Mary Taj

Efficacy and tolerability of high‐dose methotrexate in central nervous system positive or relapsed lymphoproliferative disease following liver transplant in children

Childhood post‐transplant lymphoproliferative disease (PTLD) is a heterogeneous condition in which treatment varies, from the reduction of immunosuppression to moderately intensive chemotherapy. While low‐dose chemotherapy/rituximab has been found to be effective, moderately intensive chemotherapy is required for patients who relapse, have classic non‐Hodgkin lymphoma or have fulminant PTLD. Methotrexate (Mtx) is highly effective in lymphomas and crosses the blood‐brain barrier. However, there are no data in the literature regarding its safety in post‐liver transplant patients. We describe four cases of high‐grade lymphomas (three diffuse large B cell and one T‐cell lymphoblastic), post‐liver transplant, for which chemotherapy including high‐dose Mtx (HDMTX) was the treatment of choice. In total, 20 doses of HDMTX (1–5 g/m2) were given. The treatment was well tolerated and all four patients had a good response. One case of central nervous system (CNS) diffuse large B‐cell lymphoma was treated with HDMTX alone. We conclude that, in the absence of significant organ damage, HDMTX can safely be given to liver transplant patients, but should only be administered in specialist oncology units. Proof of effectiveness as a single agent in CNS lymphoma needs further studies.

Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia

Clofarabine is a second‐generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine‐based chemotherapy regimes were effective and well‐tolerated in this heavily pre‐treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.

Immunogenicity of Pandemic (H1N1) 2009 Vaccine in Children with Cancer in the United Kingdom

BACKGROUND Children with cancer have an increased susceptibility to influenza infection. The objective of this study was to assess the immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer. METHODS Children were recruited from the Royal Marsden Hospital, England, during November 2009. The vaccination schedule consisted of 2 doses of an AS03(B)-adjuvanted vaccine given at days 0 and 21. Serological analysis was performed on blood samples obtained at day 0 and day 42. The primary immunological end point was the seroconversion rate, which was defined as the proportion of subjects with an individual 4-fold increase in hemagglutination inhibition titer and a postvaccination hemagglutination inhibition titer ≥1:32. RESULTS Fifty-four children with a median age of 6.3 years (range, 1.4-16.6 years) were vaccinated and had samples taken for serological analysis. Twenty-four (44.4%) of 54 children demonstrated seroconversion. Seroconversion rates were 33.3% (9 of 27) among children with acute lymphoblastic leukemia, 36.4% (4 of 11) among those with lymphoma or other leukemias, 66.7% (6 of 9) among those with brain tumors, and 71.4% (5 of 7) among those with other solid tumors. Seroconversion occurred in 4 (28.6%) of 14 children receiving acute lymphoblastic leukemia maintenance therapy. Univariate analysis showed significantly higher responses among children with solid tumors, compared with those with hematological malignancies (11 [68.8%] of 16 vs 13 [34.2%] of 38; P = .03), and among those not receiving treatment, compared with those receiving treatment (7 [87.5%] of 8 vs 17 [37.0%] of 46; P = .02). Multivariable analysis showed that age, cancer type, and lymphopenia did not influence seroconversion rates. CONCLUSION These data suggest that this AS03(B)-adjuvanted pandemic (H1N1) 2009 vaccine can induce limited but useful protective immune responses in children with cancer.

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.

Single agent efficacy of rituximab in childhood immunosuppression related lymphoproliferative disease: A United Kingdom children’s cancer study group (UKCCSG) retrospective review

Survival in childhood lymphoproliferative disease (LPD) remains poor, particularly in non-transplant patients. The anti-CD20 antibody rituximab shows promise but data in children is scant. A retrospective study of 22 (aged 11 months to 18 years) children treated with rituximab is presented. Two had primary immunodeficiency, two had prolonged immunosuppression and 18 had post-transplant LPD (eight bone marrow, five liver, four heart, one kidney). Nine patients had multi-organ involvement and 13 single site disease. Seventeen out of 22 had rituximab alone. In 16, a dose of 375 mg/m2 i.v. weekly was used (less in one patient due to renal dysfunction). Twelve patients received four courses and ten patients received one to three courses. Fever was the main side-effect in four. Eight (47%) had single agent response; four complete and four partial. All had other treatment prior to rituximab. Median follow-up was 35 months (range 22 – 47 months). In childhood LPD unresponsive to standard treatment, rituximab showed single agent response and requires further evaluation.

Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia.

Bacigalupo, A., Bruno, B., Saracco, P., Di Bona, E., Locascuilli, A., Locatelly, F., Gabbas, A., Dufour, C., Arcese, W., Testi, G., Broccia, G., Marotenuto, M., Coser, P., Barbui, T., Leoni, P. & Ferster, A. for the European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anaemia and the Gruppo Italiano Trapianti di Midollo Oseeo (GITMO) (2000a) Antilymphocyte globulin, cyclosporine, prednisolone and granulocyte stimulating factor for severe aplastic anaemia: an update of the GITMO/EBMT study on 100 patients. Blood, 95, 1931–1933. Bacigalupo, A., Brand, R., Oneto, R., Bruno, B., Socie, G., Passweg, J., Locasciulli, A., Van Lint, M.T., Tichelli, A., McCann, S., Marsh, J., Ljungman, P., Hows, J., Marin, P. & Schrezenmeier, H. (2000b) Treatment of acquired severe aplastic anaemia: bone marrow transplantation compared with immunosuppressive therapy – the European Group for Blood and Marrow Transplantation experience. Seminars in Haematology, 37, 69–80. Bacigalupo, A., Locatelli, F., Socie, G., Dini, G., Pession, A., Locasciulli, A., Prete, A. & Schrezenmeier, H. (2002) Fludarabine, cyclophosphamide and ATG for alternative donor transplants in aplastic anaemia – a report of the SAA Working Party. Bone Marrow Transplantation, 29(Suppl. 2), 312a. Brodsky, R.A., Sensenbrenner, L.L., Smith, B.D., Dorr, D., Seaman, P.J., Karp, J.E., Brodsky, I. & Jones, R.J. (2001) Durable treatmentfree remission following high dose cyclophosphamide for previously untreated severe aplastic anaemia. Annals of Internal Medicine, 135, 477–483. Tisdale, J.F., Dunn, D.E., Geller, N., Plante, M., Nunez, O., Dunbar, C.E., Barrett, A.J., Walsh, T.J., Rosenfeld, S.J. & Young, N.S. (2000) High dose cyclophosphamide in severe aplastic anaemia: a randomised trial. Lancet, 356, 1554–1559. Tisdale, J.F., Maciejewski, J.P., Nunez, O., Rosenfeld, S.J. & Young, N.S. (2002) Late complications following treatment for severe aplastic anaemia (SAA) with high-dose cyclophosphamide (Cy): follow up of a randomised trial. Blood, 100, 4668–4670.

Prognosis of patients with t(8;16)(p11;p13) acute myeloid leukemia

Acute myeloid leukemia (AML) accounts for 15% cases of childhood leukemia and 80% of leukemia in adults. Historically, outcome has been poor, with a 5-year overall survival (OS) of 45–66% and event...

Preliminary experience on the use of PET/CT in the management of pediatric post-transplant lymphoproliferative disorder

Post‐transplant lymphoproliferative disorder (PTLD) is a well‐known complication following prolonged immunosuppression. Contrary to other lymphomas, there is no standardized imaging approach to assess PTLD either at staging or for response to therapy. Positron emission tomography/computed tomography (PET/CT) is an imaging modality that has proven to be useful in lymphoma. However, there is still limited data concerning its use in pediatric PTLD. Our study evaluates the use of PET/CT in pediatric PTLD at our institution.

Long-term outcome for immune suppression and immune related lymphoproliferative disorder: prospective data from the United Kingdom Children's Leukaemia and Cancer Group registry 1994–2004

Abstract Prospective national registry data on 98 patients were studied to determine the long-term outcome of immune related lymphoproliferative disease (LPD) and define prognostic factors. Seventy-three developed LPD following organ transplant (26 liver, 21 heart, 15 kidney, nine bone marrow [BM], two bowel). Twenty-five had non-transplant related immunosuppression. Age was 1.1–17 years (median 8.6). Fifty-eight patients had lymphomatous, 21 systemic and 17 lymphadenopathic disease. Sixty (73%) were disseminated and 22 (27%) localized. Thirty-three (54%) were monoclonal. Seventy-three (83%) were Epstein–Barr virus (EBV) positive. Median follow-up was 7.6 years. LPD developed earlier after liver and BM as compared to heart or kidney transplant. Five-year overall survival (OS) was 58%. Prognosis was best after liver and kidney transplant (OS >77%). Mortality was higher following heart (2.5 times) and BM transplant (5 times). Adverse prognostic factors were disseminated or lymphomatous disease and lack of reduction of immunosuppression. With appropriate reduction of immunosuppression, rituximab and low-dose chemotherapy, long-term survival is high.

Childhood precursor B-cell acute lymphoblastic leukaemia and monosomy 7 with phenotypic shift at relapse; evidence for the stem cell origins of monosomy 7.

WalidSh ElSayed Peyman Eshghi Ebrahim Miri-Moghaddam Azita Zadeh-Vakili AlexanderF. Markham Rashida Anwar Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK, Shahid Beheshti Medical University, Tehran, Department of ImmunoHaematology, Zahedan University of Medical Science, and Department of Genetics, Zahedan University of Medical Science, Zahedan, Iran. E-mail: r.anwar@leeds.ac.uk