EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixtynine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had p10 000 and p40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P ¼ 0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P ¼ 0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.
Different lymphomas often demonstrate reliably characteristic architectural patterns of marrow involvement which can help differentiate them even when cytological features do not permit this, and marrow stromal and other background changes may also be useful pointers towards a particular lymphoma subtype.
Abbreviations: ADEM = acute disseminated encephalomyelitis; CNS = central nervous system; MRI = magnetic resonance imaging.Bone Marrow Transplantation (2014) 49, 854-856
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of T-lymphocyte deplete allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients with PTLD refractory to Rituximab, donor lymphocyte infusion (DLI) is established as a successful option for salvage therapy. However, although in vivo lymphocyte expansion has been correlated with good clinical outcome following DLI, the specificity and functional characteristics of EBV-specific T-cell responses remain poorly characterized. Here we describe two patients with Rituximab-refractory PTLD complicating T-cell deplete allo-HSCT, both of whom were successfully rescued with 1 × 106/Kg unselected stem cell donor-derived DLI. Prospective analyses revealed that complete clinical and radiological responses were associated with in vivo expansion of T and NK cells. Furthermore, EBV MHC tetramer, and interferon gamma analyses revealed a marked increase in EBV-specific T-cell frequency from 4 weeks after DLI. Reactivity was demonstrated against a range of EBV latent and lytic antigens, including those detected in tumor biopsy material. The immunodominant EBV-specific T cell response expanding in vivo following infusion matched the dominant response present in the DLI preparations prior to administration. Furthermore, differences in the repertoire of subdominant antigen-specific T-cells were also detected, suggesting that antigen-encounter in vivo can shape the immune response. These results demonstrate the value of prospectively studying in vivo T-cell responses, by facilitating the identification of important specificities required for clinical efficacy. Applying this approach on a larger scale promises to yield data which may be essential for the optimization of future adoptive immunotherapeutic strategies for PTLD.
A 62-year-old woman had magnetic resonance imaging (MRI) of the head after presenting with a possible transient ischaemic attack. The MRI demonstrated no evidence of a recent event but showed small T2 intense foci consistent with mature ischaemic lesions. Incidentally, 'a heterogeneous signal throughout the marrow space of the cranial vault' was reported on the axial T2 scan (left) and a lateral skull X-ray was suggested. This showed multiple 'punched out' lytic lesions throughout the skull vault (right) and she was referred to the haematology department urgently with a probable diagnosis of multiple myeloma. On review, she was asymptomatic and had a normal full blood count, creatinine and calcium. She had an IgMj paraprotein that was too low to quantitate and a normal serum free light chain ratio; her urine was negative for Bence-Jones protein. A skeletal survey demonstrated additional lesions in the mandible, some with endosteal scalloping and less convincing lesions in the right distal femur. Bone marrow aspiration and trephine biopsy were performed, these showing just 3% plasma cells. At this point, the differential diagnosis was reconsidered.The skull has two cortical layers with marrow between them. Skull lesions with lytic appearances can arise from the bone itself or occur either by distant metastasis or local invasion. The differential diagnosis for multiple lytic lesions on a skull X-ray in a patient of this age includes: multiple myeloma, metastases (particularly breast, lung, renal and prostate carcinoma), leukaemia, 'brown tumours' (osteitis fibrosa cystica secondary to hyperparathyroidism), venous lakes and vascular channels, Pacchionian granulations (hypertrophied arachnoid villi), benign lipomas and osteoporosis. Lipomas are relatively rare in the bone marrow despite the fact that it is rich in fatty tissue. MRI is useful for the detection of lipomas because they have a homogenous high signal on T1 and suppression on short T1 inversion recovery (STIR) sequences. This distinguishes them from metastases and inflammatory lesions.Our patient went on to have a further MRI showing high signal on T1, suppression on STIR and no enhancement post-contrast, in keeping with a signal of fat in a lobular pattern, that is multiple lipomas giving the X-ray appearances. A computerized tomography (CT) of the body cavities revealed no primary disease. Some lucencies in the axial skeleton on CT were also confirmed to be the signal of fat on axial MRIs. She was reassured and discharged from the haematology clinic.
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