Ayad Atra

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkins lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n= 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n= 39); IIIB with abdominal multiorgan involvement (n= 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n= 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12–92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2–92.1%) and 83.7% (95% CI 76.3–89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.

Outcome of relapsed or refractory childhood B‐cell acute lymphoblastic leukaemia and B‐cell non‐Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols

Twenty‐six children with B‐cell acute lymphoblastic leukaemia (B‐ALL) or Murphy Stage III or IV B‐cell non‐Hodgkins lymphoma (B‐NHL) progressed or relapsed after first‐line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (nu2003=u200362) or a slightly less intensive regimen (UKCCSG 9002) (nu2003=u2003112). Eight patients (4·6%) never achieved complete remission (CR) and 18 (10·3%) relapsed. Second‐line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11·5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second‐line therapy. This study confirms that the prognosis of relapsed or refractory B‐ALL/B‐NHL is poor and exceptionally so if relapse occurred less than 6u2003months from diagnosis. High‐dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

Conservative management of follicular non-Hodgkin's lymphoma in childhood.

Among 447 children with non‐Hodgkins lymphoma (NHL) on the childhood U.K. registry, seven children with follicular (NHL) were identified. Four were male and their age ranged from 4.25 to 13.5 years (median 7.5); all had localized disease, Murphys stage I (nu2003=u20034) and II (nu2003=u20033). Sites involved at presentation were cervical lymph nodes and tonsils (nu2003=u20035), ileum (nu2003=u20031) and parotid gland (nu2003=u20031). Three had complete surgical excision only and four had complete (nu2003=u20031) or incomplete excision (nu2003=u20033) followed by a short multi‐agent chemotherapy regimen (UKCCSG 9001 protocol). With a median follow‐up of 1.5 years (range 0.25–5 years) from diagnosis, six are alive in complete remission (CR) including three who had no chemotherapy.

High-dose chemotherapy in soft tissue sarcoma in children.

Soft tissue sarcomas (STS) are highly malignant tumours that constitute 5-6% of all malignant childhood neoplasms. Of these, rhabdomyosarcoma (RMS) is the most common in children, and has a characteristic two-peak age incidence, 2-5 and 15-19 years. Most children with RMS are cured with conventional chemotherapy and local therapy (surgery with or without radiotherapy). Children with metastatic disease at presentation, particularly those older than 10 years or with bone marrow or bone involvement have a much poorer outcome. In this subgroup, high-dose therapy with stem cell rescue has been studied over the last two decades. Various single or multiagent chemotherapy regimens with or without radiotherapy and autologous stem cell rescue have been used as consolidation treatment with little success. Recent trials using sequential high-dose chemotherapy in the early phase of treatment have proved to be feasible, but the beneficial effect has to be confirmed. The role of purging remains unclear. Collaboration between different international groups is urgently required, in an attempt to improve the poor outcome of children with high risk STS.

ChlVPP chemotherapy in children with stage IV Hodgkin's disease: results of the UKCCSG HD 8201 and HD 9201 studies

Summary. We reviewed the results of two consecutive United Kingdom Childrens Cancer Study Group (UKCCSG) studies of children with stage IV Hodgkins Disease (HD) treated between January 1982 and December 1999. Among 697 children with HD, 67 were diagnosed to be stage IV. The median age at diagnosis was 12·7 years (range 4·4–16·2). Thirty‐five (52%) were boys. Thirty‐nine patients (58%) had B symptoms at diagnosis. All were treated with 6–8 cycles of ChlVPP chemotherapy regimen (Chlorambucil, Vinblastine, Procarbazine and prednisolone) and only 12 had radiotherapy. The overall survival (OS) at 5 and 10 years was 80·8% and 77·2%, respectively, whilst the event‐free survival (EFS) at the same time intervals was 55·2% and 48·8% respectively. Twenty‐eight patients (41·79%) relapsed/progressed, 18 (64%) survived after further chemotherapy with or without high‐dose therapy and stem cell rescue. Twelve patients died, seven of HD, three from infections and one from secondary acute myeloblastic leukaemia (AML). Although the EFS in this study was lower than other studies, 64% of relapsed patients were salvaged with second‐line therapy. It is also anticipated that survivors treated with this non‐anthracycline‐containing regimen will have less long‐term toxicity.

An Economic Evaluation of the Use of Granulocyte Colony-Stimulating Factor After Bone Marrow Transplantation in Children

SummaryStudies that have assessed the use of granulocyte colony-stimulating factor (G-CSF) following bone marrow transplantation have shown a significantly reduced time to neutrophil recovery with the use of this agent, which may translate into a reduced duration of antimicrobial therapy and hospitalisation.We performed a pharmacoeconomic study evaluating the elective use of GCSF after bone marrow transplantation in children. 22 consecutive children who underwent bone marrow transplantation and received G-CSF 5μg/kg/day were compared with 18 such children (control group) who did not receive G-CSF.Despite a significant reduction in time to recovery of the absolute neutrophil count (ANC) to >0.5 × 109/L in G-CSF recipients compared with the control group (14 days vs 20.9 days; p < 0.0001), there was only a trend towards a reduction in the duration of intravenous antimicrobial therapy (14.5 days vS 18.6 days; p = 0.15), and there was no significant difference in the duration of hospitalisation (25.3 days vs 29.8 days). Reasons for prolonged hospitalisation beyond ANC recovery included continued use of total parenteral nutrition, treatment of graft-versus-host disease and treatment of ongoing infection.Overall, the mean total cost for patients receiving G-CSF was £ 15 001, compared with £ 15482 for the control group (1995 values).In conclusion, while there appears to be no benefit in financial terms, the release of a child from strict isolation as a result of early ANC recovery must be taken into consideration.n

Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma: is rechallenging safe?

Severe hyperlipidaemia with asparaginase therapy is rare. We report six cases, four of which developed significant problems with severe hyperlipidaemia during induction therapy for ALL and lymphoblastic lymphoma. The median triglyceride level was 22.3xa0mmol/L and the median cholesterol level was 12.3xa0mmol/L. None of the patients showed signs or symptoms of pancreatitis. Three children were re-exposed with Peg asparaginase, and one with Erwinia asparaginase, without recurrence of hyperlipidaemia or other symptoms. These cases highlight the dilemma in managing such rare cases of symptomatic hypertriglyceridaemia secondary to asparaginase and steroid therapy.

Isolated parenchymal lung involvement in children with stage IV Hodgkin's disease: results of the UKCCSG HD8201 and HD9201 studies

Summary. We retrospectively reviewed the case notes of 27 patients who were diagnosed with stage IV Hodgkins disease (HD) because of isolated parenchymal pulmonary involvement on chest radiograph and computerized tomography scan (excluding subcategory E). Ten were boys and 15 had B symptoms. Median age at diagnosis was 13·6u2003years (range 6·1–16·2). All received 6–8 cycles of ChlVPP (chlorambucil, vinblastine, procarbazine and prednisolone) and two had additional whole lung irradiation (12u2003Gy). Ten patients (37%) relapsed or progressed. Seven survive following second‐line therapy while three died, two of HD and one of secondary acute myeloid leukaemia 4u2003years from diagnosis. At the time of analysis, the median follow‐up of patients was 56u2003months (range 9–127). The event‐free survival (EFS) was 58·4% (95% CI 38·5–75·8%) at both 5 and 10u2003years from diagnosis, and the overall survival (OS) was 84·2% (95% CI 61·8–94·6%) at both 5 and 10u2003years from diagnosis. We conclude that the outcome for HD patients defined as stage IV, because of isolated parenchymal lung involvement, is encouraging and compares favourably with other extra lymphatic organ involvement. Combination chemotherapy is effective in achieving long‐term remission and whole lung irradiation is unnecessary.

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 (Pu200a=u200a0·001), non-peripheral blood stem cell source (Pu200a=u200a0·005), myeloablative conditioning (P<0·001), use of alemtuzumab in conditioning (Pu200a=u200a0·001), 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.

Osteolytic Presentation of Pediatric Acute Megakaryoblastic Leukemia

Leukemic bone pain is classically caused by periostitis, bone infarcts, and synovial infiltration [1]. Lytic painful lesions of the skeleton are rare in acute leukemia, especially in children. A 2-year-old boy with multiple lytic bony lesions, referred as a case of disseminated Langerhans cell histiocytosis (LCH), is described here. Clinical presentation was with pain involving proximal thighs, vertebral column, and over the skull. He was pale and refused to bear weight. He had a low hemoglobin level of 7.6 g/dL, white blood cell (WBC) count of 14,000/mm3 with neutrophils 8500/mm3, and thrombocytopenia of 119,000/mm3. Peripheral blood smear did not show blasts. A skeletal survey revealed widespread small lytic lesions throughout the calvarium (Figure 1) and ill-defined lucencies in the metaphyseal region of both femora. Flattening and loss of height of T11, T12, L1, L3, and L5 vertebral bodies were noted. Serum calcium level was within normal limits. Bone marrow aspirate revealed heavy infiltration with pleomorphic megakaryoblasts. Mononuclear to multinucleated blasts were present, with open nuclear chromatin and occasional nucleoli. Cytoplasm was abundant with marked blebbing, resembling “budding off” of platelet fragments (Figure 2). Many giant platelets were seen. A morphological diagnosis of acute megakaryoblastic leukemia (FrenchAmerican-British classification acute myeloid leukemia [FAB AML] subtype M7) was confirmed by flow cytometry, with a CD13− CD33− aMPO− CD117+ HLADR− CD64− CD41+ phenotype. This classical megakaryoblast morphology with cytoplasmic blebbing is reported in about 40% of non–Down syndrome AML M7 in children. The remainder of cases show completely undifferentiated blasts with prominent nucleoli and vacuolated cytoplasm [2]. Cytogenetic testing showed a normal male karyotype with no clonal abnormalities. AML M7 is rarely encountered in children in the absence of trisomy 21 or t(1;22). Pediatric hemato-oncologists should be aware of this osteolytic presentation of AML M7 [3].