Donna Lancaster

Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial.

A retrospective analysis of children with first relapse of acute lymphoblastic leukaemia (ALL), treated on the UKALL R2 protocol at four different hospitals, between June 1995 and December 2002 was performed. Of the 150 children 139 (93%) achieved a second complete remission. The overall survival (OS) and event‐free survival (EFS) for the whole group was 56% and 47% respectively. The duration of first complete remission and immunophenotype, but not sites of relapse, were predictive for survival. Using the Berlin–Frankfürt–Münster risk stratification for relapsed ALL, the OS and EFS for standard, intermediate (IR) and high risk (HR) groups were 92% and 92%, 64% and 51%, and 14% and 15%, respectively; P < 0·0001 for both OS and EFS. In the IR group, those with a very early isolated central nervous system relapse also had a significantly worse outcome (P = 0·0001). Given the poor outcome of a second relapse, clear strategies are required to identify those in the IR group who will most benefit from stem cell transplantation (SCT). A higher proportion (16%) of induction failures in the HR group suggest the need for novel agents during this phase of treatment, but SCT was associated with a lower relapse rate and better outcome than those treated with chemotherapy alone.

Defibrotide in the prevention and treatment of veno-occlusive disease in autologous and allogeneic stem cell transplantation in children

Hepatic veno‐occlusive disease (VOD) is a common (10–50%) and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We carried out a study to assess whether the use of prophylactic defibrotide in paediatric patients undergoing HSCT results in a lower frequency or severity of hepatic VOD.

Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium

PURPOSE Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.

Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations

Familial non-Hodgkin lymphoma (NHL) is rare and in most cases, no underlying cause is identifiable. We report homozygous truncating mutations in the mismatch repair gene MSH2 (226C→T; Q76X) in three siblings who each developed T-cell NHL in early childhood. All three children had hyperpigmented and hypopigmented skin lesions. Constitutional biallelic MSH2 mutations have previously been reported in five individuals, all of whom developed malignancy in childhood. Familial lymphoma has not been reported in this context or in association with biallelic mutations in the other mismatch repair genes MLH1, MSH6 or PMS2. In addition, hypopigmented skin lesions have not previously been reported in biallelic MSH2 carriers. Our findings therefore expand the spectrum of phenotypes associated with biallelic MSH2 mutations and identify a new cause of familial lymphoma. Moreover, the diagnosis has important management implications as it allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the proband, and the provision of cascade genetic testing and tumour screening for relatives.

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.

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.

Toxicity and Outcome of Children and Adolescents Participating in Phase I/II Trials of Novel Anticancer Drugs: The Royal Marsden Experience

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

ObjectiveIodine-131-labelled meta-iodobenzylguanidine (131I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. Materials and methodsA review of 44 treatments in 25 patients treated with 131I-mIBG therapy was performed. Patients received 131I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. ResultsThe mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. ConclusionA highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized 131I-mIBG therapy.

Intracranial hypertension in pediatric patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) remains one of the most common malignancies of childhood. Between April 1999 and August 2004, 9 of 207 patients treated at a Tertiary Oncology Service for ALL presented with Intracranial Hypertension (IH). Seven of the patients met the diagnostic criteria for Idiopathic Intracranial Hypertension (IIH). Four of the patients were treated with cerebrospinal fluid (CSF) drainage alone and four required Acetazolamide. Two of the four patients who were treated with Acetazolamide required subsequently a lumbar‐peritoneal (LP) shunt. One patient succumbed to his disease before receiving any specific treatment. Pediatr Blood Cancer 2009;52:418–420.

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.