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Less than 5% of patients with CLL undergo histological transformation to diffuse large B cell lymphoma (DLBL) while transformation to Classical Hodgkins lymphoma (CHL) is also recognised. It has been assumed that such events reflect genetic changes in the CLL clone but there is now emerging evidence to suggest that at least some transformation events may be Epstein Barr virus (EBV) related neoplasms not clonally related to CLL. In this analysis we have reviewed the clinical and laboratory features of 15 CLL patients with biopsy proven histological transformation to DLBL and 2 patients who developed CHL. Histological sections were assessed for the expression of a wide range of immunophenotypic markers as well as EBV latent membrane protein 1 (LMP-1). Of the 15 patients developing DLBL 5 appeared on phenotypic grounds to be related to the underlying CLL clone. In the remaining patients the tumour cells appeared phenotypically distinct as they lacked CD5 and CD23 and demonstrated expression of germinal centre markers in some instances. LMP1 positivity was demonstrable in 5 patients with DLBL (1 apparently related and 4 unrelated to the underlying CLL). Of the 2 patients who developed CHL 1 was associated with EBV and lacked CD20 expression. The 6 patients with EBV+ tumours were heavily pretreated (median prior therapies 4, range 1–5) while the median time from original diagnosis to histological transformation was 74.5 months (range 17–114). Previous therapies included chlorambucil (n= 4), fludarabine monotherapy (n=3), FC (n=2), FCR (n=1 patient), high dose methyl prednisolone (n= 1) and alemtuzumab (n=2). 2 patient received only one line of therapy for CLL but one of these was heavily immunosuppressed with steroids and azathioprine for autoimmune neutropenia. 4 patients presented with nodal disease and 2 patients presented with extranodal disease (bone marrow and liver). The outcome of the EBV associated tumours in these patients was death in 2 patients (opportunistic infection and complications of intensive chemotherapy), remission with intensive combination chemotherapy in 2 patients one of whom died 10 months later of progressive CLL and spontaneous remission of nodal disease in 1 patient. 1 patient is still undergoing intensive chemotherapy and the outcome is not known yet. We would conclude that not all transformation events in CLL occur within the original clone. The majority appear to be clonally distinct and a significant proportion of these appear to be EBV associated. This presumably occurs as a result of both the underlying immune-deficiency seen in CLL as well the potent immunosuppressive agents given as therapy. This phenomenon may also be a feature of other B-cell disorders as we have recently seen a phenotypically and genotypically distinct EBV associated DLBL in a patient treated with chlorambucil, CHOP and FCR for mantle cell lymphoma. The natural history of these tumours remains uncertain at this stage but it is clear that at least a minority may resolve spontaneously. All biopsies demonstrating histological transformation in CLL patients should be assessed for the presence of EBV.

Cancer patients have historically had a very poor outcome following ICU admission. Outcome has however improved over the last decade. We aim to identify factors that predict survival for critically ill patients with hematological malignancy and which can be readily identified prior to admission. This would improve selection of patients suitable for ICU admission, which represents a limited resource. We also assessed the ability of the APACHE II score to predict prognosis in these patients. Since the ICU admission case mix will vary between hospitals, one non-surgical admission within +/− 1 week of each hematological admission acted as a control group. Factors which might affect outcome were assessed by multivariate regression analysis. Factors included were age, hematological diagnosis (acute or chronic leukemia, myeloma, lymphoma), time from hematological diagnosis to ICU admission (0–6 months, 6–12 months, >12 months), degree of prior treatment (admission prior to diagnosis, during first line therapy, after first line), remission status, prior stem cell transplant, documented infection and length of neutropenia (none, 1–10 days, >10 days). For hematology patients, predicted hospital mortality was calculated from the APACHE II score by the formula of Knaus et al (Critical Care Medicine 1985). The APACHE scores of hematology patients were compared to controls by a two-sample t test. Predicted and actual mortalities were compared using a one sample test of proportion. The impact of mechanical ventilation (MV) on mortality was assessed by risk ratios. We identified 111 patients with hematological malignancy (acute leukemia n=42, chronic leukemia n=11, myeloma n=19 and lymphoma n=39) admitted to ICU in one teaching and three district general hospitals (November 2000 - January 2006). Median age of hematological patients was 59 years (range 17–84) and M: F ratio 1.22:1. Control patients (n=111) were similar with median age 63 years (range 17–86) and M: F ratio 1.09:1. For control patients, overall ICU and hospital survival rates were 70% and 55% respectively while survival for hematology patients was approximately half at 44% and 24% respectively. In multivariate regression analysis, only increasing age predicted poor outcome (p=0.016). There was a trend to poor outcome if patients were not in complete remission (p=0.066) or had documented infection (p=0.06). All other variables were not significant. APACHE scores were significantly higher in hematology patients (median 27) compared to controls (median 19) p<0.001. Predicted hospital mortality for hematology patients was 56%, significantly lower than actual mortality (77%) p<0.001. For controls, hospital survival was slightly reduced for MV v’s not receiving MV (risk ratio = 1.37; 95% C.I. = 0.91, 2.05). Hematology patients hospital survival was significantly worse for MV - 5/55, 9% v’s no MV 20/44, 45% (risk ratio = 5.00; 95% CI = 2.04, 12.50). The pre-admission variables assessed did not predict mortality and should not be used for this. Despite high APACHE scores, predicted hospital mortality underestimated mortality for patients with hematological malignancy. Need for MV still predicts poor outcome in this group but without MV nearly half survive to hospital discharge.