that is in other lymphomas et al, This was to be consistent with the development of in AITL. The being the of in cells because of and the of aberrant cells to the immune by the of aberrant and a of monoclonal proliferation. However, at the first T-cell receptor shows clonal T-cell that the tumour is at the not by cytogenetic that have a low The presence of T-cell and the expansion of B-cell the as to which cells the aberrant In one using a the of immunophenotype and it was shown that the aberrant with were CD3 T cells et al, It is that the seen in AITL from B cells that are likely to have an The proportion of aberrant cells reported on compared with is consistent with the morphology of AITL, with a few neoplastic cells an of reactive cells et al, In a the of on clinical only the presence of aberrant was to be an and no on survival et al, known to be in have rarely been in AITL. and expression and and that both are suggesting that this is not in the majority of AITL patients et al, 2001). The other that has been is of the of the a role in the development of diffuse large B-cell lymphomas. Despite the expression of in most patients with AITL (Ree et al, 1999; Attygalle et al, Yuan et al, no were in the of the et al, 2001). lymphoma is the of cancer in in the with patients of these are peripheral T-cell lymphomas, and AITL for of all lymphomas (Rudiger et al, with an patients in the in a centre suggests that AITL patients are being that the may be (Ree et al, 1998; Attygalle et al, 2002a). AITL is a disease of the with most patients presenting within the and (Tobinai et al, 1988; et al, et al, et al, 1999; Attygalle et al, 2002a). There is no of the disease to et al, et al, et al, 1999; Attygalle et al, 2002a). The patients have a and have been reported in the and small suggests that the of AITL may be in than (Rudiger et al, 2002). AITL typically with systemic characterized by B and generalized lymphadenopathy, mimicking an infectious The majority of patients show and and a skin is also seen in a half of The reported of presenting and observed in AITL are in III (Tobinai et al, 1988; et al, et al, 1999). show the presence of anaemia and there is and both the and the rate are A significant proportion of patients have including a and immune The most and are shown in (Tobinai et al, 1988; et al, et al, 1999). A number of have been reported in association with AITL. These include anaemia et al, (Seehafer et al, 1980; et al, 2001; et al, et al, et al, and disease et al, 1999). The clinical syndrome of AITL with a of inflammatory and neoplastic and the changes in peripheral blood and on bone examination are usually of the lymph node may be but is rarely because cytological appearances can be within normal and architectural features be the same a also has limited The diagnosis of AITL can only be by biopsy and histological examination of one of the lymph where characteristic features can be best the and clinical of AITL are limited because of the of the disease. of the is based on small patient numbers and a limited number of case The clinical of the AITL remains with a survival of than and a survival of around et al, et al, 1999). patients of infectious rather than tumour suggesting that an immunodeficiency to the agent and such as with or without and with or without or have been reported et al, et al, et al, et al, 1999). Although a rate of can be with appears to be to et al, 1999). Other including with et al, 2000), et al, et al, 1999; et al, and & 1996) can be but studies are based on a small number of patients, which not significant has been used for to as a of its and & et al, & et al, et al, et al, 1999). In the majority of the patients, the is but is not than that observed with which has a on the immune most on T cells, but also has a direct on lymphocytes, has also been et al, et al, 1997; et al, 1999). on neoplastic T cells may an important role in the of but once studies are limited to a few case has been used as agent in a few patients, either or in AITL, with et al, 2002). There are published data the of by blood cell in this of lymphoma patients after with this et al, 1999). AITL is a systemic disease characterized by the monoclonal proliferation of T cells expressing CD3 and CD4. In most patients, the tumour cells are by numerous cells. This a number of both diagnosis and the of the of the tumour cells, not the clinical of these patients remains in the of other lymphomas. In this the of the aberrant expression of CD10 as of neoplastic T cells of AITL be This an phenotypic for diagnosis for the first as well as a to the of AITL tumour cells. in with AITL on the we in the of the disease and in to in large clinical

Sickle Cell Disease (SCD) is a common autosomal recessive hemoglobinopathy caused by a point mutation in the &#x3b2;-globin gene, leading to aberrant production of Hemoglobin S (HbS). The pathophysiological process initiated by this mutation triggers a cascade of symptoms, including erythrocyte sickling, vasococcus occlusions, chronic hemolysis, and widespread inflammatory reactions, culminating in a multitude of clinical complications. Unfortunately, in resource-poor regions, the increasing incidence of SCD outstrips the capabilities of public healthcare systems, thereby creating a dire and urgent requirement for readily available and optimized therapies. Hydroxyurea (HU) has proven itself as a definitive treatment that promotes fetal hemoglobin production, prevents clinical complications, and thereby provides a promising, cost-effective alternative to chronic blood transfusions. Recent findings indicate that microRNAs (miRNAs) play a pivotal role in regulating hematopoiesis and globin switching, thereby making them fundamental mediators and targets of HU therapy. In this review, we explore beyond the traditional frontiers of HU therapy by critically evaluating its rationale as a two-way modifier of the miRNA-scope, which affects crosstalk within a ceRNA network, promotes upregulation of desirable miRNAs, and also triggers HU-induced adaptive miRs that can potentially destabilize therapeutic responses or even induce adverse reactions. More importantly, this review proposes a new, comprehensive conceptual framework to overcome and explore the constraints of monotherapy. In a nimble review of prior findings, we clarify and establish which specific alterations of HU-induced miRs would form a rational basis and hypotensive stimulus of mimicking therapy and thereby differentiate which specific alterations of upregulated or downregulated miRs should form a systemic basis of antagomiring therapy and thus lay out a specific and comprehensive roadmap of combinatorial medicine and therapy in managing SCD.

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the incidence of moderate-to-severe acute graft-versus-host disease (aGVHD) is approximately 13% to 47%. Currently, the standard regimen for the prevention of aGVHD is a calcineurin inhibitor (CNI) plus short-course methotrexate (MTX), with the addition of mycophenolate mofetil (MMF), anti-human thymocyte globulin (ATG), or anti-CD25 monoclonal antibody depending on the type of donor. This study aims to evaluate whether the addition of sitagliptin to standard aGVHD prophylaxis can further reduce the incidence and severity of aGVHD, while enhancing stem cell engraftment and improving the overall prognosis of patients undergoing allo-HSCT.&#xa0;The clinical data of 66 patients with malignant hematopoietic diseases who underwent allogeneic hematopoietic stem cell transplantation for the first time at the Department of Hematology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between 1 January 2022 and 1 January 2024 were retrospectively collected. According to the aGVHD prophylaxis regimen received, the patients were divided into the Sitagliptin group (n&#x2009;=&#x2009;33) and the Standard group (n&#x2009;=&#x2009;33). Statistical methods were used to compare the clinical outcomes between the two groups, including hematopoietic engraftment, acute GVHD, chronic GVHD, and overall survival (OS) after allogeneic hematopoietic stem cell transplantation.&#xa0;By day&#x2009;+&#x2009;100 after transplantation, all patients in both groups had achieved engraftment. The Sitagliptin group had faster neutrophil engraftment than the Standard group (median 9 days, 95% CI 8.55&#x2013;9.45 vs. median 11 days, 95% CI 10.39&#x2013;11.61; p&#x2009;<&#x2009;0.001).&#xa0;The cumulative incidence of grade II&#x2013;IV aGVHD by day&#x2009;+&#x2009;100 was 39.4% (95% CI 17%&#x2013;35%) in the Standard group compared with 30.3% in the Sitagliptin group (p&#x2009;=&#x2009;0.26). Corresponding values for grade III&#x2013;IV aGVHD were 12.1% (95% CI 3.7%&#x2013;25.8%) in the Standard group versus 9.1% (95% CI 2.3%&#x2013;21.9%) in the Sitagliptin group (p&#x2009;=&#x2009;0.70).&#xa0;For organ-specific aGVHD, the incidence of liver aGVHD was significantly lower in the Sitagliptin group (3.1%, 95% CI 0.2%&#x2013;14%) than in the Standard group (18.2%, 95% CI 7.2%&#x2013;33.1%; p&#x2009;=&#x2009;0.044). The online version contains supplementary material available at 10.1007/s00277-026-07036-7.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment, which carries a high risk of complications and mortality, highlighting the necessity of discussions about life threat. This study explores the perspectives of patients, informal caregivers (ICs), and healthcare professionals (HCPs) regarding the timing, content, and challenges of these discussions. Multicenter cross-sectional survey in comprehensive care centers across Germany, involving patients with allo-HSCT, ICs, and HCPs. Questionnaires assessed perceived concerns about life threat, communication needs, and attitudes toward death. Statistical analyses included descriptive statistics, group comparisons, and multivariate logistic regressions. A total of 61 patients, 31 ICs and 125 HCPs participated in this study. Patients and ICs had a high need for discussion about life threat at diagnosis, which was corroborated by HCPs. At further time points in the transplant trajectory, there were more discrepancies between patients&#x2018;/ICs&#x2018; and HCPs&#x2019; perceptions towards conversations about life threat. While 61.7% of patients preferred having their ICs present during discussions, ICs often felt overlooked, with only 50% finding conversations with HCPs helpful. HCPs&#x2019; avoidance of death was associated with a reduced likelihood of reporting a need for conversation in patients in the event of severe complications. These findings highlight a discrepancy between patients&#x2019; and ICs&#x2019; preferred timing for conversations about life threat and HCPs&#x2019; perceptions of when patients actually express such a need. To bridge this gap, earlier and ongoing conversations are essential. Training programs should address HCPs&#x2019; discomfort in discussing prognosis and improve interdisciplinary teamwork to standardize end-of-life communication. Trial registration number: DRKS00027290 (German Clinical Trials Register) on 10.01.2022. The online version contains supplementary material available at 10.1007/s00277-026-06981-7.

The multicenter, noninterventional, observational MMY4032 study is a large-scale, real-world study exploring daratumumab (DARA) in Chinese patients (n&#x2009;=&#x2009;212) with multiple myeloma (MM) who have received&#x2009;&#x2264;&#x2009;3 prior lines of therapy. In the first interim analysis (median follow-up, 10.5 months), DARA was often initiated in second-line therapy, often given in combination with a proteasome inhibitor and/or immunomodulatory drug, and induced high response rates (overall response rate [ORR], 71.8%) and acceptable safety. Here, we report treatment patterns, efficacy, and safety from the second interim analysis with a longer median follow-up of 16.2 months. At the time of this analysis, median duration of DARA exposure was 8.2 months. Among 189 response-evaluable patients, the ORR was 74.1% and the very good partial response or better rate was 55.6%. Minimal residual disease&#x2013;negativity rate was 60.0% among tested patients. Median progression-free and overall survival were 32.8 months and not reached, respectively; 12-month rates were 77.9% and 87.8%. Response and survival rates were higher with DARA initiation in earlier lines of therapy. Median time to next treatment was not reached with most DARA-based regimens. Adverse drug reactions and serious adverse events were reported in 20.3% and 15.6% of patients, respectively. Overall, with longer follow-up of the MMY4032 study, responses deepened, and survival rates remained high with DARA-based regimens, with more favorable outcomes observed with earlier DARA initiation. No new safety concerns were observed. These real-world data continue to support early use of DARA-based regimens as a standard of care for Chinese patients with MM. The online version contains supplementary material available at 10.1007/s00277-026-06972-8.

To evaluate the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in combination with salvage chemotherapy in patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma (R/R DE-DLBCL). We performed a retrospective analysis of 35 patients with R/R DE-DLBCL treated at two hematology centers from June 2021 to June 2024. All patients received zanubrutinib combined with one of several salvage regimens, including zR-MINE, zR-DHAP, zR-GemOx, or zR2. Endpoints included objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The median age was 60 years, and 91.4% of patients had the non-germinal center B-cell (non-GCB) subtype. At the end of therapy, the ORR and CRR were 45.7% (16/35) and 42.9% (15/35), respectively. After a median follow-up of 33.0 months, median PFS and OS were 8.0 and 12.0 months, respectively. Relapsed patients achieved a significantly higher CRR than refractory patients (56.5% vs. 16.7%, p&#x2009;=&#x2009;0.034). On multivariate analysis, longer duration of response to prior therapy was an independent protective factor for OS (HR 0.88, 95% CI 0.77&#x2013;0.99; p&#x2009;=&#x2009;0.041). Grade 3&#x2013;4 hematologic AEs were mainly neutropenia (42.8%) and thrombocytopenia (14.3%). Pulmonary infection was the most common non-hematologic AE (34.3%), and overall toxicity was manageable. Zanubrutinib combined with salvage chemotherapy demonstrates clinically meaningful activity with a manageable safety profile in patients with R/R DE-DLBCL and may represent a therapeutic option for this high-risk population. Sensitivity analysis confirmed the robustness of the observed survival benefit. The online version contains supplementary material available at 10.1007/s00277-026-06974-6.

Objective primary mediastinal B-cell lymphoma (PMBCL) is a distinct, aggressive lymphoma predominantly affecting young adults. While dose-intensive regimens are often recommended, their associated long-term toxicities and the necessity of consolidative radiotherapy remain major concerns. Given that PMBCL was explicitly excluded from the landmark POLARIX trial, we sought to evaluate the real-world efficacy and safety of first-line Pola-R-CHP in this specific population. Methods this single-center study analyzed 16 consecutive patients with newly diagnosed PMBCL treated with six cycles of Pola-R-CHP between September 2023 and June 2025. Efficacy was assessed via PET/CT (Lugano 2014 criteria) and safety via NCI-CTCAE v5.0. Results the median age was 30 years, with a female predominance (62.5%). Bulky disease was present in 62.5% of patients, and 87.5% had low-risk aaIPI scores. All patients completed six cycles of Pola-R-CHP treatment, achieving an objective response rate of 100%. The end-of-treatment complete metabolic response rate was 93.8%, with profound response deepening observed between interim and final assessments. After a median follow-up of 16.4 months, no relapses or deaths occurred, with all patients remaining in sustained remission. The most common grade 3&#x2013;4 adverse event was neutropenia (43.8%). Pola-related peripheral neuropathy was predominantly low-grade (56.3% grade 1&#x2013;2). Conclusion our findings provide the first preliminary clinical evidence that Pola-R-CHP is a highly effective and well-tolerated frontline strategy for PMBCL in this real-world cohort, which warrants further validation in larger, multicenter studies. The online version contains supplementary material available at 10.1007/s00277-026-07024-x.

Bone marrow toxicity, or immune effector cell-associated hematotoxicity (ICAHT), is a notable complication of CAR T-cell therapy, characterized by persistent cytopenia&#x2019;s and typically classified into three phenotypes: transient, intermittent and aplastic. This study aimed to characterize the bone marrow immune landscape associated with ICAHT phenotype( aplastic and intermittent) by analyzing patients with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene ciloleucel (axi-cel) who developed ICAHT, in comparison to healthy controls and between the two ICAHT subtypes. Bone marrow samples were profiled using mass cytometry (CyTOF) with a 41-antibody panel. Compared to healthy individuals, ICAHT patients showed increased frequencies of activated/effector T cells and reduced levels of B cells and CD34+ early hematopoietic cells. Within the ICAHT cohort, patients with the aplastic phenotype exhibited significantly higher levels of CAR T cells, activated T cells, regulatory T cells (Tregs), Th1, and Th17 cells, along with a higher proportion of CD34+ early hematopoietic cells. In contrast, the intermittent phenotype was characterized by a greater abundance of na&#xef;ve T cells, Th2 cells, and myeloid lineage markers such as CD33, CD11b, and CD11c. In this small, exploratory analysis, distinct immunological patterns were observed between intermittent and aplastic ICAHT phenotypes, suggesting potentially different mechanisms of hematopoietic disruption after CAR T-cell therapy that require confirmation in larger studies. The online version contains supplementary material available at 10.1007/s00277-026-06993-3.

Bispecific antibodies (BiTEs) have transformed the therapeutic landscape of relapsed/refractory multiple myeloma (RRMM), offering deep and durable responses even in heavily pretreated patients. However, their use carries substantial infectious risk due to immunosuppression, particularly hypogammaglobulinemia, induced by T-cell-redirecting therapy. To define the real-world incidence of grade 3&#x2013;4 infections, we conducted a systematic review and meta-analysis of retrospective studies including RRMM patients treated with BiTEs currently approved for clinical use. Ten studies encompassing 1,373 patients were analysed using a random-effects model of pooled proportions. The overall rate of grade 3&#x2013;4 infections was 0.25 (95% CI, 0.22&#x2013;0.30) after a median follow-up of 8.3 months, with moderate heterogeneity (I&#xb2;=52.9%). Subgroup analyses showed comparable pooled event rates for teclistamab&#x2014;anti-CD3/BCMA&#x2014;(0.26; 95% CI, 0.22&#x2013;0.31) and talquetamab&#x2014;anti-CD3/GPRC5D&#x2014;(0.23; 95% CI, 0.14&#x2013;0.33). Meta-regression revealed an inverse association between infection rates and mean number of prior therapy lines (p&#x2009;=&#x2009;0.002) and prior BCMA exposure (p&#x2009;=&#x2009;0.0019), likely because, in real world setting, clinicians select fitter, immunologically stable patients for BiTEs therapy. In summary, approximately one in four RRMM patients receiving BiTEs experiences severe infection. These findings underscore the need for proactive monitoring and standardized preventive measures, including immunoglobulin replacement, prophylaxis, vaccination, to ensure safe, effective integration of BiTEs into routine MM care. The online version contains supplementary material available at 10.1007/s00277-026-07026-9.

Breast hematopoietic neoplasms (BHN) are rare and may either primarily (PBHN) or secondarily (SBHN) involve breast tissue. The widespread use of needle biopsy for diagnosis of breast lesions necessitates knowledge of their presentation, radiologic aspects, histomorphology, and outcomes for seeking appropriate hematopathology consultation. Herein, we present our clinical experience as an academic institution and referral center of BHN in the past 20 years. We identified 59 patients diagnosed at the University of Chicago Medical Center between 2002-2021. Demographic, pathologic, radiologic, therapy, relapse data, and vital status were abstracted. Data were examined using univariable statistics with event-free and overall survival (EFS, OS) as primary outcomes examined with the lymphoma subgroup using Cox PH regression adjusted for age. The cases included 27 (46%) PBHN and 32 (54%) SBHN in a cohort comprising 93% females, mostly white (56%). The mean age at diagnosis was 58.8 years. Lymphomas were the most frequent BHN (86.4% of all cases). Patients with primary breast lymphomas (PBL) were significantly older than those with secondary breast lymphomas (SBL) (61.2 vs. 49.8 yrs, p<0.02). The most frequent lymphomas were extranodal marginal zone lymphoma (MZL) (32.2%) and diffuse large B-cell lymphoma/high grade B-cell lymphoma, not otherwise specified (DLBCL/HGBCL, NOS) (33.9%). Over half of MZLs and DLBCLs were primary in the breast. Within B-cell lymphomas, 20 (37%) were high grade with inferior 10-yr overall survival (OS) (age-adjusted HR 5.47, 95% CI 1.38, 21.64) compared to low-grade without any impact on event free survival (EFS). This is one of the largest cohorts so far describing BHN. DLBCL and MZL remain the most common lymphomas involving this site. Most patients were diagnosed via core needle biopsy (CNB) and did not have a prior BHN. Radiographically, the presentation may closely mimic breast carcinoma. FDG PET is a mainstay in the diagnosis and management of BHN.

This study aimed to evaluate the prevalence of vitamin D deficiency and to assess the effects of vitamin D supplementation on myocardial and hepatic iron burden and organ function in children with transfusion-dependent beta-thalassemia (TDT). A cross-sectional observational study was conducted in the pediatric hematology department of our institution. Patients aged three years and older with transfusion-dependent beta-thalassemia were included. Baseline and post-treatment laboratory assessments included serum calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH), and 25-hydroxyvitamin D [25(OH)D] levels. All patients received vitamin D supplementation according to their deficiency status. Cardiac and hepatic iron deposition were evaluated using T2* magnetic resonance imaging (MRI), and left ventricular ejection fraction (LVEF) was assessed by echocardiography. A total of 88 pediatric patients were enrolled. The largest proportion of patients was aged 4&#x2013;9 years (n&#x2009;=&#x2009;53), followed by those aged 10&#x2013;14 years (n&#x2009;=&#x2009;22) and 15&#x2013;19 years (n&#x2009;=&#x2009;13). The cohort consisted of 54.5% males (n&#x2009;=&#x2009;48) and 45.5% females (n&#x2009;=&#x2009;40). Patients were categorized into three groups based on serum 25(OH)D levels: severe deficiency (<&#x2009;10 ng/mL), mild deficiency (10&#x2013;20 ng/mL), and sufficiency (&#x2265;&#x2009;20 ng/mL). Three months after vitamin D supplementation, statistically significant improvements were observed in both cardiac and hepatic MRI T2* values (p&#x2009;<&#x2009;0.05). Vitamin D supplementation was associated with significant improvement in myocardial and hepatic iron parameters, suggesting a potential beneficial role in reducing iron-induced organ dysfunction. These findings highlight the importance of routine vitamin D monitoring and management in children with transfusion-dependent beta-thalassemia.

For patients with transfusion-dependent &#x3b2;-thalassemia (TDT) and suboptimal response to iron chelator monotherapy, dual oral iron chelation (DOIC) with deferasirox (DFX) and deferiprone (DFP) represents a practical strategy to enhance iron removal. This narrative review synthesizes contemporary evidence for its use, with a focus on identifying clinical signals from real-world data and highlighting gaps requiring prospective investigation. We conducted a narrative review informed by a structured literature search of PubMed, Scopus, and regional databases (January 2016 to January 2025) for studies evaluating DOIC (DFX&#x2009;+&#x2009;DFP) in pediatric and adult TDT. Outcomes of interest included serum ferritin, MRI T2*, hepatic iron concentration, adherence, and safety. Study quality and risk of bias were assessed qualitatively using standard criteria for observational research. Evidence from clinical cohort studies and real-world audits indicates that DFX&#x2009;+&#x2009;DFP therapy produces additive or synergistic reductions in systemic iron burden, with mean serum ferritin declines of 25 to 45%. Recent real-world pediatric data (2024 to 2025) report over 80% of patients achieving ferritin below 2000 ng/mL, with high adherence rates (>&#x2009;85%). MRI trends show improvement in hepatic and cardiac iron, though meaningful organ-specific changes typically require more than 24 months of therapy. The safety profile is consistent with established monotherapy profiles, primarily comprising mild gastrointestinal effects and transient transaminase elevations, with no reported agranulocytosis in reviewed cohorts. Study limitations include small samples, heterogeneous dosing protocols, and absence of randomized controlled trial data. DOIC with DFX and DFP is an effective and tolerable regimen for TDT patients with inadequate iron control on single agents. It leverages pharmacologic synergy within an all-oral, adherence-friendly regimen suitable for real-world use, including resource-limited settings. Prospective randomized trials with serial MRI endpoints are warranted to establish its superiority over optimized monotherapy for organ protection and long-term outcomes.

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome is a rare multisystem disease, often presenting diagnostic challenges. Here, we report a case of POEMS syndrome in an elderly patient with refractory peritoneal effusion and hypoalbuminemia as the main manifestations. Physical examination revealed cutaneous hyperpigmentation of upper and lower extremities. Tests revealed elevated vascular endothelial growth factor (VEGF) and hypogonadism, while imaging showed enlargement of armpits and groin lymph nodes. Lymph node biopsy excluded tuberculosis and malignancy. Electroneuromyography (EMG) disclosed polyneuropathy of the lower extremities. Finally, he was diagnosed with POEMS syndrome via bone marrow biopsy. Notably, he presented endoscopic snakeskin-like appearance of stomach, which was consistent with previous research. POEMS syndrome, a rare cause of ascites, is frequently missed or misdiagnosed. Thus, clinicians should maintain high vigilance. In patients with unexplained refractory ascites and symptoms like neuropathy, lymph nodes enlargement, and endocrine disorders, screening for VEGF levels and M protein should be performed to facilitate early identification of POEMS syndrome. The online version contains supplementary material available at 10.1007/s00277-026-06991-5.

Decitabine, including its new oral formulation (decitabine-cedazuridine, DEC-C), is commonly used in AML and MDS, particularly in older or unfit patients. While its clinical efficacy and tolerability are well documented, evidence regarding patient-reported outcomes (PROs) and health-related quality of life (HRQoL) remains limited. We conducted a review of the available literature on PROs in patients with AML and MDS treated with decitabine, with the aim of evaluating its impact on HRQoL, symptom burden, and patient preferences. A systematic literature search of PubMed up to October 2024 identified studies evaluating HRQoL or PROs in adult AML and/or MDS patients receiving decitabine, regardless of study design. Ten studies met the inclusion critera. Decitabine-based regimens were associated with preservation of HRQoL compared with intensive chemotherapy and improvements in fatigue and physical functioning versus best supportive care. In patients with AML, baseline HRQoL scores were found to be predictive of survival outcomes. Surveys consistently indicated strong patient preference for oral DEC-C due to reduced treatment burden and greater convenience, though longitudinal data remain limited. In conclusion, currently available HRQoL evidence for decitabine provides meaningful insight to guide further research. Findings from patient surveys and the availability of decitabine in both intravenous and oral formulations emphasize new treatment aspects that can be effectively captured through PROs. Their systematic integration may help uncover critical issues such as symptom burden, adherence, and patient priorities, ultimately fostering more patient-centered care.

Congenital sideroblastic anemia (CSA) and thalassemia are both hereditary disorders of erythropoiesis, primarily affecting erythroid cells. Their typical manifestations include anemia and iron overload. In this study, we conducted clinical and molecular analyses on a male patient who was concurrently diagnosed with thalassemia and CSA. The patient underwent a series of tests including complete blood count, bone marrow smear, and serum ferritin levels. Whole exome sequencing technology was employed for genetic mutation analysis, and bioinformatics methods were utilized to assess the functional impact of the predicted variants. The patient was previously diagnosed with alpha thalassemia (with genotype of --SEA/-&#x3b1;4.2), and has been receiving frequent blood transfusions over the past two years, presenting with severe anemia (Hb level of 44&#xa0;g/L), iron overload, and 52% ring sideroblasts in the bone marrow. Whole exome sequencing revealed a hemizygous nonsense mutation (c.224&#xa0;C&#x2009;>&#x2009;A) in the 5-aminolevulinate synthase (ALAS2) gene, which introduces a premature stop codon at the 75th amino acid position in the N-terminal region (P.S75X). Family analysis showed that the patient, her mother, and her sister all carry this variant, suggesting it is a de novo mutation. Computational analysis using various online software tools predicted the variant to be deleterious. The patient was treated with a combination of vitamin B&#x2086;, folic acid, and deferasirox. After six months, the Hb level increased to 104&#xa0;g/L, while the serum ferritin level initially rose and subsequently decreased. This study identified and reported a novel variant, ALAS2 c.224&#xa0;C&#x2009;>&#x2009;A (P.S75X), which led to the co-occurrence of sideroblastic anemia in a male patient with thalassemia. The anemia symptoms induced by this variant were responsive to pyridoxine (vitamin B&#x2086;) supplementation therapy. The online version contains supplementary material available at 10.1007/s00277-026-06984-4.

High-frequency plateletpheresis is crucial for meeting transfusion demands but poses a significant risk of cumulative iron depletion in donors. Current screening protocols relying solely on hemoglobin (Hb) fail to detect latent iron deficiency (LID), a condition where depleted iron stores coexist with normal Hb levels. This study investigated the longitudinal trajectory of iron parameters in high-frequency plateletpheresis donors and quantified the impact of LID on donor deferral and attrition. A retrospective longitudinal cohort study was conducted on 538 eligible plateletpheresis donors at a regional blood center in China from January 2021 to December 2024. Donors were stratified into high-frequency (&#x2265;&#x2009;10 donations/year) and low-frequency (<&#x2009;10 donations/year) groups. Longitudinal changes in serum ferritin and Hb were modeled using Generalized Estimating Equations (GEE), adjusting for time-varying inflammation (WBC) and demographics. The association between baseline LID (ferritin&#x2009;<&#x2009;30 ng/mL) and temporary Hb deferral was assessed using a multivariable modified Poisson regression. Predictors of donor attrition (lapse&#x2009;>&#x2009;12 months) were identified using a time-dependent Cox proportional hazards model. High-frequency donors exhibited a precipitous decline in serum ferritin over four years (&#x3b2; = -0.42, p&#x2009;<&#x2009;0.001), with a significant time-by-frequency interaction (&#x3b2; = -0.15, p&#x2009;<&#x2009;0.001), while Hb levels remained stable. Baseline LID was a potent predictor of future temporary deferral (Adjusted Relative Risk&#x2009;=&#x2009;3.8, 95% CI: 2.6&#x2013;5.5). Survival analysis revealed that both the experience of a deferral event (Hazard Ratio [HR]&#x2009;=&#x2009;2.42, 95% CI: 1.85&#x2013;3.16) and baseline LID (HR&#x2009;=&#x2009;1.58, 95% CI: 1.21&#x2013;2.06) were independent predictors of donor attrition. Subgroup analyses confirmed these risks were consistent across sex, age, and residence status. High-frequency plateletpheresis induces progressive LID that is masked by stable Hb levels. LID serves as a silent precursor to both operational deferral and long-term donor attrition through physiological and psychological pathways. Integrating routine ferritin monitoring and personalized donation intervals into donor management strategies is essential to safeguard donor health and ensure a sustainable platelet supply. The online version contains supplementary material available at 10.1007/s00277-026-06992-4.

Hodgkin Lymphoma (HL) is a heterogeneous malignant disorder in the human body's lymphatic system with distinct clinical and molecular features. The objective of this research was to assess the hematological and molecular status of HL patients in Palestine and explore potential prognostic indicators and potential targets requiring further evaluation. Certain hematological factors, i.e., anemia, increased levels of lactate dehydrogenase, and inflammatory markers, are included in the International Prognostic Score (IPS) for HL. This study highlights the clinical value of accessible hematological biomarkers in resource-limited healthcare settings. A retrospective cohort study was conducted on 557 HL lymph node biopsies (2017-2023) from Palestinian Health Information Center (PHIC) database and hospital medical records. Hematological parameters (hemoglobin, MCV) and biochemical markers (ESR, LDH) were analyzed. Claudin-6 (CLDN6) mRNA expression was quantified in lymph node tissues from HL patients (n&#x2009;=&#x2009;25) and healthy donors (n&#x2009;=&#x2009;25) via qRT-PCR, while protein levels were assessed by Western blot. Serum GATA-4 concentrations were measured by ELISA. Nodular Sclerosis was the most common form, which predominantly occurred in young patients with a relatively equal sex distribution. The highest frequency was found in Hebron. Hemoglobin levels differed between subtypes, with the lymphocyte-depleted subtype showing the lowest mean hemoglobin values; the Lymphocyte-Depleted (LD) subtype exhibited the lowest hemoglobin and MCV (74.77 fL), indicating microcytic anemia. ESR was elevated across subtypes, with the highest levels observed in the NOS (63.5&#xa0;mm/h), reflecting aggressive disease. Male mortality was highest in Mixed Cellularity (87.5%) and NS (75%), while LD and Lymphocyte-Predominant subtypes showed no male deaths. Molecularly, CLDN6 mRNA and GATA-4 levels were significantly elevated in HL tissues (P&#x2009;<&#x2009;0.001), though Claudin-6 protein expression remained unchanged, suggesting post-transcriptional regulation. This study represents the first combined hematological and molecular characterization of Hodgkin lymphoma in Palestine and provides preliminary evidence for CLDN6-GATA4 regulatory involvement in HL pathogenesis. The hematological changes in Palestinian HL patients are unique. The roles of CLDN6 and GATA-4 as potential markers remain preliminary and require further validation in the context of Hodgkin lymphoma.

With the widespread application of third-generation sequencing (TGS) technology, an increasing number of rare or previously unreported &#x3b2;-globin gene variants have been discovered. This study aims to characterize two rare complex &#x3b2;-globin gene variants identified in the Chinese population using TGS, aiming to enrich the spectrum of globin gene variations in this ethnic group. Two unrelated Chinese families residing in Fujian Province were recruited for this study. Hematological screening was conducted via routine blood tests and capillary hemoglobin (Hb) electrophoresis. To detect both common and rare globin gene variants, a combination of conventional thalassemia gene detection, TGS, gap-PCR, and Sanger sequencing was employed. Hematological screening of the proband from Family 1 revealed a decreased Hb level (102&#xa0;g/L), elevated Hb A2 (9.3%), and an abnormal Hb band in zone 10. TGS identified a rare &#x3b1;&#x3b1;&#x3b1;anti4.2 variant co-existing with Hb Stockholm [&#x3b2;7(A4)Glu&#x2009;>&#x2009;Asp; HBB:c.24G&#x2009;>&#x2009;T] in this proband. Pedigree analysis showed that the proband&#x2019;s 6-month-old daughter inherited the &#x3b1;&#x3b1;&#x3b1;anti4.2 variant (presenting with reduced MCV and MCH) but without Hb variant. The 29-year-old female proband from Family 2 exhibited remarkably reductions in MCV, MCH, and Hb A2, along with an abnormal Hb band in zone 12. Conventional testing detected the common &#x2013;SEA deletion, while TGS further identified an additional rare Hb Pyrgos [&#x3b2;83(EF7)Gly&#x2009;>&#x2009;Asp; HBB:c.251G&#x2009;>&#x2009;A] variant combined with a rare IVS-II-180(T&#x2009;>&#x2009;C) (HBB:c.315&#x2009;+&#x2009;180&#xa0;T&#x2009;>&#x2009;C) variant in the proband. This study is the first to describe these two rare complex Hb variants in the Chinese population. Our findings expand the knowledge of rare Hb variants and further strengthen the clinical utility of TGS in thalassemia gene testing. The online version contains supplementary material available at 10.1007/s00277-026-06997-z.