Parameswaran Anoop

The feasibility of plerixafor as a second-line stem cell mobilizing agent in children.

In patients heavily pretreated with myelosuppressive chemotherapy or irradiation, Granulocyte colony stimulating factor (G-CSF) may fail to mobilize stem cells from the bone marrow. Plerixafor is emerging as a reliable alternate option in such situations in adult patients. Robust data in support of the high efficacy and safety of plerixafor are available in adults. Very little evidence is available on the usefulness of this drug among children. We report our experience with plerixafor usage on 5 occasions in pediatric patients, with a success rate of 60%. No significant side effects were encountered in any patient.

Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia.

Abstract Patients with childhood relapsed and refractory mature B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukemia (B-ALL) are rare and have a dismal prognosis. The previous UK national analysis of 26 children over a 7-year period prior to 1996 had highlighted the poor outcome, with only three survivors. This 10-year multicenter study evaluated recent data, since 2000. Of 33 children, nine survived (27.3%), with a median follow-up of 4.3 years. On exclusion of six children treated with palliative intent, the survival was one-third (nine of 27; 33.3%). All patients with primary refractory disease (n = 7) and all except one with early relapse (n = 11) died. Administration of four doses of 375 mg/m2 of rituximab was associated with a longer survival (p = 0.006). Response to reinduction (p < 0.001) and autologous hematopoietic stem cell transplant (auto-HSCT) (p = 0.003) were significant on multivariate analysis. Patients with a time to relapse of at least 6 months are potentially curable and must be offered intensive treatment with salvage chemotherapy, rituximab and auto-HSCT.

Severe liver dysfunction from hepatitis C virus reactivation following alemtuzumab treatment for chronic lymphocytic leukaemia

patients. Although the achievement of transfusion independence may appear delayed compared to the standard 10 mg/d schedule, the reduction of haematological toxicity may be an important aspect in this patient population. In addition, with respect to the more conventional dose reduction schedule of 5 mg/d, our scheme has the advantage of lowering the cost of treatment by 50% in a subset of patients in which costeffectiveness of new generation drugs as compared to best supportive care is still controversial (Goss et al, 2006; Greemberg et al, 2008). Despite the limited series of patients treated and the short follow-up, we believe that the rate of response together with the reduced toxicity and the good economic impact of the adjusted dose, strongly suggest that this schedule should be explored in a larger cohort of patients with 5qMDS.

Ocular and cerebral aspergillosis in a non-neutropenic patient following alemtuzumab and methyl prednisolone treatment for chronic lymphocytic leukaemia

To the Editor, Unlike with acute forms of leukaemia, fungal infections are rare in chronic lymphocytic leukaemia (CLL). Most previous reports have been on patients with prolonged neutropenia or after allogeneic stem cell transplantation (SCT). We would like to document a patient with CLL who had a fungal infection at unusual sites as a result of combination therapy with alemtuzumab (Campath-1H) and methyl prednisolone. This patient was neither neutropenic nor had he received SCT. A 65-year-old man was on treatment with alemtuzumab, methyl prednisolone and ciclosporin for relapsed CLL and autoimmune haemolytic anaemia. He had a neutrophil count of 2.7 9 10/L with normal serum levels of immunoglobulins and was hence not on prophylactic antimicrobials. He presented with acute onset of pain in his right eye and developed a partial loss of vision in his right temporal field over the next 24 h in the absence of fever or raised inflammatory markers. He was referred to a tertiary care centre for ophthalmological evaluation and management. Examination of the right eye revealed pan-uveitis with a vitreous abscess (Fig. 1). A vitreous biopsy showed infection by Aspergillus fumigatus. MRI scan of the brain revealed a 4 mm ring-enhancing lesion in the cortex of the left frontal lobe, consistent with cerebral aspergillosis (Fig. 2). Toxoplasma serology was negative. A highresolution CT scan of his chest was normal. He was treated with oral voriconazole and intravitreal amphotericin instillations complicated by vitreal haemorrhage due to thrombocytopenia. Both the fungal infection and the haemorrhage improved over the next 6 weeks and his vision cleared gradually. A repeat MRI scan of his brain showed complete resolution of the lesion. The combination of alemtuzumab and high-dose methyl prednisolone (CamPred) is now increasingly being used to treat patients with CLL refractory to purine analogues and those with deletions of the TP53 gene [1–3]. Alemtuzumab, a humanised anti-CD52 monoclonal antibody, targets both B and T lymphocytes in addition to monocytes, macrophages and a subset of antigen-presenting dendritic cells. It thus significantly impairs the immunological surveillance mechanisms against infections. Whilst on this heavily immunosuppressive regimen, a high index of suspicion against viral reactivations and fungal

Evaluation of an immunoturbidimetric D-dimer assay and pretest probability score for suspected venous thromboembolism in a district hospital setting

Abstract Venous thromboembolism is a leading cause of co-morbidity and death in hospital patients. This observational study looks at the usefulness of pretest probability and immunoturbidimetric D-dimer levels for the diagnosis of thromboembolic episodes in outpatients (108 of 197; 54·8%) and inpatients (89 of 197; 45·2%). Across 197 consecutive patients, D-dimers showed 100% sensitivity (95% CI, 87–100%). As a result, the combination of normal D-dimers and low or intermediate probability score yielded a negative predictive value of 100% (95% CI, 90·6–100%). The tests lacked specificity and positive predictive value. Normal D-dimer level in patients with low or intermediate pretest probability makes venous thromboembolism an unlikely diagnosis and may obviate the need for confirmatory scans. All other patients will need diagnostic imaging. Clinicians should be aware of the above utility and limitations while making management decisions for patients with suspected thromboembolism.

Transient erythrocyte changes caused by infiltration of liver by plasma cell leukemia

Marked erythrocyte anisopoikilocytosis was noted in a 52-year-old man with relapsed IgD multiple myeloma. Complete blood count showed a white cell count of 14,100/mm with 40% circulating plasma cells. Most of the red blood cells (RBCs) were either target cells or microspherocytes, with occasional acanthocytes, stomatocytes, and knizocytes (Images 1 and 2a). The direct antiglobulin test was negative. He had no history of a hemoglobinopathy or an RBC membrane disorder and had normal erythrocyte morphology during remission. He had renal impairment and grossly deranged liver function with elevated alanine aminotransferase of 128 u/l (normal <40 u/l), gamma glutamyltransferase of 591 u/l (normal <50 u/l) and bilirubin of 174 umol/l (normal <17 umol/l). An ultrasound scan (USS) of liver showed hepatomegaly with diffusely abnormal coarse echogenicity, consistent with infiltration by myeloma. He had hypercalcemia and hypophosphatemia at presentation, which resolved with treatment over the next 3 weeks.He was treated with a combination of bortezomib, doxorubicin, and dexamethasone, to which he responded rapidly with clearance of plasma cells, normalization of liver function, improvement in renal function and reduction of paraprotein level. All the red cell changes disappeared serially over a period of 4 weeks (Image 2b–d). USS of liver was repeated at this stage and showed normal size and echo pattern of liver. In retrospect, this patient had hepatic infiltration by plasma cell leukemia, which reversed completely with chemotherapy. The RBC changes were secondary to this and all abnormalities resolved with return of normal liver function. Target cells and acanthocytes are well described changes with hepatic dysfunction and are believed to be the result of net membrane accumulation of cholesterol, alteration in phospholipids and decreased lecithin cholesterol acyltransferase (LCAT) activity [1,2]. Knizocytes are triconcave red cells with a band of hemoglobin in the center with an area of pallor on either side and are known to occur in hemolytic states or liver dysfunction. The prominent acquired microspherocytosis noted in this patient is more difficult to explain. In the absence of autoimmune hemolysis, the most likely reason for spherocytosis was the hypophosphatemia which persisted until the 3rd week of treatment. Depletion of phosphate can cause low erythrocyte adenosine triphosphate levels, which in turn can result in spherocytosis [3]. Reversible erythrocyte anisopoikilocytosis of such severity has not been reported so far in conjunction with hepatic infiltration by plasma cell leukemia.

Epstein-Barr virus infections after allogeneic stem cell transplantation: a comparison between non-malignant and malignant hematological disorders.

Abstract Hematological cancers and non-malignant hematological disorders are biologically diverse conditions and are treated differently. We compared the pattern of EBV infections following allogeneic stem cell transplantation between the above two groups of hematological disorders. Eighty-three transplants were evaluated over a consecutive 7-year period at a single center. No difference was found in the incidence of post-transplant EBV infections between the two groups, though a higher median peak viral load was noted in the non-malignant group (P=0·04). Pre-transplant immunosuppressive therapy with antithymocyte globulin (ATG) significantly increased the risk of post-transplant EBV infections (P=0·04) in the non-malignant group patients. No significance was found for prior cytotoxic chemotherapy among the malignant group of patients. Alemtuzumab based conditioning was not associated with an increased risk for EBV infections in either of the groups. Treatment with two or more courses of ATG was found to be significantly associated with post-transplant EBV-related PTLD (P=0·01). Post-transplant EBV infections did not influence overall survival (non-malignant, P=0·66; malignant, P=0·41) in either of the subgroups. There were no deaths directly attributable to EBV infections.

First report of fatal human infections with the cactophilic yeast Sporopachydermia cereana

Sporopachydermia cereana is a cactophilic yeast, which is not recognised as a human pathogen. We describe two fatal infections with this fungus in profoundly neutropenic patients. S. cereana escapes detection by conventional mycological identification methods. This organism may be an under-recognised cause of fatal fungal sepsis among immunocompromised patients.

Rheumatologic manifestations of benign and malignant haematological disorders

Diseases of blood and lymphoreticular system can have multisystem manifestations. Rheumatologic involvement has been reported in association with many benign and malignant haematological disorders; these patients are equally likely to present to both clinical rheumatologists and haematologists. This review focuses on the well-described rheumatologic features, other occasionally reported rheumatologic manifestations and unusual musculoskeletal complications related to the treatment in patients with underlying haematological conditions. The aim of this review is to help increase the awareness of rheumatologic manifestations seen in the blood disorders and to highlight the potential diagnostic pitfalls.

Clinical profile and outcome of urotheliotropic viral haemorrhagic cystitis following haematopoietic stem cell transplantation: a 7-year tertiary centre analysis

Abstract Viral haemorrhagic cystitis (HC) is a significant complication after haematopoietic stem cell transplantation (HSCT), with a potential for major morbidity. The aim of this 7-year analysis of 1160 HSCT patients was to evaluate risk factors for the incidence, severity, toxicity of therapy, clinical course, and outcome of this condition. The overall incidence of HC was 5·8%, with most cases occurring after allogeneic HSCT. Unrelated donors (P = 0·001), non-peripheral blood stem cell source (P = 0·005), myeloablative conditioning (P<0·001), use of alemtuzumab in conditioning (P = 0·001), and severe acute graft versus host disease (P<0·001) were independent risk factors for an increased incidence of HC post-allogeneic transplant on multivariate analysis. Severe forms of HC were associated with grades II–IV acute graft versus host disease and a longer duration of haematuria. Contrary to previous studies which were carried out on smaller patient populations, busulphan, cyclophosphamide, anti-thymocyte globulin, and total body irradiation were not found to independently increase the risk of viral HC, unless used in a myeloablative combination. Neither duration of viriuria nor peak viral load in urine influenced the severity of HC on multivariate analysis. Severe HC contributed to the deaths of two patients. Overall survival was not statistically different between patient subgroups with non-severe and severe HC.