Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: data from 56 children treated on NOPHO-AML protocols and a review of the literature

Abstract Children with Down syndrome (DS) and myeloid leukaemia have a significantly higher survival rate than other children, but they also experience considerable treatment-related toxicity. We analysed data on 56 children with DS who were treated on the Nordic Society for Paediatric Haematology and Oncology-acute myeloid leukaemia (NOPHO-AML)88 and NOPHO-AML93 protocols and reviewed the literature. In the dose-intensive NOPHO-AML88 protocol, 8 out of 15 patients (53%) experienced an event. In the less dose-intensive NOPHO-AML93 protocol, 7 out of 41 patients (17%) had an event. Therapy was reduced in 29 patients (52%) with in average 75% and 67% of the scheduled dose of anthracycline and cytarabine, respectively. Treatment-related death occurred in seven who all received full treatment. Relapse and resistant disease occurred at a similar rate in those receiving full and reduced treatment. Review of major series of myeloid leukaemia of DS showed no clear relationship between dose and survival; however, it appears that both a reduction in treatment dose and a less intensively timed treatment regimen improved the outcome. Further studies are needed to define the optimal regimen for treating myeloid leukaemia of DS

To Justice H.B. Higgins

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldDespite continuously more successful treatment of childhood acute lymphoblastic leukaemia (ALL), 2-5% of children still die of other causes than relapse. The Nordic Society of Paediatric Haematology and Oncology-ALL92 protocol included 1652 patients < or =15 years of age with precursor B- and T-cell ALL diagnosed between 1992 and 2001. Induction deaths and deaths in first complete remission (CR1) were included in the study. A total of 56 deaths (3%) were identified: 19 died during induction (1%) and 37 in CR1 (2%). Infection was the major cause of death in 38 cases. Five patients died of early death before initiation of cytotoxic therapy. Five patients died because of toxicity of inner organs and one of accidental procedure failures. Seven patients died of complications following allogenic haematopoietic stem cell transplantation (HSCT) in CR1. Girls were at higher risk of treatment-related death (TRD) [relative risk (RR) = 2.2; 95% confidence interval (CI(95%)): 1.2-4.0, P < 0.01], mostly because of infections. Risk of TRD was also higher in children with Down syndrome (RR = 4.5; CI(95%): 2.0-10.2, P < 0.00). In conclusion, 3% of children with ALL died of TRD, with bacterial infections as the most common cause of death. Girls and Down syndrome patients had a higher risk of TRD. Infections still remain a major challenge in childhood ALL

Early and treatment-related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984-2003

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldDespite major improvements in the cure rate of childhood acute myeloid leukaemia (AML), 5-15% of patients still die from treatment-related complications. In a historical prospective cohort study, we analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment-related deaths (TRD) in 525 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-84, -88 and -93 trials. Seventy patients (13%) died before starting treatment or from treatment-related complications. The death rate rose from 11% in NOPHO-AML-84 to 29% in -88, but then fell to 8% in -93. Sixteen patients (3%) died within the first 2 weeks, mainly from bleeding or leucostasis. Hyperleucocytosis, age <2 or ≥10 years were risk factors. After day 15, 10% of patients died from treatment-related complications with infection as the main cause of death. Risk factors were age <2 or ≥10 years and treatment according to the NOPHO-AML-88 protocol. The number of EDs and TRDs in AML is high. Therefore optimal antifungal prophylaxis is essential, and studies on the benefit of antibacterial prophylaxis and individual risk factors for ED and TRD are needed

Unidentified actor as Hassan, an unidentified actor as the Caliph and the soldiers in the J.C. Williamson London production of Hassan and how he came to make the golden journey to Samarkand, act 5 scene 1 The garden, 1923 [picture] /

From: Hassan : and how he came to make the golden journey to Samarkand / James Elroy Flecker ; arranged for the stage by Basil Dean ; music by Frederick Delius.; Condition: Damage on edges.; Inscriptions: "Caliph ordering Hassan to see the torture"--Handwritten, on verso.; Part of the collection: J.C. Williamson collection of photographs.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3805710; No programs held in PROMPT collection

Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThree consecutive protocols for childhood acute myeloid leukaemia (AML) have been used in the Nordic countries since 1984: the Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML84 was of moderate intensity, NOPHO-AML88 of high intensity with upfront loading and aggressive consolidation. NOPHO-AML93 utilized the same treatment blocks as NOPHO-AML88, but after the first block those children with a hypoplastic non-leukaemic bone marrow were allowed to recover from aplasia. Poor responders received intensified induction therapy. Between January 1993 and December 2000, 219 children without Down's syndrome were entered on NOPHO-AML93. Compared with NOPHO-AML88, the event-free survival (EFS) at 7 years increased from 41% to 49% (P = 0.06) and 7-year overall survival increased from 47% to 64% (P < 0.01). Toxic death during induction was reduced from 10% to 3%. Survival was similar in patients receiving stem cell transplantation or chemotherapy only in first remission. The major prognostic factors in NOPHO-AML93 were response to therapy and cytogenetics. A total of 67% of patients achieved remission after the first induction course and showed an EFS of 56% compared with 35% in those not in remission (P < 0.01). Cytogenetic results were obtained in 95% of patients. Patients with t(9;11) (p22;q23) (n = 16) experienced a significantly better EFS (86%) than other cytogenetic groups. The overall outcome was improved by employing the previous toxic protocol with different timings, and through individualizing therapy according to the initial response of the patient

Improved outcome after relapse in children with acute myeloid leukaemia

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldIn the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 +/- 4%. Of 122 patients who received re-induction therapy, 77% entered remission with 40 +/- 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 +/- 5% compared with 48 +/- 6% in late relapse. For children receiving re-induction therapy, survival in early relapse was 29 +/- 6% and 51 +/- 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 +/- 9, 5 +/- 5 and 41 +/- 5%, respectively. Survival was 62 +/- 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re-induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%

Post-induction residual disease in translocation t(12;21)-positive childhood ALL

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: t(12;21)(p1 3;q22), the most frequent chromosomal translocation found in childhood acute lymphoblastic leukemia (ALL), occurs in approximately 25% of B-lineage ALL cases and has been claimed to carry a good prognosis. PROCEDURE: As part of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-MRD 95 study, which includes children from Iceland, Norway, and Denmark diagnose d with ALL, patients were screened for the presence of t(12; 21) by reverse transcriptase-polymerase chain reaction (RT-PCR) at diagnosis, and their residual disease was quantified after 4 weeks of induction therapy (prednisolone, vincristine, doxorubicin, i.t. methotrexate) by a competitive, clone-specific, semi-nested PCR analysis. RESULTS: Among 96 children diagnosed with ALL, and quantified for post induction residual disease, 32 were t(12;21)-positive. The median residual disease was similar for B-precursor ALL patients with and without t(12;21) (0.009 vs. 0.03%, P = 0.12). CONCLUSIONS: Al though patients with t(12;21)-positive ALL have been claimed to have a good outcome, these data indicate that this does not reflect a high sensitivity to prednisolone, vincristine, and doxorubicin given during induction therapy

Social outcomes in young adult survivors of low incidence childhood cancers

Introduction The intensity and duration of childhood cancer treatment may disrupt psychosocial development and thereby cause difficulties in transition into adulthood. The study objective was to assess social outcomes in early adulthood after successful treatment for childhood acute myeloid leukemia (AML), Wilms tumor (WT) and infratentorial astrocytoma (IA). Methods Nordic patients treated for AML, WT and IA from 1985 to 2001 identified from a database administered by NOPHO (Nordic Society of Paediatric Haematology and Oncology) were invited to participate in a postal survey. All cancer-free survivors treated at age > 1 year who were > 19 years at time of study were eligible. Seventy-four percent; 247/335 responded. An age-equivalent group (N= 1,814) from a Norwegian Census Study served as controls. Results Mean age of survivors was 23 years (range 1934), 55% females. The proportion with academic education (>= 4 years) was similar in survivors and controls (28 vs. 32%). Fifty-nine percent of survivors were employed compared to 77% among controls (p <. 01). More survivors were recipients of social benefits (6.7 vs. 3.1%, p <. 01). There were no differences in marital status but parenthood was more common among controls (37 vs. 27%, p=. 01). Controls lived longer in their parental homes (p=. 01). Cancer type or treatment intensity had no statistically significant impact on results, except for parenthood. Conclusions and Implications for Cancer Survivors The study revealed important differences in social outcomes between survivors and controls early in adult life. Specific difficulties pertain to studying social status in early adulthood because of the natural transition characteristics for this age group. Therefore, longer follow-up is warranted

Acute leukaemia in children with Down syndrome: a population-based Nordic study

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldTo determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population-based leukaemia registry were analysed. Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3.9%) with DS were identified. 2.1% of the children with acute lymphoid leukaemia (ALL) and 14.0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non-DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non-DS children and treatment results did not improve over time. In AML, DS patients showed a significant female predominance and all but one were <5 years old. DS patients with AML had significantly lower platelet and white blood cell counts and two-thirds were type M7 as according to the French-American-British classification. None of the patients <5 years of age had typical AML cytogenetic aberrations. Outcome was far better in the DS group. DS patients treated for AML after 1992 had an excellent outcome (probability of event-free survival, 83 +/- 6%). The high proportion of female DS patients with AML is unexplained. The differing treatment results in AML versus ALL need further evaluation and represent a challenge for the coming years